Faculty Profiles - KIM Hye-Sook

Papers - KIM Hye-Sook

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Anti-Diabetic Potential of Sargassum horneri and Ulva australis Extracts In Vitro and In Vivo Reviewed

Young-Hyeon Lee, Hye-Ran Kim, Min-Ho Yeo, Sung-Chun Kim, Ho-Bong Hyun, Young-Min Ham, Yong-Hwan Jung, Hye-Sook Kim, Kyung-Soo Chang

Current Issues in Molecular Biology 45 ( 9 ) 7492 - 7512 2023.9

Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Sargassum horneri (SH) and Ulva australis (UA) are marine waste resources that cause environmental and economic problems when entering or multiplying the coastal waters of Jeju Island. We analyzed their anti-diabetic efficacy to assess their reusability as functional additives. The alpha-glucosidase inhibitory activity of SH and UA extracts was confirmed, and the effect of UA extract was higher than that of SH. After the induction of insulin-resistant HepG2 cells, the effects of the two marine extracts on oxidative stress, intracellular glucose uptake, and glycogen content were compared to the positive control, metformin. Treatment of insulin-resistant HepG2 cells with SH and UA resulted in a concentration-dependent decrease in oxidative stress and increased intracellular glucose uptake and glycogen content. Moreover, SH and UA treatment upregulated the expression of IRS-1, AKT, and GLUT4, which are suppressed in insulin resistance, to a similar degree to metformin, and suppressed the expression of FoxO1, PEPCK involved in gluconeogenesis, and GSK-3β involved in glycogen metabolism. The oral administration of these extracts to rats with streptozotocin-induced diabetes led to a higher weight gain than that in the diabetic group. Insulin resistance and oral glucose tolerance are alleviated by the regulation of blood glucose. Thus, the SH and UA extracts may be used in the development of therapeutic agents or supplements to improve insulin resistance.

DOI： 10.3390/cimb45090473

Extract of Torreya nucifera Pericarps Exhibits a Parasiticidal Effect on the Nematode Parasite, Trichinella spiralis Reviewed

Mi Jin Jeong, Shin Ae Kang, Sun Nyoung Yu, Soon Cheol Ahn, Shin-ichi Miyoshi, Hye-Sook Kim, Hak Sun Yu

Journal of Medicinal Food 26 ( 9 ) 624 - 630 2023.9

Evaluating the activity of N-89 as an oral antimalarial drug Reviewed

Nagwa S. M. Aly, Hiroaki Matsumori, Thi Quyen Dinh, Akira Sato, Shin-ichi Miyoshi, Kyung-Soo Chang, Hak Sun Yu, Takaaki Kubota, Yuji Kurosaki, Duc Tuan Cao, Gehan A. Rashed, Hye-Sook Kim

Parasites, Hosts and Diseases 61 ( 3 ) 282 - 291 2023.8

Authorship：Corresponding author Publishing type：Research paper (scientific journal) Publisher：Korean Society for Parasitology

Despite the recent progress in public health measures, malaria remains a troublesome disease that needs to be eradicated. It is essential to develop new antimalarial medications that are reliable and secure. This report evaluated the pharmacokinetics and antimalarial activity of 1,2,6,7-tetraoxaspiro[7.11]nonadecane (N-89) using the rodent malaria parasite Plasmodium berghei in vivo. After a single oral dose (75 mg /kg) of N-89, its pharmacokinetic parameters were measured, and t<sub>1/2</sub> was 0.97 h, T<sub>max</sub> was 0.75 h, and bioavailability was 7.01%. A plasma concentration of 8.1 ng/ml of N-89 was maintained for 8 h but could not be detected at 10 h. The dose inhibiting 50% of parasite growth (ED<sub>50</sub>) and ED<sub>90</sub> values of oral N-89 obtained following a 4-day suppressive test were 20 and 40 mg/kg, respectively. Based on the plasma concentration of N-89, we evaluated the antimalarial activity and cure effects of oral N-89 at a dose of 75 mg/kg 3 times daily for 3 consecutive days in mice harboring more than 0.5% parasitemia. In all the N-89- treated groups, the parasites were eliminated on day 5 post-treatment, and all mice recovered without a parasite recurrence for 30 days. Additionally, administering oral N-89 at a low dose of 50 mg/kg was sufficient to cure mice from day 6 without parasite recurrence. This work was the first to investigate the pharmacokinetic characteristics and antimalarial activity of N-89 as an oral drug. In the future, the following steps should be focused on developing N-89 for malaria treatments; its administration schedule and metabolic pathways should be investigated.

DOI： 10.3347/phd.23044

Evaluation of schistosomula lung antigen preparation and soluble egg antigen vaccines on experimental schistosomiasis mansoni Reviewed

Nagwa S. M. Aly, Hye-Sook Kim, Maysa A. Eraky, Asmaa A. El Kholy, Basma T. Ali, Shin-ichi Miyoshi, Rabab E. Omar

Parasites, Hosts and Diseases 61 ( 3 ) 251 - 262 2023.8

Publishing type：Research paper (scientific journal) Publisher：Korean Society for Parasitology

Schistosomiasis causes significant morbidity and mortality worldwide. This study aimed to assess the effect of schistosomula lung antigen preparation (SLAP) and soluble egg antigen (SEA) on a murine schistosomiasis mansoni model. Ninety laboratory-bred male Swiss albino mice were divided into 6 groups. Two doses of the vaccine were given at 2-week intervals. All mice were subcutaneously infected with 80±10 Schistosoma mansoni cercariae 2 weeks after the last vaccination dose. They were sacrificed 7 weeks post-infection. Parasitological and histopathological studies were conducted to assess the effect of inoculated antigens (single or combined). The results showed that the combination of SLAP and SEA (combination group) led to a significant reduction in worm burden (65.56%), and liver and intestine egg count (59% and 60.59%, respectively). The oogram pattern revealed a reduction in immature and mature eggs (15±0.4 and 10±0.8, respectively) and an increased number of dead eggs in the combination group (P<0.001). In terms of histopathological changes, the combination group showed notably small compact fibrocellular egg granuloma and moderate fibrosis in the liver. A high percentage of destroyed ova was observed in the intestine of the combination group. This study demonstrates for the first time the prophylactic effect of combined SLAP and SEA vaccine. The vaccine induced a significant reduction in the parasitological and pathological impacts of schistosomiasis mansoni in hepatic and intestinal tissues, making it a promising vaccine candidate for controlling schistosomiasis.

DOI： 10.3347/phd.22154

Maternal and Fetal Effects of Gestational Vitamin D Concentration Reviewed

Ki-Wook Kwon, Young-Hyeon Lee, Min-Ho Yeo, Sang-Hyun Park, Hye-Ran Kim, Hye-Sook Kim, Kyung-Soo Chang

Healthcare 11 ( 16 ) 2325 - 2325 2023.8

Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Most (90%) vitamin D synthesis occurs in the skin using sunlight (ultraviolet rays), and 10% is obtained through food. Vitamin D is an essential nutrient for skeletal growth and maintenance, cell proliferation and differentiation, and immune function. This study investigated whether maternal serum vitamin D concentrations induce maternofetal effects. Hematological analysis, serological changes, and precision fetal ultrasound findings were analyzed by maternal vitamin D concentration in gestational weeks 22–25 to ascertain direct effects on fetal growth. Bone density–vitamin D concentration correlation was analyzed. No hematologic or serological effect of maternal vitamin D concentration was detected; however, the sexually transmitted infection and cross-infection rates were inversely proportional to maternal vitamin D concentration. No significant correlation between vitamin D concentration and vertebral and femoral BMD was detected. For fetal growth, biparietal diameter, head circumference, abdominal circumference, femur length, and humerus length were analyzed. Humerus (p < 0.05) and femur (p < 0.001) lengths were higher in the vitamin D-sufficient group than in the vitamin D-deficient group. Vitamin D concentration did not positively affect hematologic changes and bone density; maternal vitamin D concentration essentially affected fetal bone growth. Vitamin D inhibits sexually transmitted infections in mothers and promotes fetal bone growth. Prevention of vitamin D deficiency, supplementation, or outdoor activities is recommended.

DOI： 10.3390/healthcare11162325

Anti-Obesity Potential of Sargassum horneri and Ulva australis Extracts: Study In Vitro and In Vivo Reviewed

Young-Hyeon Lee, Hye-Ran Kim, Min-Ho Yeo, Sung Chun Kim, Ho-Bong Hyun, Young-Min Ham, Yong-Hwan Jung, Hye-Sook Kim, Kyung-Soo Chang

Applied Sciences 13 ( 15 ) 8951 - 8951 2023.8

Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Current research highlights the use of natural products or phytochemicals as drugs and functional additives to treat obesity with few side effects. Sargassum horneri (SH) and Ulva australis (UA) are marine waste resources on Jeju Island, Republic of Korea. In this study, we analyzed their antioxidant and anti-obesity efficacies to confirm their potential as functional additives. We prepared SH and UA extracts using 80% ethanol and observed that free radical scavenging activity and total phenol content were high in SH extracts, and total flavonoid content was elevated in UA extracts. Additionally, 3T3-L1 cells were treated with SH and UA extracts, and the ability of the extracts to inhibit adipocyte differentiation was examined using Oil Red O staining and analysis of neutral fat content. We confirmed that the mRNA expression of the C/EBPα, PPARγ, and SREBP1c genes that act on adipocyte differentiation, and of FAS, a fatty acid synthase, was suppressed. Experiments in a mouse model of obesity showed that 12-week administration of a high-fat diet with 1% extract added to drinking water resulted in lower weight gain compared to the high-fat diet alone. These results suggest that SH and UA extracts have antioxidant properties and are effective in obesity prevention. Therefore, the two marine waste resources are potential functional additive candidates for preventing obesity.

DOI： 10.3390/app13158951

Extracellular Leakage Protein Patterns in Two Types of Cancer Cell Death: Necrosis and Apoptosis Reviewed

Akira Sato, Akira Shimotsuma, Tetsuya Miyoshi, Yui Takahashi, Naoki Funayama, Yoko Ogino, Akiko Hiramoto, Yusuke Wataya, Hye-Sook Kim

ACS Omega 8 ( 28 ) 25059 - 25065 2023.7

Pioneer Use of Antimalarial Transdermal Combination Therapy in Rodent Malaria Model Reviewed

Nagwa S. M. Aly, Hiroaki Matsumori, Thi Quyen Dinh, Akira Sato, Shin-Ichi Miyoshi, Kyung-Soo Chang, Hak Sun Yu, Duc Tuan Cao, Hye-Sook Kim

Pathogens 12 ( 3 ) 398 - 398 2023.3

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：MDPI AG

We have previously reported 1,2,6,7-tetraoxaspiro [7.11]nonadecane (N-89) as a promising antimalarial compound. In this study, we evaluated the effect of transdermal therapy (tdt) of N-89 in combination (tdct) with other antimalarials as an application for children. We prepared ointment formulas containing N-89 plus another antimalarial drug, specifically, mefloquine, pyrimethamine, or chloroquine. In a 4-day suppressive test, the ED50 values for N-89 alone or combined with either mefloquine, pyrimethamine, or chloroquine were 18, 3, 0.1, and 3 mg/kg, respectively. Interaction assays revealed that N-89 combination therapy showed a synergistic effect with mefloquine and pyrimethamine, but chloroquine provoked an antagonistic effect. Antimalarial activity and cure effect were compared for single-drug application and combination therapy. Low doses of tdct N-89 (35 mg/kg) combined with mefloquine (4 mg/kg) or pyrimethamine (1 mg/kg) gave an antimalarial effect but not a cure effect. In contrast, with high doses of N-89 (60 mg/kg) combined with mefloquine (8 mg/kg) or pyrimethamine (1 mg/kg), parasites disappeared on day 4 of treatment, and mice were completely cured without any parasite recurrence. Our results indicated that transdermal N-89 with mefloquine and pyrimethamine provides a promising antimalarial form for application to children.

DOI： 10.3390/pathogens12030398

Diagnosis of Toxoplasmosis Using Surface Antigen Grade 1 Detection by ELISA, Nano-Gold ELISA, and PCR in Pregnant Women Reviewed

Nagwa SM Aly, Hye-Sook Kim, Yasmin M Marei, Azza S Elhamshary, Ibrahim R Bayoumi, Rabab E Omar, Dina A Mohammed, Shin-Ichi Miyoshi, Gehan A Rashed

International Journal of Nanomedicine Volume 18 1335 - 1345 2023.3

Antimalarial effect of synthetic endoperoxide on synchronized Plasmodium chabaudi infected mice Reviewed

Nagwa S. M. Aly, Hiroaki Matsumori, Thi Quyen Dinh, Akira Sato, Shin-Ichi Miyoshi, Kyung-Soo Chang, Hak Sun Yu, Fumie Kobayashi, Hye-Sook Kim

Parasites, Host and Diseases (The Korean Journal of Parasitology) 61 ( 1 ) 33 - 41 2023.2

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Korean Society for Parasitology

The discovery of new antimalarial drugs can be developed using asynchronized <i>Plasmodium berghei</i> malaria parasites in vivo in mice. Studies on a particular stage are also required to assess the effectiveness and mode of action of drugs. In this report, we used endoperoxide 6-(1,2,6,7-tetraoxaspiro [7.11] nonadec-4-yl) hexan-1-ol (N-251) as a model antimalarial compound on <i>P. chabaudi</i> parasites. We examined the antimalarial effect of N-251 against ring-stage- and trophozoite-stage-rich <i>P. chabaudi</i> parasites and asynchronized <i>P. berghei</i> parasites using the 4-day suppressive test. The ED<sub>50</sub> values were 27, 22, and 22 mg/kg, respectively, and the antimalarial activity of N-251 was verified in both rodent malaria parasites. To assess the stage-specific effect of N-251 in vivo, we evaluated the change of parasitemia and distribution of parasite stages using ring-stage- and trophozoite-stage-rich <i>P. chabaudi</i> parasites with one-day drug administration for one life cycle. We discovered that the parasitemias decreased after 13 and 9 hours post-treatment in the ring-stage- and trophozoite-stage-rich groups, respectively. Additionally, in the ring-stage-rich N-251 treated group, the ring-stage parasites hindered trophozoite parasite development. For the trophozoite-stage-rich N-251 treated group, the distribution of the trophozoite stage was maintained without a change in parasitemia until 9 hours. Because of these findings, it can be concluded that N-251 suppressed the trophozoite stage but not the ring stage. We report for the first time that N-251 specifically suppresses the trophozoite stage using <i>P. chabaudi</i> in mice. The results show that <i>P. chabaudi</i> is a reliable model for the characterization of stage-specific antimalarial effects.

DOI： 10.3347/phd.22119

Formulation and evaluation of the antimalarial N-89 as a transdermal drug candidate Reviewed

Nagwa S.M. Aly, Hiroaki Matsumori, Thi Quyen Dinh, Akira Sato, Shin-Ich Miyoshi, Kyung-Soo Chang, Hak Sun Yu, Hye-Sook Kim

Parasitology International 93 102720 - 102720 2022.12

Synthesis of 1,5-diaryl-2-fluoro-6,7-dioxabicyclo[3.2.2]nonanes with high antimalarial activity utilizing photoinduced electron-transfer oxygenation reactions Reviewed

Masaki Kamata, Rie Maeda, Jun Hayakawa, Hye-Sook Kim

Tetrahedron Letters 96 153752 - 153752 2022.4

Comparison of Microbial Detection of Hemodialysis Water in Reasoner’s 2A Agar (R2A) and Trypticase Soy Agar (TSA) Reviewed

Sang-Hyun Park, Young-Hyeon Lee, Min-Ho Yeo, Hi-Ryun Lee, Hye-Sook Kim, Kyung-Soo Chang

Journal of Bacteriology and Virology 51 ( 2 ) 79 - 88 2021.6

Intracellular microRNA expression patterns influence cell death fates for both necrosis and apoptosis. Reviewed International journal

Akira Sato, Akihiro Yamamoto, Akira Shimotsuma, Yoko Ogino, Naoki Funayama, Yui Takahashi, Akiko Hiramoto, Yusuke Wataya, Hye-Sook Kim

FEBS open bio 10 ( 11 ) 2417 - 2426 2020.11

Language：English Publishing type：Research paper (scientific journal)

MicroRNAs (miRNAs) are small noncoding RNA molecules that interact with target mRNAs at specific sites to induce cleavage of the mRNA or inhibit translation. Such miRNAs play a vital role in gene expression and in several other biological processes, including cell death. We have studied the mechanisms regulating cell death (necrosis in original F28-7 cells and apoptosis in their variant F28-7-A cells) in the mouse mammary tumor cell line FM3A using the anticancer agent floxuridine (FUdR). We previously reported that inhibition of heat-shock protein 90 by the specific inhibitor geldanamycin (GA) in F28-7 cells causes a shift from necrosis to apoptosis. In this study, we investigated the intracellular miRNA expression profiles of FUdR-treated F28-7 cells (necrotic condition), GA plus FUdR-treated F28-7 cells (apoptotic condition), and FUdR-treated F28-7-A cells (apoptotic condition) through miRNA microarray analysis. In addition, we knocked down Dicer, a key molecule for the expression of mature miRNAs, in F28-7 cells to examine whether it modulates FUdR-induced cell death. Our analysis revealed that the miRNA expression patterns differ significantly between these cell death conditions. Furthermore, we identified miRNA candidates that regulate cell death. Knockdown of Dicer in FUdR-treated necrosis-fated cells caused a partial shift from necrosis to apoptosis. These findings suggest that modulation of miRNA expression patterns influences the decision of cell death fate toward necrosis or apoptosis. Our findings may serve as a basis for further study of the functions of miRNAs in cell death mechanisms.

DOI： 10.1002/2211-5463.12995

Anticancer Strategy Targeting Cell Death Regulators: Switching the Mechanism of Anticancer Floxuridine-Induced Cell Death from Necrosis to Apoptosis. Reviewed International journal

Akira Sato, Akiko Hiramoto, Hye-Sook Kim, Yusuke Wataya

International journal of molecular sciences 21 ( 16 ) 2020.8

Language：English Publishing type：Research paper (scientific journal)

Cell death can be broadly characterized as either necrosis or apoptosis, depending on the morphological and biochemical features of the cell itself. We have previously reported that the treatment of mouse mammary carcinoma FM3A cells with the anticancer drug floxuridine (FUdR) induces necrosis in the original clone F28-7 but apoptosis in the variant F28-7-A. We have identified regulators, including heat shock protein 90, lamin-B1, cytokeratin-19, and activating transcription factor 3, of cell death mechanisms by using comprehensive gene and protein expression analyses and a phenotype-screening approach. We also observed that the individual inhibition or knockdown of the identified regulators in F28-7 results in a shift from necrotic to apoptotic morphology. Furthermore, we investigated microRNA (miRNA, miR) expression profiles in sister cell strains F28-7 and F28-7-A using miRNA microarray analyses. We found that several unique miRNAs, miR-351-5p and miR-743a-3p, were expressed at higher levels in F28-7-A than in F28-7. Higher expression of these miRNAs in F28-7 induced by transfecting miR mimics resulted in a switch in the mode of cell death from necrosis to apoptosis. Our findings suggest that the identified cell death regulators may play key roles in the decision of cell death mechanism: necrosis or apoptosis.

DOI： 10.3390/ijms21165876

Direct interaction analysis of microRNA-351-5p and nuclear scaffold lamin B1 mRNA by the cell-free in vitro mRNA/miRNA binding evaluation system. Reviewed International journal

Akira Sato, Yoko Ogino, Akira Shimotsuma, Akiko Hiramoto, Hye-Sook Kim, Yusuke Wataya

Nucleosides, nucleotides & nucleic acids 1 - 7 2020.1

Language：English

We previously demonstrated that miR-351-5p regulates nuclear scaffold lamin B1 expression and mediates the anticancer floxuridine-induced necrosis shift to apoptosis in mammalian tumor cells. Notably, it is unknown whether lamin B1 mRNA is a direct target of miR-351-5p. Here, we show that miR-351-5p interacts with a lamin B1 mRNA partial sequence by using the cell-free in vitro miRNA and mRNA binding evaluation system. In addition, the interaction of miR-351-5p/lamin B1 mRNA was suppressed by an miR-351-5p inhibitor. Our findings are important in exploring the functions of miRNAs in cellular processes, including cell death.

DOI： 10.1080/15257770.2019.1702675

Pharmacokinetic analysis of new synthetic antimalarial N-251 Reviewed

Kazuaki Okada, Akira Sato, Akiko Hiramoto, Rena Isogawa, Yuji Kurosaki, Kazutaka Higaki, Shin-Ichi Miyoshi, Kyung-Soo Chang, Hye-Sook Kim

Tropical Medicine and Health 47 ( 1 ) 2019.12

Genomic and biological features of Plasmodium falciparum resistance against antimalarial endoperoxide N-89. Reviewed International journal

Masayuki Morita, Kosuke Hayashi, Akira Sato, Akiko Hiramoto, Osamu Kaneko, Rena Isogawa, Yuji Kurosaki, Shin-Ichi Miyoshi, Kyung-Soo Chang, Yusuke Wataya, Hye-Sook Kim

Gene 716 144016 - 144016 2019.10

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

Drug resistance of malaria parasites remains a problem affecting antimalarial treatment and control of the disease. We previously synthesized an antimalarial endoperoxide, N-89, having high antimalarial effects in vitro and in vivo. In this study we seek to understand the resistant mechanism against N-89 by establishing a highly N-89-resistant clone, named NRC10H, of the Plasmodium falciparum FCR-3 strain. We describe gene mutations in the parent FCR-3 strain and the NRC10H clone using whole-genome sequencing and subsequently by expression profiling using quantitative real-time PCR. Seven genes related to drug resistance, proteolysis, glycophosphatidylinositol anchor biosynthesis, and phosphatidylethanolamine biosynthesis exhibited a single amino acid substitution in the NRC10H clone. Among these seven genes, the multidrug resistance protein 2 (mdr2) variant A532S was found only in NRC10H. The genetic status of the P. falciparum endoplasmic reticulum-resident calcium binding protein (PfERC), a potential target of N-89, was similar between the NRC10H clone and the parent FCR-3 strain. These findings suggest that the genetic alterations of the identified seven genes, in particular mdr2, in NRC10H could give rise to resistance of the antimalarial endoperoxide N-89.

DOI： 10.1016/j.gene.2019.144016

A trial for a DNA diagnosis of Plasmodium vivax malaria recently reemerging in the Republic of Korea using microtiter plate hybridization assay. Reviewed

J Y Chai, M D Oh, S H Lee, S M Guk, K H Oh, Y K Park, HS Kim, Y Wataya

The American Journal of Tropical Medicine and Hygiene 63 ( 1 ) 80 - 84 2000.7

The antimalarial activity of transdermal N-89 mediated by inhibiting ERC gene expression in P. berghei-infected mice Reviewed

Hiroaki. Matsumori, Thi Quyen Dinh, Shin-ichi Miyoshi, Masayuki Morita, Hye-Sook Kim

Parasitology International in press 2025

Toloese Generates Nitric Oxide through Natural Radiation of Far Infrared Rays, Reducing Serum Glucose, Cholesterol, and Triglycerides. Reviewed International journal

Min-Ho Yeo, Young-Hyeon Lee, Mi-Jin Ryu, Yong-Hak Choi, Hye-Sook Kim, Kyung-Soo Chang

Healthcare (Basel, Switzerland) 12 ( 12 ) 2024.6

Language：English Publishing type：Research paper (scientific journal)

Toloese, a bed composition, is formulated with a combination of minerals of various wavelengths by utilizing a specific ratio and particle size. A maturation mixing technique is used without additional compression processes, resulting in the natural formation of numerous fine pores in the bed structure. At 40 °C, far infrared radiation in the range of 5-20 μm is emitted with a 0.916 radiant ratio, and the measured emitted radiant energy is 3.69 × 102 W/m2·μm. This study aimed to investigate the influence of far infrared radiation emitted from a Toloese bed on endogenous nitric oxide production. Clinical trials were conducted with 20 healthy adults aged 20 years. Blood samples were collected before and after Toloese bed usage for 1 h daily for 3 weeks. Nitric oxide levels in the saliva and blood of men and women significant increased after they used the Toloese bed for 1 h. Additionally, sweating sharply increased in the upper and lower body regions after Toloese bed usage. No hematological changes or adverse effects were observed, but blood glucose, cholesterol, and triglycerides decreased after Toloese bed usage compared with those before Toloese bed usage. These findings demonstrated that far infrared radiation emitted by the Toloese bed induced endogenous nitric oxide production and contributed to significant reductions in blood glucose, cholesterol, and triglyceride levels.

DOI： 10.3390/healthcare12121227

新規抗マラリア薬候補化合物,1,2,6,7-tetraoxaspiro[7.11]nonadecane(N-89)の作用機序に関する研究

坂本沙祐里, 森田将之, 平本一幸, 金恵淑, 綿矢有佑, 平岡修

就実大学薬学雑誌 11 9 - 19 2024.1

Language：Japanese Publisher：就実大学薬学部「就実大学薬学雑誌」編集委員会

1,2,6,7-tetraoxaspiro[7.11]-nonadecane(N-89)のマラリア小胞体局在性カルシウム結合タンパク質(PfERC)に対する種々のin vitro実験から、鉄イオンと細胞内モータータンパク質が関与しN-89の作用機序の解明につながるような知見が得られたので報告した。N-89を生理的環境に近い条件にて電子スピン共鳴法(ESR)測定を行った。その結果、Fe2+の存在下でラジカルを産生することが示された。次に、N-89処理がPfERCに及ぼす影響についてSDS-PAGEにより解析を行い、環状過酸化化合物がFe2+の存在下において特異的にPfERCを切断するものと考えられた。さらに、Fe3+の存在によりPfERCのAggregates形成が誘導されるが、この誘導はEDTAやDFOの添加により解消されることが分かった。PfERCはPlm Xが関与するEgress/Invasion経路のタンパク質分解カスケードおよび細胞質内モータータンパク質、PfGAP45をCa2+存在下で調節することによって、Merozoite体とヘモゾインのEgress/Invasionを進行させていると考えられた。

Oral activity of the antimalarial endoperoxide 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) against Leishmania donovani complex Reviewed

Kofi Dadzie Kwofie, Kai Sato, Chizu Sanjoba, Akina Hino, Rieko Shimogawara, Michael Amoa-Bosompem, Irene Ayi, Daniel A. Boakye, Abraham K. Anang, Kyung-Soo Chang, Mitsuko Ohashi, Hye-Sook Kim, Nobuo Ohta, Yoshitsugu Matsumoto, Shiroh Iwanaga

PLOS Neglected Tropical Diseases 13 ( 3 ) e0007235 - e0007235 2019.3

Potent Antimalarial Activity of Two Arenes Linked with Triamine Designed To Have Multiple Interactions with Heme. Reviewed International journal

Yosuke Sakata, Kosuke Yabunaka, Yuko Kobayashi, Hirohisa Omiya, Naoki Umezawa, Hye-Sook Kim, Yusuke Wataya, Yoshimi Tomita, Yosuke Hisamatsu, Nobuki Kato, Hirokazu Yagi, Tadashi Satoh, Koichi Kato, Haruto Ishikawa, Tsunehiko Higuchi

ACS medicinal chemistry letters 9 ( 10 ) 980 - 985 2018.10

Language：English

Based on the idea that compounds designed to exhibit high affinity for heme would block hemozoin formation, a critical heme-detoxification process for malarial parasites, we synthesized a series of compounds with two π-conjugated moieties at terminal amino groups of triamine. These compounds exhibited moderate to high antimalarial activities in vitro toward both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum. In a P. berghei-infected mouse model, 3a and 12a showed potent antimalarial activities compared to artesunate, as well as a prolonged duration of antimalarial effect. We found a good correlation between protective activity against hemin degradation and antimalarial activity. Compounds 8b and 3a strongly inhibited hemozoin formation catalyzed by heme detoxification protein.

DOI： 10.1021/acsmedchemlett.8b00222

Multiple antiviral activities of the antimalarial and anti-hepatitis C drug candidates N-89 and N-251. Reviewed International journal

Youki Ueda, Weilin Gu, Hiromichi Dansako, Hye-Sook Kim, Sayaka Yoshizaki, Nobuaki Okumura, Tomohiro Ishikawa, Hironori Nishitsuji, Fumihiro Kato, Takayuki Hishiki, Shinya Satoh, Koji Ishii, Michiaki Masuda, Kunitada Shimotohno, Masanori Ikeda, Nobuyuki Kato

Biochemistry and biophysics reports 15 1 - 6 2018.9

Language：English

The chemically synthesized endoperoxide compound N-89 and its derivative N-251 were shown to have potent antimalarial activity. We previously demonstrated that N-89 and N-251 potently inhibited the RNA replication of hepatitis C virus (HCV), which belongs to the Flaviviridae family. Since antimalarial and anti-HCV mechanisms have not been clarified, we were interested whether N-89 and N-251 possessed the activity against viruses other than HCV. In this study, we examined the effects of N-89 and N-251 on other flaviviruses (dengue virus and Japanese encephalitis virus) and hepatitis viruses (hepatitis B virus and hepatitis E virus). Our findings revealed that N-89 and N-251 moderately inhibited the RNA replication of Japanese encephalitis virus and hepatitis E virus, although we could not detect those anti-dengue virus activities. We also observed that N-89 and N-251 moderately inhibited the replication of hepatitis B virus at the step after viral translation. These results suggest the possibility that N-89 and N-251 act on some common host factor(s) that are necessary for viral replications, rather than the possibility that N-89 and N-251 directly act on the viral proteins except for HCV. We describe a new type of antiviral reagents, N-89 and N-251, which are applicable to multiple different viruses.

DOI： 10.1016/j.bbrep.2018.05.007

Insights into the mode of action of 1,2,6,7-tetraoxaspiro [7.11] nonadecane (N-89) against adult Schistosoma mansoni worms Reviewed

Blay E. A, Kumagai T, Yamabe M, Hino A, Shimogawara R, Kim H.-S, Sato A, Ichimura K, Ayi I, Iwanaga S, Ohta N

Parasitology International 67 ( 4 ) 403 - 412 2018.8

Language：English Publishing type：Research paper (scientific journal)

Control of morbidity associated with schistosomiasis via chemotherapy largely relies on the drug praziquantel. Repeated therapy with praziquantel has created concerns about the possible selection of resistant worms and necessitated the search for novel drugs to treat schistosomiasis. Here, a murine model was infected with Schistosoma mansoni and treated with oral 1,2,6,7-tetraoxaspiro [7.11] nonadecane (N-89), which caused a significant reduction in fecundity and egg burden and reduced morbidity when administered at 5-weeks post-infection. The analysis showed that the mode of action occurred through the ingestion of activated N-89 by the worms, and that there was no direct external effect on the S. mansoni worms. Ultrastructural analysis of the treated worms showed disruptions in the gut lumen and the presence of large volumes of material, suggestive of undigested blood meals or red blood cells. In addition, there were reduced vitelline cells in female worms and damage to sub-tegmental musculature in male worms. Eggs recovered from the treated mice showed both damage to the eggs and the production of immature eggs. Expression of mRNA responsible for gut and digestive function and egg production was also significantly affected by N-89 treatment, whereas control genes for musculature showed no significant changes. Thus, N-89 drastically affected the total digestive function and egg production of S. mansoni worms. Physiological processes requiring heme uptake such as egg production and eggshell formation were subsequently affected, suggesting that the compound could be a possible therapeutic drug candidate for schistosomiasis control.

DOI： 10.1016/j.parint.2018.03.006

Potential of synthetic endoperoxides against Trichomonas vaginalis in vitro Reviewed

Min-Young Seo, Jae-Sook Ryu, Akira Sato, Yuji Kurosaki, Kyung-Soo Chang, Hye-Sook Kim

PARASITOLOGY INTERNATIONAL 66 ( 5 ) 619 - 621 2017.10

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Metronidazole is well known for medicine against Trichomonas vaginalis infection, but it has side effects though it is effective, and especially because reports of metronidazole-tolerant species are increasing, the development of new medicine is being required. Here, we noticed the killing effects of endoperoxide compounds, N-89 and N-251 as new antimalarial drug candidates, on T. vaginalis and searched the possibility of development of new medicine. We added each of metronidazole, artemisinin, and two of new endoperoxides (N-89 and N-251) to metronidazole-resistant and -sensitive species and compared its anti-trichomonal efficacy. For metronidazole, IC50 value, 50% of killing concentration for T. vaginalis, was very low for metronidazole-sensitive isolates (11.7 to 22.8 mu M), but was high for metronidazole-resistant ones (182.9 to 730.4 mu M). The IC50 values of N-89 and N-251 were 41.0 to 60.0 mu M, and 82.0 to 300.0 mu M for metronidazole-sensitive and-resistant isolates, respectively. In conclusion, we found the endoperoxides, N-89 and N-251, have anti-trichomonal effect against metronidazole-resistant T. vaginalis as well as metronidazole-sensitive ones. These results indicate that the anti-richomonal effects for our endoperoxides are equivalent or better in metronidazole-resistant T. vaginalis in comparison to metronidazole.

DOI： 10.1016/j.parint.2017.05.008

Role of the uridine/cytidine kinase 2 mutation in cellular sensitiveness toward 3-ethynylcytidine treatment of human cancer cells Reviewed

Akira Sato, Takeshi Takano, Akiko Hiramoto, Tomoharu Naito, Akira Matsuda, Masakazu Fukushima, Yusuke Wataya, Hye-Sook Kim

ANTI-CANCER DRUGS 28 ( 7 ) 781 - 786 2017.8

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

A nucleosidic medicine, 1-(3-C-ethynyl--d-ribo-pentofuranosyl)cytosine [3-ethynylcytidine (ECyd)], is a potent inhibitor of RNA polymerase I and shows anticancer activity to various human solid tumors in vitro and in vivo. ECyd is phosphorylated to 3-ethyntlcytidine 5-monophosphate by uridine/cytidine kinase 2 (UCK2) and subsequently further to diphosphate and triphosphate (3-ethyntlcytidine 5-diphosphate, 3-ethyntlcytidine 5-triphosphate). 3-Ethyntlcytidine 5-triphosphate is an active metabolite that can inhibit RNA polymerase I competitively, causing cancer cell death. Here, to identify the UCK2 mutation for detecting responder or nonresponder to ECyd, we investigated the relationship between point mutation of the UCK2 gene and response to ECyd in various human solid tumors. We identified several functional point mutations including the splice-site mutation of the UCK2 gene IVS5+5 G>A. In addition, we found that the IVS5+5 G>A variant generates an aberrant mRNA transcript, namely, truncated mRNA was produced and normal mRNA levels were markedly decreased in the ECyd-resistant cancer cell line HT1080. We concluded that these findings strongly suggest that the IVS5+5 G>A variant would affect the expression level of the UCK2 transcript, resulting in decreased sensitivity to ECyd.

DOI： 10.1097/CAD.0000000000000519

Evaluation of preclinical antimalarial drugs, which can overcome direct acting antivirals-resistant hepatitis C viruses, using the viral reporter assay systems Reviewed

Youki Ueda, Hiromichi Dansako, Shinya Satoh, Hye-Sook Kim, Yusuke Wataya, Hiroyuki Doi, Masanori Ikeda, Nobuyuki Kato

VIRUS RESEARCH 235 37 - 48 2017.5

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Persistent hepatitis C virus (HCV) infection causes chronic liver diseases and is a major global health problem. Recently developed treatments with direct-acting antivirals (DAAs) have largely improved the sustained virologic response rate of patients with chronic hepatitis C. However, this approach is still hindered by its great expense and the problem of drug resistance. Using our cell-based HCV assay systems, we reported that the preclinical antimalarial drugs N-89 and N-251 exhibited potent anti-HCV activities. In this study we used our assay systems to evaluate the anti-HCV activities of six kinds of DAAs individually or in combination with N-89 or N-251. The results showed that the DAAs had potent anti-HCV activities and N-89 or N-251 contributed additive or synergistic effect. Using DAA-resistant HCV-RNA-replicating cells, which were prepared by continuous treatment with each DAA, we demonstrated that N-89 and N-251 could overcome all of the DAA-resistant HCVs. These preclinical drugs would have been potential as components of a therapeutic regimen that also included combinations of various DAAs. In addition, sequence analysis of the NS3-NS5B regions of the DAA-resistant HCV genomes newly found several amino acid (aa) substitutions that were suggested to contribute to DAA-resistance in addition to the aa substitutions already known to cause DAA-resistance. Among these new aa substitutions, we found that two substitutions in the NS3 region (D79G and S174Y) contributed to simeprevirand/or asunaprevir-resistance.

DOI： 10.1016/j.virusres.2017.03.015

Novel synthetic compounds with endoperoxide structure damage juvenile stage of Schistosoma mansoni by targeting lysosome-like organelles Reviewed

Masafumi Yamabe, Takashi Kumagai, Rieko Shimogawara, Emmanuel Awusah Blay, Akina Hino, Koichiro Ichimura, Akira Sato, Hye-Sook Kim, Nobuo Ohta

PARASITOLOGY INTERNATIONAL 66 ( 1 ) 917 - 924 2017.2

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

The new synthetic compound 1,2,6,7-tetraoxaspiro[7.11]nonadecan (N-89), a novel anti-malaria drug candidate, is also a promising drug candidate against schistosomiasis with killing effects against juvenile stage of S. mansoni. In order to investigate how N-89 kills schistosomes, we used a derivative of N-89, 6-(1,2,6,7-tetraoxaspiro[7.11] nonadec-4-yl)hexan-1-ol (N-251), which enables us to conjugate with fluorescent reagents. Firstly, N-251 showed strong killing effects to larvae of S. mansoni in vitro. Ultrastructural analysis showed the disruptions of the lysosome-like organelles or the acetabular glands, followed by cytoplasmic lysis inside the worm body in N-251 -treated group under electron microscopy. For rhodamine-conjugated N-251 and organelle markers, we observed that N-251 accumulated in acidic organelle. In addition, LysoTracker signals in these acidic organelles disappeared in N-251-treated group over time. Finally, we observed that the activity of cathepsin B, a lysosome-specific enzyme, was also decreased together with alternation of acidic organelle marker signal by N-251-treated group. These results suggested that our synthesized compounds induced the dysfunction or the disruption of acidic lysosome-like organelles and finally led to worm death. (C) 2016 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.parint.2016.10.013

In vitro inhibition of Toxoplasma gondii by the anti-malarial candidate, 6-(1,2,6,7-tetraoxaspiro[7.1 1]nonadec-4-yl)hexan-1-ol Reviewed

Chun-Feng Xin, Hye-Sook Kim, Akira Sato, Hak-Jae Lee, You-Won Lee, Kyoung-Ho Pyo, Eun-Hee Shin

PARASITOLOGY INTERNATIONAL 65 ( 5 ) 494 - 499 2016.10

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

An anti-malarial candidate, 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-l-ol (N-251), was studied to characterize its potential as a novel anti-Toxoplasma gondii drug. In the present study, IC50 and LC50 of N-251 on host cells and T. gondii were compared to those of artemisinin and sulfadiazine. The IC50 on Huh-7 cells was 10.19 mu g/ml, 67.69 mu g/ml and 310.17 mu g/ml for N-251, artemisinin, and sulfadiazine, respectively. The LC50 for anti-T. gondii effect was shown to be 1.11 mu g/ml, 5.79 mu g/ml, and 5.45 mu g/ml for N-251, artemisinin and sulfadiazine, respectively. N-251 concentration causing complete parasiticidal effect with minimal cytotoxicity on host cells was determined to be 5 mu g/ml. Additionally, the anti-T. gondii effect of N-251 was confirmed by ultrastructural changes, loss of organelles, degenerated morphology and the increase of amylopectin as detected by transmission electron microscope (TEM). Accordingly, the present study suggests that the anti-malarial synthetic endoperoxide, N-251, is an emerging drug candidate more effective than artemisinin and sulfadiazine. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.parint.2016.06.013

MicroRNA-351 Regulates Two-Types of Cell Death, Necrosis and Apoptosis, Induced by 5-fluoro-2'-deoxyuridine Reviewed

Akira Sato, Takuya Omi, Akihiro Yamamoto, Akito Satake, Akiko Hiramoto, Mitsuko Masutani, Sei-ichi Tanuma, Yusuke Wataya, Hye-Sook Kim

PLOS ONE 11 ( 4 ) 2016.4

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Cell-death can be necrosis and apoptosis. We are investigating the mechanisms regulating the cell death that occurs on treatment of mouse cancer cell-line FM3A with antitumor 5-fluoro-2'-deoxyuridine (FUdR): necrosis occurs for the original clone F28-7, and apoptosis for its variant F28-7-A. Here we report that a microRNA (miR-351) regulates the cell death pattern. The miR-351 is expressed strongly in F28-7-A but only weakly in F28-7. Induction of a higher expression of miR-351 in F28-7 by transfecting an miRNA mimic into F28-7 resulted in a change of the death mode; necrosis to apoptosis. Furthermore, transfection of an miR-351 inhibitor into F28-7-A resulted in the morphology change, apoptosis to necrosis, in this death-by-FUdR. Possible mechanism involving lamin B1 in this miR-351's regulatory action is discussed.

DOI： 10.1371/journal.pone.0153130

New antimalarial endoperoxides for drug-resistant Plasmodium falciparum: The current situation Reviewed

Kim H.-S, Katamoto A, Sato A, Wataya Y, Doi H

Okayama Igakkai Zasshi (Journal of Okayama Medical Association) 127 231 - 235 2015.12

Improvement of Oral Bioavailability of N-251, a Novel Antimalarial Drug, by Increasing Lymphatic Transport with Long-Chain Fatty Acid-Based Self-Nanoemulsifying Drug Delivery System Reviewed

Chikako Imada, Takuma Takahashi, Makoto Kuramoto, Kazufumi Masuda, Ken-ichi Ogawara, Akira Sato, Yusuke Wataya, Hye-Sook Kim, Kazutaka Higaki

PHARMACEUTICAL RESEARCH 32 ( 8 ) 2595 - 2608 2015.8

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER/PLENUM PUBLISHERS

Purpose The objective of this study was to improve the absorption behavior of N-251, a novel antimalarial drug, by preparing an appropriate self-nanoemulsifying drug delivery system (SNEDDS).
Methods Two different types of SNEDDS formulations, medium-chain fatty acid-based SNEDDS (MC-SNEDDS) and long-chain fatty acid-based SNEDDS (LC-SNEDDS), were prepared based on pseudo-ternary phase diagram, and examined for their in vivo oral absorption behavior in rats.
Results Oral dosing of MC-SNEDDS formulations significantly improved the bioavailability (BA) of N-251 compared with N-251 powders. However, its high hepatic extraction limited the BA of N-251 to only 0.49 for MC-SNEDDS B, the best formulation of MC-SNEDDS. LC-SNEDDS formulations, especially LC-SNEDDS F provided the highest BA, 0.65, and successfully attenuated the inter-individual difference in the absorption behavior. Furthermore, it was confirmed that lymphatic transport of N-251 for LC-SNEDDS F was significantly increased up to around 3.19 times larger than that for MC-SNEDDS B. Simulation study suggested that 20 to 39% of N-251 uptaken by the small intestine would be delivered to lymphatic system after oral administration of LC-SNEDDS F.
Conclusions SNEDDS formulations significantly improved the absorption behavior of N-251 and long-chain fatty acid-based lipid further improved it by avoiding the hepatic first-pass elimination.

DOI： 10.1007/s11095-015-1646-x

Stage specific activity of synthetic antimalarial endoperoxides, N-89 and N-251, against Plasmodium falciparum Reviewed

Masayuki Morita, Takahiko Koyama, Hitomi Sanai, Akira Sato, Akiko Hiramoto, Araki Masuyama, Masatomo Nojima, Yusuke Wataya, Hye-Sook Kim

PARASITOLOGY INTERNATIONAL 64 ( 1 ) 113 - 117 2015.2

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

We have reported that two endoperoxides, N-89 and N-251, synthesized in 2001, possess potent antimalarial activities. Aiming at their eventual use for curing malaria in humans, we have been investigating various aspects of their antimalarial actions. Here we show that N-89 and N-251 inhibit the growth of Plasmodium falciparum within human erythrocytes in vitro at its lifecycle stage 'trophozoite' specifically. It is known that artemisinin compounds, which are currently used for curing malaria, have other stage-specificities. Therefore, it is likely that the antimalarial mechanism of N-89 and N-251 differs from those of artemisinin compounds. As malaria parasites resistant to artemisinin-based combination therapy are currently emerging in some tropical regions, N-89 and N-251 are candidates for overcoming these new problems. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.parint.2014.10.007

Role of activating transcription factor 3 protein ATF3 in necrosis and apoptosis induced by 5-fluoro-20-deoxyuridine Reviewed

Akira Sato, Kentaro Nakama, Hiroki Watanabe, Akito Satake, Akihiro Yamamoto, Takuya Omi, Akiko Hiramoto, Mitsuko Masutani, Yusuke Wataya, Hye-Sook Kim

FEBS JOURNAL 281 ( 7 ) 1892 - 1900 2014.4

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Necrosis and apoptosis are the two major forms of cell death. We have studied the mechanisms that regulate the cell death observed during treatment of mouse cancer cell line FM3A with the anticancer drug 5-fluoro-2-deoxyuridine (FUdR). To detect causal differences between necrosis and apoptosis, we exploited the necrosis in original clone F28-7 and the apoptosis in its variant F28-7-A that occur on treatment with FUdR. Activating transcription factor3 (ATF3) was strongly induced during necrosis but not apoptosis. In addition, we found that ATF3 expression is regulated by heat shock protein90 (HSP90) at the mRNA stage. Knockdown of Atf3 by siRNA in the F28-7 cells resulted in apoptotic morphology rather than necrotic morphology. These results suggest that ATF3 is a cell-death regulator in necrosis and apoptosis.

DOI： 10.1111/febs.12752

Molecular dynamics and energetic perceptions of substrate recognition by thymidylate kinase Reviewed

Mahmoud Kandeel, Yoshihiro Noguchi, Kentaro Oh-Hashi, Hye-Sook Kim, Yukio Kitade

JOURNAL OF THERMAL ANALYSIS AND CALORIMETRY 115 ( 3 ) 2089 - 2097 2014.3

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Plasmodium deoxyguanylate pathways are an attractive area of investigation for future metabolic and drug discovery studies due to their unusual substrate specificities. We investigated the energetic contribution to thymidylate kinase substrate binding, and the forces underlying ligand recognition. The binding constant varied from 8 x 10(4) M-1 at 290 K to 6 x 10(4) M-1 at 310 K for dGMP, and from 16 x 10(4) M-1 at 290 K to 4 x 10(4) M-1 at 310 K for TMP. Delta C (p) was estimated as -1.75 kJ mol(-1) K-1 for TMP and +2 kJ mol(-1) K-1 for dGMP. In comparison with TMP, the binding of dGMP to PfTMK produced less favorable enthalpy change, positive or favorable entropic contribution at lower temperature, positive heat capacity change, negative , positive Delta S (other), higher total solvent-exposed surface area and more or less rigid body binding. These changes indicate unfavorable conditions for proper binding and lower conformational changes, and suboptimal structural reordering during dGMP binding.

DOI： 10.1007/s10973-013-3319-5

New Preclinical Antimalarial Drugs Potently Inhibit Hepatitis C Virus Genotype 1b RNA Replication Reviewed

Youki Ueda, Midori Takeda, Kyoko Mori, Hiromichi Dansako, Takaji Wakita, Hye-Sook Kim, Akira Sato, Yusuke Wataya, Masanori Ikeda, Nobuyuki Kato

PLOS ONE 8 ( 8 ) e72519 2013.8

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Background: Persistent hepatitis C virus (HCV) infection causes chronic liver diseases and is a global health problem. Although new triple therapy (pegylated-interferon, ribavirin, and telaprevir/boceprevir) has recently been started and is expected to achieve a sustained virologic response of more than 70% in HCV genotype 1 patients, there are several problems to be resolved, including skin rash/ageusia and advanced anemia. Thus a new type of anti-HCV drug is still needed.
Methodology/Principal Findings: Recently developed HCV drug assay systems using HCV-RNA-replicating cells (e.g., HuH-7-derived OR6 and Li23-derived ORL8) were used to evaluate the anti-HCV activity of drug candidates. During the course of the evaluation of anti-HCV candidates, we unexpectedly found that two preclinical antimalarial drugs (N-89 and its derivative N-251) showed potent anti-HCV activities at tens of nanomolar concentrations irrespective of the cell lines and HCV strains of genotype 1b. We confirmed that replication of authentic HCV-RNA was inhibited by these drugs. Interestingly, however, this anti-HCV activity did not work for JFH-1 strain of genotype 2a. We demonstrated that HCV-RNA-replicating cells were cured by treatment with only N-89. A comparative time course assay using N-89 and interferon-alpha demonstrated that N-89-treated ORL8 cells had more rapid anti-HCV kinetics than did interferon-alpha-treated cells. This anti-HCV activity was largely canceled by vitamin E. In combination with interferon-alpha and/or ribavirin, N-89 or N-251 exhibited a synergistic inhibitory effect.
Conclusions/Significance: We found that the preclinical antimalarial drugs N-89 and N-251 exhibited very fast and potent anti-HCV activities using cell-based HCV-RNA-replication assay systems. N-89 and N-251 may be useful as a new type of anti-HCV reagents when used singly or in combination with interferon and/or ribavirin.

DOI： 10.1371/journal.pone.0072519

Applications of triphenylpyrylium salt-sensitized electron-transfer photo-oxygenation reactions to the synthesis of benzo-fused 1,4-diaryl-2,3- dioxabicyclo[2.2.2]octanes as new antimalarial cyclic peroxides Reviewed

Masaki Kamata, Jun-Ichi Hagiwara, Tomoko Hokari, Chiharu Suzuki, Ryohta Fujino, Sayaka Kobayashi, Hye-Sook Kim, Yusuke Wataya

Research on Chemical Intermediates 39 ( 1 ) 127 - 137 2013.1

Language：English Publishing type：Research paper (scientific journal)

Benzo-fused 1,4-diaryl-2,3-dioxabicyclo[2.2.2]octanes 4a-d (4a: Ar = C 6H5, 4b: Ar = p-FC6H4, 4c: Ar = p-MeC6H4, 4d: Ar = p-MeOC6H4) were synthesized by 2,4,6-triphenylpyrylium tetrafluoroborate (TPPBF 4)-sensitized photoinduced electron-transfer (PET)-promoted oxygenation reactions, and their in-vitro antimalarial activity was evaluated. The results showed that these substances have sufficiently high activity to enable them to serve as antimalarial lead compounds. In addition, TPPBF 4-biphenyl-cosensitized PET oxygenation was shown to be an efficient method for introduction of an O-O moiety in the construction of antimalarial cyclic peroxides. Graphical Abstract: New antimalarial bicyclic peroxides 4 were synthesized by TPPBF4-sensitized photoinduced electron-transfer oxygenation reactions.[Figure not available: see fulltext.] © 2012 Springer Science+Business Media B.V.

DOI： 10.1007/s11164-012-0637-3

Plasmodium falciparum Endoplasmic Reticulum-Resident Calcium Binding Protein Is a Possible Target of Synthetic Antimalarial Endoperoxides, N-89 and N-251 Reviewed

Masayuki Morita, Hitomi Sanai, Akiko Hiramoto, Akira Sato, Osamu Hiraoka, Takaya Sakura, Osamu Kaneko, Araki Masuyama, Masatomo Nojima, Yusuke Wataya, Hye-Sook Kim

JOURNAL OF PROTEOME RESEARCH 11 ( 12 ) 5704 - 5711 2012.12

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER CHEMICAL SOC

The endoperoxide artemisinin is a current first-line antimalarial and a critical component of the artemisinin-based combination therapies (ACT) recommended by WHO for treatment of Plasmodium falciparum, the deadliest of malaria parasites. However, recent emergence of the artemisinin-resistant P. falciparum urged us to develop new antimalarial drugs. We have shown that synthetic endoperoxides N-89 and its hydroxyl derivative N-251 had high antimalarial activities both in vivo and in vitro. However, the mechanisms including the cellular targets of the endoperoxide antimalarials are not well understood. Thus, in this study, we employed chemical proteomics to survey potential molecular targets of endoperoxides by evaluating P. falciparum proteins capable to associate with endoperoxide structure (N-346, a carboxyamino derivative of N-89). We also analyzed the protein expression profiles of malaria parasites treated with N-89 or N-251 to explore possible changes associated with the drug action. From these experiments, we found that P. falciparum endoplasmic reticulum-resident calcium binding protein (PfERC) had high affinity to the endoperoxide structure (N-346) and was decreased by treatment with N-89 or N-251. PfERC is a member of CREC protein family, a potential disease marker and also a potential target for therapeutic intervention. We propose that the PfERC is a strong candidate of the endoperoxide antimalarial's target.

DOI： 10.1021/pr3005315

抗マラリア薬として開発中の化合物に見出された強力な抗HCV活性(Potent anti-HCV activities found in preclinical anti-malarial drugs)

上田優輝, 森京子, 団迫浩方, 金惠淑, 綿矢有佑, 池田正徳, 加藤宣之

日本癌学会総会記事 71回 116 - 116 2012.8

Andirolides H-P from the flower of andiroba (Carapa guianensis, Meliaceae) Reviewed

Yuji Tanaka, Asami Sakamoto, Takanobu Inoue, Takeshi Yamada, Takashi Kikuchi, Tetsuya Kajimoto, Osamu Muraoka, Akira Sato, Yusuke Wataya, Hye Sook Kim, Reiko Tanaka

Tetrahedron 68 ( 18 ) 3669 - 3677 2012.5

Three new gedunins, an andirobin, three mexicanolides, and two phragmalin-type limonoids named andirolides H (1), I (2), J (3), K (4), L (5), M (6), N (7), O (8), and P (9) were isolated from an oil of the flower of Carapa guianensis Aublet (Meliaceae). Their structures including the absolute configurations were determined by means of the NMR and CD spectra as well as FABMS. Andirolide H (1) showed antimalarial activity against Plasmodium falciparum in vitro. © 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2011.12.076

Antimalarial activity of 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) and its carboxylic acid derivatives Reviewed

Akira Sato, Satoru Kawai, Akiko Hiramoto, Masayuki Morita, Natsuki Tanigawa, Yukari Nakase, Yuka Komichi, Masahiro Matsumoto, Osamu Hiraoka, Kazuyuki Hiramoto, Hidekazu Tokuhara, Araki Masuyama, Masatomo Nojima, Kazutaka Higaki, Hikoya Hayatsu, Yusuke Wataya, Hye-Sook Kim

PARASITOLOGY INTERNATIONAL 60 ( 4 ) 488 - 492 2011.12

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Malaria is one of the world's deadliest diseases and is becoming an increasingly serious problem as malaria parasites develop resistance to most of the antimalarial drugs used today. We previously reported the in vitro and in vivo antimalarial potencies of 1,2,6,7-tetraoxaspiro[7.11]nonadecane (N-89) and 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-l-ol (N-251) against Plasmodium falciparum and Plasmodium berghei parasites. To improve water-solubility for synthetic peroxides, a variety of cyclic peroxides having carboxyl functionality was prepared based on the antimalarial candidate, N-251, and their antimalarial activities were determined. The reactions of N-89 and its derivatives with Fe(II) demonstrated a highly efficient formation of the corresponding carbon radical which may be suspected as a key for the antiparasitic activity. Published by Elsevier Ireland Ltd.

DOI： 10.1016/j.parint.2011.08.017

Schistosomicidal and antifecuridity effects of oral treatment of synthetic endoperoxide N-89 Reviewed

Toshie Taniguchi, Takashi Kumagai, Rieko Shimogawara, Shizuko Ichinose, Akiko Hiramoto, Akira Sato, Masayuki Morita, Masatomo Nojima, Hye-Sook Kim, Yusuke Wataya, Nobuo Ohta

PARASITOLOGY INTERNATIONAL 60 ( 3 ) 231 - 236 2011.9

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

1,2,6,7-Tetraoxaspiro[7.11]nonadecane (N-89) is a chemically synthesized compound with good efficacy against malaria parasites. We observed strong anti-schistosomal activities of N-89 both in vitro and in vivo. In a murine model with experimental infection of Schistosoma mansoni, orally administered N-89 at the dose of 300 mg/kg resulted in a significant reduction in worm burden (63%) when mice were treated at 2-weeks postinfection. Strong larvicidal effects of N-89 were confirmed in vitro; schistosomula of S. mansoni were killed by N-89 at an EC50 of 16 nM. In contrast, no significant reduction in worm burden was observed when N-89 was administered at 5 weeks postinfection in vivo. However, egg production was markedly suppressed by N-89 treatment at that time point. On microscopic observation, the intestine of N-89-treated female worms seemed to be empty compared with the control group, and the mean body length was significantly shorter than that of controls. Nutritional impairment in the parasite due to N-89 treatment was possible, and therefore quantification of hemozoin was compared between parasites with or without N-89 treatment. We found that the hemozoin content was significantly reduced in N-89 treated parasites compared with controls (P<0.001). The surface of adult worms was observed by scanning and transmission electron microscopy, but there were no apparent changes. Taken together, these observations suggested that N-89 has strong antischistosomal effects, probably through a unique mode of drug efficacy. As N-89 is less toxic to mammalian host animals, it is a possible drug candidate against schistosomiasis. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.parint.2011.02.007

Antimalarial activity of endoperoxide compound 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol Reviewed

Akira Sato, Akiko Hiramoto, Masayuki Morita, Masahiro Matsumoto, Yuka Komich, Yukari Nakase, Natsuki Tanigawa, Osamu Hiraoka, Kazuyuki Hiramoto, Hikoya Hayatsu, Kazutaka Higaki, Satoru Kawai, Araki Masuyama, Masatomo Nojima, Yusuke Wataya, Hye-Sook Kim

PARASITOLOGY INTERNATIONAL 60 ( 3 ) 270 - 273 2011.9

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Plasmodium falciparum, the major causative parasite for the disease, has acquired resistance to most of the antimalarial drugs used today, presenting an immediate need for new antimalarial drugs. Here, we report the in vitro and in vivo antimalarial activities of 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) against P. falciparum and Plasmodium berghei parasites. The N-251 showed high antimalarial potencies both in the in vitro and the in vivo tests (EC(50) 2.3 X 10(-8) M; ED(50) 15 mg/kg (per oral)). The potencies were similar to that of artemisinin in vitro and greater than artemisinin's activity in vivo (p.o.). In addition, N-251 has little toxicity: a single oral administration at 2000 mg/kg to a rat gave no health problems to it. Administration of N-251 to mice bearing 1% of parasitemia (per oral 68 mg/kg, 3 times a day for 3 consecutive days) resulted in a dramatic decrease in the parasitemia: all the 5 mice given N-251 were cured without any recurrence, with no diarrhea or weight loss occurring in the 60 days of experiment. N-251 deserves more extensive clinical evaluation, desirably including future trials in the human. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.parint.2011.04.001

Association of RNase L with a Ras GTPase-activating-like protein IQGAP1 in mediating the apoptosis of a human cancer cell-line Reviewed

Akira Sato, Tomoharu Naito, Akiko Hiramoto, Kazato Goda, Takuya Omi, Yukio Kitade, Takuma Sasaki, Akira Matsuda, Masakazu Fukushima, Yusuke Wataya, Hye Sook Kim

FEBS Journal 277 4464 - 4473 2010.11

Mammalian intracellular ribonuclease L (RNase L) is a latent endoribonuclease that functions against viral infections as an apoptosis-inducing protein, and its activity requires intracellular 5′-end-triphosphorylated-2′,5′ oligoadenylates (2-5A) as an activator. Previously, we showed that RNase L can be activated in human cancer cell line HT1080 by an RNA polymerase I inhibitor, 1-(3-C-ethynyl-β-D-ribo- pentofuranosyl)cytosine (3′-ethynylcytidine; ECyd). In ECyd-treated cells, knockdown of the RNase L resulted in a marked decrease in c-jun N-terminal kinase (JNK) phosphorylation, thereby inhibiting apoptosis. We investigate RNase L binding partners by focused proteomic approach using immunoprecipitation with anti-RNase L IgG and mass spectrometry. We found that the IQ motif-containing Ras GTPase-activating-like protein 1 (IQGAP1) can associate with RNase L, and that phosphorylation occurs on the IQGAP1. ECyd-induced JNK phosphorylation and apoptosis were inhibited when IQGAP1 was knocked down with a small interfering RNA. These results raise the interesting possibility that the RNase L-IQGAP1 association may regulate JNK phosphorylation in RNase L-madiated apoptosis. It is likely IQGAP1 works as a regulator in apoptosis.© 2010 The Authors Journal compilation © 2010 FEBS.

DOI： 10.1111/j.1742-4658.2010.07833.x

GERANYL DERIVATIVES OF ISOQUINOLINE ALKALOIDS SHOW INCREASED BIOLOGICAL ACTIVITIES Reviewed

Yumi Nishiyama, Kinuko Iwasa, Suguru Okada, Sousuke Takeuchi, Masataka Moriyasu, Miyoko Kamigauchi, Junko Koyama, Atsuko Takeuchi, Harukuni Tokuda, Hye-Sook Kim, Yusuke Wataya, Kazuyoshi Takeda, Yi-Nan Liu, Pei-Chi Wu, Kenneth F. Bastow, Toshiyuki Akiyama, Kuo-Hsiung Lee

HETEROCYCLES 81 ( 5 ) 1193 - 1229 2010.5

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Three types of isoquinoline alkaloids were tested for antimicrobial, cytotoxic, anti-malarial, anti-oxidant, and anti-HIV activities, as well as inhibitory activity against Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. N- or O-Geranylation contributed to increased potency in four types of activities except anti-HIV and anti-oxidant. Some types of alkaloids may be useful as lead compounds for developing potential chemotherapeutic agents. N,N-Geranylated salsolinol was significantly active in three different assays, antimicrobial, cytotoxic, and EBV-EA, and may be a most useful compound.

DOI： 10.3987/COM-10-11912

Protein Expression Profiles of Necrosis and Apoptosis Induced by 5-Fluoro-2 '-deoxyuridine in Mouse Cancer Cells Reviewed

Akira Sato, Akito Satake, Akiko Hiramoto, Yusuke Wataya, Hye-Sook Kim

JOURNAL OF PROTEOME RESEARCH 9 ( 5 ) 2329 - 2338 2010.5

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER CHEMICAL SOC

We have investigated the molecular mechanisms regulating the necrosis and apoptosis that occur on treatment of mouse mammary tumor FM3A cells with 5-fluoro-2'-deoxyuridine (FUdR), a potent anticancer agent, using the original clone F28-7 and its variant F28-7-A cells. Previously, we reported an interesting observation that FUdR induces a necrotic morphology in F28-7 but an apoptotic morphology in F28-7-A cells. We have now analyzed the protein expression profiles of these FUdR-induced necrosis and apoptosis. Thus, proteome analysis of these clones by two-dimensional gel electrophoresis and mass spectrometry showed that the cytoplasmic intermediate filament protein, cytokeratin-19, is expressed at a significantly higher level in F28-7 than in F28-7-A cells. This strong expression was detected both in untreated and FUdR-treated stages of F28-7 cells. We interpreted this phenomenon as suggesting that cytokeratin-19 possesses a function in leading the cell to apoptosis. We performed a knockdown of cytokeratin-19 expression in F28-7 cells by use of the small interfering RNA technique. Indeed, a lowering of the cytokeratin-19 expression down to the level in F28-7-A occurred, and the FUdR-induced death morphology of this knockdown F28-7 was apoptosis, instead of the necrosis usually observable in the FUdR-treated F28-7. It is known that the cytoskeletal protein cytokeratin-19 undergoes caspase-mediated degradation during apoptosis. Our present finding provides an interesting possibility that cytokeratin-19 may have a key role in regulating cell-death morphology.

DOI： 10.1021/pr9010537

Selective accumulation of rhodacyanine in plasmodial mitochondria is related to the growth inhibition of malaria parasites Reviewed

D. Morisaki, H.-S. Kim, H. Inoue, H. Terauchi, S. Kuge, A. Naganuma, Y. Wataya, H. Tokuyama, M. Ihara, K. Takasu

Chemical Science 1 ( 2 ) 206 - 209 2010

Antimalarial artemisinin and tetraoxane endoperoxides behave differently in the oxidative degradation of unsaturated phospholipid Reviewed

Naokazu Kumura, Hirotaka Furukawa, Arnold N. Onyango, Minoru Izumi, Shuhei Nakajima, Hideyuki Ito, Tsutomu Hatano, Hye-Sook Kim, Yusuke Wataya, Naomichi Baba

CHEMISTRY AND PHYSICS OF LIPIDS 160 S28 - S29 2009.8

Role of RNase L in apoptosis induced by 1-(3-C-ethynyl-β-d-ribo- pentofuranosyl)cytosine Reviewed

Tomoharu Naito, Tatsushi Yokogawa, Satoshi Takatori, Kazato Goda, Akiko Hiramoto, Akira Sato, Yukio Kitade, Takuma Sasaki, Akira Matsuda, Masakazu Fukushima, Yusuke Wataya, Hye Sook Kim

Cancer Chemotherapy and Pharmacology 63 837 - 850 2009.4

Purpose: 1-(3-C-Ethynyl-β-d-ribo-pentofuranosyl)cytosine (ECyd), a ribonucleoside analog, has a potent cytotoxic activity against cancer cells. The present studies have been performed to elucidate the overall mechanisms of ECyd-induced apoptotic cell death. Methods: Cultured cells of mouse mammary carcinoma FM3A and human fibrosarcoma HT 1080 lines were used. The efficacy of RNA synthesis inhibition by ECyd was assessed by kinetic analysis using nuclei isolated from FM3A cells. RNA status in ECyd-treated cells was investigated by Northern blots, and the cleavage sites of RNA were identified by rapid amplification of 5′ cDNA ends (5′-RACE). The effect of protein functions on the ECyd-induced apoptotic pathway was analyzed by siRNA and immunohistochemical techniques. Apoptotic cells were detected by TdT-mediated dUTP-biotin Nick End Labeling (TUNEL) assay. Results: ECyd induces inhibition of RNA synthesis in vitro and in vivo, which appears to be a major cause for the apoptosis. It is known that ECyd is converted inside the cell into its 5′-triphosphate (ECTP). We have now found in test-tube experiments that ECTP strongly inhibits the activity of RNA polymerase I by competing with CTP. In the absence of robust RNA synthesis, the cellular RNAs would be destined to break down. RNase L was found to be playing a role in the breakdown: thus, the 28S rRNA-fragmentation pattern observed for the ECyd-treated cells was very similar to that observable in an in vitro treatment of the 28S ribosomes with RNase L. Association of RNase L with the cytotoxic action of ECyd was confirmed by use of the siRNA-mediated suppression of the cellular RNase L. Thus, the cells in which the RNase L was knocked-down were highly resistant to the cytotoxic action of ECyd. Further events, downstream of the RNase L action that can lead to the eventual apoptosis, would conceivably involve the phosphorylation of c-jun N-terminal kinase and subsequent decrease in mitochondrial membrane-potential. Evidence to support this flow of events was obtained by siRNA-experiments. Conclusion: The results from this study demonstrated that RNase L is activated after the inhibition of RNA polymerase, and induces mitochondria-dependent apoptotic pathway. We propose this new role for RNase L in the apoptotic mechanism. These findings may open up the possibility of finding new targets for anticancer agents. © 2008 Springer-Verlag.

DOI： 10.1007/s00280-008-0810-y

Toxoplasma gondii: A simple high-throughput assay for drug screening in vitro Reviewed

ChunMei Jin, Kusuma Kaewintajuk, JingHua Jiang, WooJin Jeong, Masaki Kamata, Hye-Sook Kim, Yusuke Wataya, Hyun Park

EXPERIMENTAL PARASITOLOGY 121 ( 2 ) 132 - 136 2009.2

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Toxoplasma gondii is the etiologic agent of toxoplasmosis. Although the combination of sulfadiazine and pyrimethamine is used as therapy for this disease, these drugs can have serious side effects and its use is limited in pregnancy. Therefore there is a need for new anti-T gondii drugs in the clinic. Some systems for T. gondii drug screening have been described, but these have limitations and can be difficult. In order to solve these problems, we established a system to screen drugs in vitro that involved using cell viability methods to calculate drug selectivities, which are Trypan blue, [3-(4,5-dimethylthiazol-zyl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazoliuzolium, inner salt] (MTS) method and lactate dehydrogenase (LDH) assay. These assays were simple to establish and perform. The IC(50) values calculated from the morphological assay were not significantly different from the EC(50) values calculated using the other three methods. In particular, the results of the morphological assay showed a distinct association with the MTS assay (R = 0.9841). These assays could be used for a wide range of applications in the screening of new drugs and may provide an alternative to the techniques currently used to screen for candidate anti-T. gondii compounds in vitro. In this study, we also tested many compounds and identified some that had a good anti-T gondii effect in vitro based on the MTS assay. This simple and fast system allowed us to determine which compounds to investigate further using in vivo experiments. (C) 2008 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.exppara.2008.10.006

Synthesis of Novel Conjugates of Tetraoxane Endoperoxide with Bis (Quaternary Ammonium Salts)

KUMURA Naokazu, FURUKAWA Hirotaka, KOBAYASHI Michiyo, ONYANGO Arnold N., IZUMI Minoru, NAKAJIMA Shuhei, KIM Hye-Sook, WATAYA Yusuke, BABA Naomichi

Agricultural and Biological Chemistry 73 ( 1 ) 217 - 220 2009

Language：English Publisher：Japan Society for Bioscience, Biotechnology, and Agrochemistry

Novel water-soluble conjugates of 1,2,4,5-tetraoxane bis(quaternary ammonium salts) were synthesized in a relatively stable crystalline form via four steps starting from methyltrioxorhenium-catalyzed endo-peroxidation of ethyl 4-oxocyclohexanecarboxylate with hydrogen peroxide in hexafluoro-2-propanol. The assay for the in vitro toxicity of water-soluble tetraoxanes 5a–5d to malaria parasites indicate that they were inactive against the Plasmodium falciparum FCR-3 strain.

DOI： 10.1271/bbb.80571

Other Link： https://jlc.jst.go.jp/DN/JALC/00324722978?from=CiNii

Different behavior of artemisinin and tetraoxane in the oxidative degradation of phospholipid

Kumura, N, Furukawa, H, Onyango, A.N, Izumi, M, Nakajima, S, Ito, H, Hatano, T, Kim, H.-S, Wataya, Y, Baba, N

Chemistry and Physics of Lipids 160 ( 2 ) 114 - 120 2009

Synthesis and silencing properties of siRNAs possessing lipophilic groups at their 3 '-termini

Yoshihito Ueno, Koshi Kawada, Tomoharu Naito, Aya Shibata, Kayo Yoshikawa, Hye-Sook Kim, Yusuke Wataya, Yukio Kitade

BIOORGANIC & MEDICINAL CHEMISTRY 16 ( 16 ) 7698 - 7704 2008.8

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Short-interfering RNAs (siRNAs) conjugated with lipophilic groups at their 3'-termini were synthesized. The properties of the synthesized siRNAs were examined in detail, and it was found that at low concentrations, their silencing abilities were dependent on the positions of the modi. cations and the types of organic molecules attached. Although the modi. cation of siRNAs with palmitic acid or oleic acid at the 3'-end slightly reduced their silencing activities, siRNAs had enough abilities to induce RNAi at 10 nM concentrations. On the other hand, the modi. cation of siRNAs with cholesterol at the 3'-end of the passenger strand was tolerated; however, the modi. cation at the guide strand significantly reduces its silencing activity. The siRNAs modified with the lipophilic groups did not possess ability to penetrate the plasma membranes of HT-1080 cells without the transfection reagent. However, the results described in this report will aid in designing novel siRNAs with cell membrane-permeable molecules. (C) 2008 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmc.2008.07.010

Gene expression profiles of necrosis and apoptosis induced by 5-fluoro-2 '-deoxyuridine

Akira Sato, Akiko Hiramoto, Yusuke Uchikubo, Eriko Miyazaki, Akito Satake, Tomoharu Naito, Osamu Hiraoka, Tsuyoshi Miyake, Hye-Sook Kim, Yusuke Wataya

GENOMICS 92 ( 1 ) 9 - 17 2008.7

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

5-Fluoro-2'-deoxyuridine (FUdR), a potent anticancer agent, exerts its effects by inhibiting thymidylate synthase, an essential machinery for DNA synthesis in cell proliferation. Also, cell death is caused by FUdR, primarily due to an imbalance in the nucleotide pool resulting from this enzyme inhibition. We have investigated the cancer cell death induced by FUdR, focusing on its molecular mechanisms. Using mouse mammary tumor FM3A cell lines, the original clone F28-7 and its variant F28-7-A cells, we previously reported an interesting observation that FUdR induces a necrotic morphology in F28-7, but induces, in contrast, an apoptotic morphology in F28-7-A cells. In the present study, to understand the molecular mechanisms underlying these differential cell deaths, i.e., necrosis and apoptosis, we investigated the gene expression changes occurring in these processes. Using the cDNA microarray technology, we found 215 genes being expressed differentially in the necrosis and apoptosis. Further analysis revealed differences between these cell lines in terms of the expressions of both a cluster of heat shock protein (HSP)-related genes and a cluster of apoptosis-related genes. Notably, inhibition of HSP90 in F28-7 cells caused a shift from the FUdR-induced necrosis into apoptosis. These findings are expected to lead to a better understanding of this anticancer drug FUdR for its molecular mechanisms and also of the general biological issue, necrosis and apoptosis. (C) 2008 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.ygeno.2008.02.002

Detection of malaria parasites in mosquitoes from the malaria-endemic area of Chakaria, Bangladesh

Akter Tangin, Yuka Komichi, Yukiko Wagatsuma, Haque Rashidul, Yusuke Wataya, Hye-Sook Kim

BIOLOGICAL & PHARMACEUTICAL BULLETIN 31 ( 4 ) 703 - 708 2008.4

Language：English Publishing type：Research paper (scientific journal) Publisher：PHARMACEUTICAL SOC JAPAN

Malaria is one of the major public health problems of Bangladesh. We investigated the mosquito populations infected with malaria parasites in a malaria-endemic area Chakaria, Bangladesh, where Anopheles dirus and Anopheles minimus are the principal vectors. Anopheles mosquitoes were collected with a CDC miniature light trap from inside households in June 2007. A total of 868 mosquitoes were collected, among which females numbered 669 (77.1%). The species of female Anopheles mosquitoes were identified morphologically, and 651 were A. minimus and the remaining 18 were other Anopheles species. Malaria parasite DNA from individual female mosquitoes was extracted and distinguished using the microtiter plate hybridization (MPH) technique targeting the 18S rRNA of human malaria parasites. Nineteen mosquitoes were malaria parasite positive: 12 for Plasmodium falciparum, 1 for Plasmodium vivax, and 6 for both R falciparum and P vivax. This is the first time that the MPH technique was used for distinguishing malaria parasites in mosquitoes and the first report from Chakaria. Our results may contribute to planning and assessing malaria control strategies in Chakaria.

DOI： 10.1248/bpb.31.703

Association of nuclear membrane protein lamin B1 with necrosis and apoptosis in cell death induced by 5-fluoro-2 '-deoxyuridine

Akira Sato, Akiko Hiramoto, Akito Satake, Eriko Miyazaki, Tomoharu Naito, Yusuke Wataya, Hye-Sook Kim

NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 27 ( 5 ) 433 - 438 2008

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS INC

We report that anticancer 5-fluoro-2'-deoxyuridine (FUdR) shows cytotoxicity against mouse cancer cell line FM3A, using a progeny clone F28-7 and its variant F28-7-A. In this process, the cell-death morphology is different between F28-7 and F28-7-A cells, that is, necrosis in F28-7 but apoptosis in F28-7-A cells. In the proteomic analysis of these cells before their exposure to FUdR, the nuclear inner-membrane protein lamin B1 is up-regulated in F28-7 but not in F28-7-A, suggesting that lamin B1 may possess a function to regulate the morphology of cell-death. A knockdown of lamin B1 expression in F28-7 cells was performed by use of the small interfering RNA technique, resulting in a decrease of the lamin B1-expression level down to the level in F28-7-A. Remarkably, the FUdR-induced death morphology of this knocked-down F28-7 was apoptosis, definitely different from the necrosis that occurs in the FUdR-treated original F28-7. Thus, the swelling feature for the necrosis was no longer observable, and instead cell shrinkage typical of apoptosis took place in almost all the cells examined. This finding suggests a new role for lamin B1 as a regulator in cell death.

DOI： 10.1080/15257770802086864

In vitro antimalarial activity of flavonoids and chalcones

Soon Sung Lim, Hye-Sook Kim, Dong-Ung Lee

BULLETIN OF THE KOREAN CHEMICAL SOCIETY 28 ( 12 ) 2495 - 2497 2007.12

Preparation of quinoline hexose analogs as novel chloroquine-resistant malaria treatments (1). Synthesis of 4-hydroxyquinoline-beta-glucosides

Hiroshi Suzuki, Nagwa S. M. Aly, Yusuke Wataya, Hye-Sook Kim, Ikumi Tamai, Masaki Kita, Daisuke Uemura

CHEMICAL & PHARMACEUTICAL BULLETIN 55 ( 5 ) 821 - 824 2007.5

Language：English Publishing type：Research paper (scientific journal) Publisher：PHARMACEUTICAL SOC JAPAN

Quinoline hexose analogs are expected to be useful as novel agents for treatment of chloroquine-resistant malaria. Here, we report preparation of 4-hydroxy quinoline-beta-glucosides from anilines in 4 steps.

DOI： 10.1248/cpb.55.821

Proteome analysis of new antimalarial endoperoxide against Plasmodium falciparum

Nagwa S. M. Aly, Akiko Hiramoto, Hitomi Sanai, Osamu Hiraoka, Kazuyuki Hiramoto, Hiroyuki Kataoka, Jin-Ming Wu, Araki Masuyama, Masatomo Nojima, Satoru Kawai, Hye-Sook Kim, Yusuke Wataya

PARASITOLOGY RESEARCH 100 ( 5 ) 1119 - 1124 2007.4

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

N-89, a new antimalarial endoperoxide, was selected as a promising antimalarial compound showing high activity and selectivity. To study the mechanism of N-89 action, N-89 resistant strain (NRC10) was obtained by intermittent drug pressure. NRC10 bad a tenfold increase in the EC50 value of N-89. No cross-resistance was obtained with other antimalarial compounds. Comparative proteome analysis of N-89 sensitive and NRC10 strains revealed over-expression of 12 spots and down-regulation of 14 spots in NRC10. Fifteen proteins were identified of Plasmodium falciparum origin. The identified proteins representing several functions, mainly related to the glycolytic pathway, and metabolism of protein and lipid. Our results suggest that identified proteins may be candidates of antimalarial endoperoxide targets.

DOI： 10.1007/s00436-007-0460-8

Proteome and transcriptome analysis of cell death induced by 5-fluoro-2'-deoxyuridine. International journal

Akira Sato, Eriko Miyazaki, Akito Satake, Akiko Hiramoto, Osamu Hiraoka, Tsuyoshi Miyake, Hye-Sook Kim, Yusuke Wataya

Nucleic acids symposium series (2004) ( 51 ) 433 - 4 2007

Language：English Publishing type：Research paper (scientific journal)

5-fluoro-2'-deoxyuridine (FUdR) inhibits thymidylate synthase. We have been investigated the molecular mechanisms of cell death in mouse mammary tumor FM3A cells, F28-7 strain and its mutant F28-7-A strain, after treated with FUdR. Previously, we have been reported that F28-7 strain induced DNA cleavage into chromosomal sized fragments and subsequently develop necrosis, but F28-7-A strain induced DNA cleavage into oligonucleosomal sized fragments and subsequently develop apoptosis after treated with FUdR. To understand the molecular mechanisms of regulate of two differential cell death necrosis and apoptosis, we identify cell death regulator by using proteome and transcriptome analysis. When compared with the proteome of F28-7 and F28-7-A strain after treated with FUdR, it was found that 5 proteins were up-regulated and 11 proteins were down-regulated in F28-7-A strain. Furthermore, transcriptome analysis shows that 94 genes were up-regulated and 164 genes were downregulated in F28-7-A strain. Identified proteins and genes were involved in various cellular processes such as cell cycle regulation, apoptosis, proliferation, and differentiation. Our results suggested that numerous features indicated the coordinated regulation of molecular networks from various aspects of necrosis or apoptosis at the proteome and transcriptome levels.

Design, synthesis and in vitro antimalarial activity of spiroperoxides

Hong-Xia Jin, Qi Zhang, Hye-Sook Kim, Yusuke Wataya, He-Hua Liu, Yikang Wu

TETRAHEDRON 62 ( 33 ) 7699 - 7711 2006.8

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Several spiroperoxy antimalarial compounds were designed and synthesized using the hydrogen peroxide in UHP (urea-H2O2 complex) as the source of the peroxy bond. Incorporation of the H2O2 into the organic molecule framework through ketal exchange reaction in the present cases was greatly facilitated by the potential to form a five- or six-membered cyclic hemiketal due to the presence of a hydroxyl group gamma or beta to the ketone carbonyl group. When the electron-withdrawing group in the Michael acceptor was a nitro group, the closure of the peroxy ring occurred readily under the hydroxidation conditions. Presence of a benzene ring fused to the peroxy ling effectively reduced the degrees of freedom in the transition state for the ring-closure step and made the otherwise very difficult seven-membered 1,2-dioxepane rather easy to form through the intramolecular Michael addition. (c) 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2006.05.065

Antimalarial effect of bis-pyridinium salts, N,N '-hexamethylenebis(4-carbamoyl-1-alkylpyridinium bromide)

K Fujimoto, D Morisaki, M Yoshida, T Namba, K Hye-Sook, Y Wataya, H Kourai, H Kakuta, K Sasaki

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 16 ( 10 ) 2758 - 2760 2006.5

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

The in vitro antimalarial activity of bis-pyridinium salts, N,N'-hexamethylenebis(4-carbamoyl-1-decylpyridinium bromide) and their derivatives, against the Plasmodium falciparum FCR-3 strain (ATCC 30932, chloroquine-sensitive) was evaluated. All test compounds exhibited antimalarial activity over a concentration range of 3.5 mu M to 10 nM. The chain length of the N1-alkyl moiety was found to be very beneficial in terms of antimalarial activity, and in this series of compounds, the most appropriate N1-alkyl chain length was found to be eight. (C) 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2006.02.030

Trichomonicidal Activity of Herbal Extracts Used in Traditional Medicine in Korea.

Youn-Chul Kim, Jae-Sook Ryu, Hyoung-Jun Kim, Kyung-Min Choi, Hye-Sook Kim, Hyun Park

Korean J.Oriental Physiology & Pathology 2006

A case of mixed infection of Plasmodium falciparum and Plasmodium ovale from nigeria: Difficulty of microscopic diagnosis after inappropriate treatment.

Haruki, K, Kaku, K, Yamamoto, T, Katagiri, T, Sakurai, Y, Hirose, W, Kim, H.-S, Wataya, Y

Clinic. Parsitol., 2006

An apoptotic pathway of 3'-Ethynylcytidine(ECyd) involving the inhibition of RNA synthesis mediated by RNase L. International journal

Tomoharu Naito, Tatsushi Yokogawa, Hye-Sook Kim, Akira Matsuda, Takuma Sasaki, Masakazu Fukushima, Yukio Kitade, Yusuke Wataya

Nucleic acids symposium series (2004) ( 50 ) 103 - 4 2006

Language：English Publishing type：Research paper (scientific journal)

RNase L is an endoribonuclease that requires 2'-5' oligoadenylate to cleave single-stranded RNA. Although the antiviral effects of RNase L are well known because of its viral RNA degradation activity recently but it has been suggested that RNase L is concerned in mitochondrial-caspase dependent apoptotic signaling pathway induced by a number of anticancer agents. Moreover, it has variety of functions including translation and transcription of proteins. In this report, we found that 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl) cytosine (ECyd), which inhibits RNA synthesis through competitive inhibition of RNA polymerase I induced 28S rRNA fragmentation. The cleavage pattern of rRNA induced by ECyd was similar and the cleavage sites were identical to those cleaved by RNase L. Additionaly, apoptosis induced by ECyd was elevated following the protein expression of RNase L in the tumor cells when treated with IFN-alpha2a which was known to induce RNase L expression. To identify the role of RNase L in apoptosis induced by ECyd, we detected the decreased level of RNase L by several folds in the tumor cell lines through a small interfering RNA (siRNA). These results indicated that RNase L might integrate apoptotic signals induced by ECyd and provide the possibility to be a novel clinical target for cancer chemotherapy.

Proteome and transcriptome analysis of 5-fluoro-2'-deoxyuridine-induced cell death mechanisms. International journal

Akira Sato, Eriko Miyazaki, Akito Satake, Akiko Hiramoto, Osamu Hiraoka, Tsuyoshi Miyake, Hye-Sook Kim, Yusuke Wataya

Nucleic acids symposium series (2004) ( 50 ) 101 - 2 2006

Language：English Publishing type：Research paper (scientific journal)

5-Fluoro-2'-deoxyuridine (FUdR) inhibits thymidylate synthase. The inhibition of thymidylate synthase causes an imbalance of intracellular deoxyribonucleoside triphosphate (dNTP) pools which subsequently induced cell death. We have been investigated the molecular mechanisms of cell death in mouse mammary tumor FM3A cells, F28-7 strain and its mutant F28-7-A strain, after treated with FUdR. We have previously been reported that F28-7 strain induced DNA cleavage into chromosomal sized fragments and subsequently develop necrosis, but F28-7-A strain induced DNA cleavage into oligonucleosomal sized fragments and subsequently develop apoptosis after treated with FUdR. In this report, in order to understand the molecular mechanisms of regulate of two differential cell death necrosis and apoptosis, we identify cell death regulator by using proteome and transcriptome analysis. When compared with the proteome from F28-7 strain and F28-7-A strain, it was found that ten proteins were increased and six proteins were decreased in F28-7-A strain. Furthermore, transcriptome analysis shows that 127 genes were increased and 181 genes were decreased in F28-7-A strain. These differentially expressed proteins and genes were involved in various cellular processes such as cell cycle regulation, apoptosis, proliferation, and differentiation. These two techniques clarified numerous features in F28-7 strain and F28-7-A strain. Our results revealed that numerous features indicated the coordinated regulation of molecular networks from various aspects of necrosis or apoptosis at the proteome and transcriptome levels.

1,2,4,5-Tetraoxacycloalkanes: Synthesis and antimalarial activity

A Masuyama, JM Wu, M Nojima, HS Kim, Y Wataya

MINI-REVIEWS IN MEDICINAL CHEMISTRY 5 ( 11 ) 1035 - 1043 2005.11

Language：English Publisher：BENTHAM SCIENCE PUBL LTD

In this short review the methods of preparation of novel 1,2,4,5-tetraoxacycloalkanes and the related peroxides are summarized, with the emphasis on the usefulness of 1,1-bishydroperoxides as the precursor. Also, their antimalarial activities in vitro and in vivo are discussed.

DOI： 10.2174/138955705774575255

Synthesis and biological activity of fatty acid derivatives of quinine

N Kumura, M Izumi, S Nakajima, S Shimizu, HS Kim, Y Wataya, N Baba

BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY 69 ( 11 ) 2250 - 2253 2005.11

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

Derivatives of quinine with fatty acids including polyunsaturated fatty acids were prepared. They showed moderate antimalarial activity as compared with quinine itself using Plasmodium falciparum. The activities were not dependent on whether the fatty acyl group was saturated or unsaturated. On the other hand, the derivatives showed significantly higher cytotoxicity against a mammary tumor cell line FM3A than quinine itself. Calculating from these data, an acetyl derivative of quinine with the shortest acyl group was found to give the highest selectivity.

DOI： 10.1271/bbb.69.2250

Synthesis and in vitro antimalarial activity of several simple analogues of peroxyplakoric acid

HH Liu, HX Jin, Q Zhang, YK Wu, HS Kim, Y Wataya

CHINESE JOURNAL OF CHEMISTRY 23 ( 11 ) 1469 - 1473 2005.11

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-V C H VERLAG GMBH

Several simple analogues of peroxyplakoric acid were synthesized by using Kobayashi's method to construct the key 1,2-dioxane core and tested in vitro for antimalarial activity. The scope and limitation of the method was also briefly examined.

DOI： 10.1002/cjoc.200591469

Co-catalyzed autoxidation of alkene in the presence of silane. The effect of the structure of silanes on the efficiency of the reaction and on the product distribution

JM Wu, S Kunikawa, T Tokuyasu, A Masuyama, M Nojima, HS Kim, Y Wataya

TETRAHEDRON 61 ( 42 ) 9961 - 9968 2005.10

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

A systematic investigation of the structural effect of silanes on the Co-catalyzed reductive oxygenation of alkene in the presence of silane (Mukaiyama-Isayama reaction) showed that the efficiency of the reaction decreases with the increase of the steric bulk of the silanes. A similar trend was observed for the metal-exchange reaction between Co(III)-alkylperoxo complex and silane, too. The peroxidation of (S)-limonene, followed by deprotection of the derived silyl peroxides, provides a mixture of the corresponding monocyclic hydroperoxide 24 and the bicyclic one 25, the ratio being a marked function of the steric bulk of silanes. (c) 2005 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2005.08.025

Gastrodia elata blume and an active component, p-hydroxybenzyl alcohol reduce focal ischemic brain injury through antioxidant related gene expressions

SJ Yu, Kim, JR, CK Lee, JE Han, JH Lee, HS Kim, JH Hong, SG Kang

BIOLOGICAL & PHARMACEUTICAL BULLETIN 28 ( 6 ) 1016 - 1020 2005.6

Language：English Publishing type：Research paper (scientific journal) Publisher：PHARMACEUTICAL SOC JAPAN

Ischaemic stroke is a leading cause of death and long-lasting disability. Gastrodia elata blume (GEB) is a Chinese herb that is widely used to treat convulsive disorders, such as epilepsy, and p-hydroxybenzyl alcohol (HBA) is the active ingredient in GEB. The present study was conducted to evaluate the effects of GEB and HBA on the brain damage and transcriptional levels of Protein disulfide isomerase (PDI) and 1-Cys peroxiredoxin (1-Cys Prx) genes known to play a role in antioxidant systems after transient focal ischemia in the rat brain. Focal ischemia was induced in rats by middle cerebral artery occlusion (MCAO). All animals underwent ischemia for I h, followed by 24 h of reperfusion. Coronal brain slices were stained with 2,3,5-triphenyltetrazolium chloride or total RNA was extracted for the analysis of gene expression. Histopathologic analysis revealed a significant (p < 0.05) decrease in infarct size in the ipsilateral brain with GEB extracts or HBA. Moreover, the levels of PDI and 1-Cys Prx transcription were significantly increased in the GEB extract- or HBA-treated group compared with the untreated group (p < 0.05). This study therefore indicated that GEB and HBA provide neuroprotection by preventing brain damage through the increased expression of genes encoding antioxidant proteins after transient focal cerebral ischemia and may be effective as neuroprotective agents at the cellular and molecular levels in the brain.

DOI： 10.1248/bpb.28.1016

Synthesis and evaluation of beta-carbolinium cations as new antimalarial agents based on pi-delocalized lipophilic cation (DLC) hypothesis

K Takasu, T Shimogama, C Saiin, HS Kim, Y Wataya, R Brun, M Ihara

CHEMICAL & PHARMACEUTICAL BULLETIN 53 ( 6 ) 653 - 661 2005.6

Language：English Publishing type：Research paper (scientific journal) Publisher：PHARMACEUTICAL SOC JAPAN

Several beta-carbolines including naturally occurring substances and their corresponding cationic derivatives were synthesized and evaluated for antimalarial (anti plasmodial) activity in vitro and in vivo. A tetracyclic carbolinium salt was elucidated for antileishmanial and antitrypanosomal activities in vitro as well as antiplasmodial activity. Quarternary carbolinium cations showed much higher potencies in vitro than electronically neutral beta-carbolines and a good correlation was observed between pi-delocalized lipophilic cationic (DLC) structure and antimalarial efficacy. beta-Carbolinium compounds exhibit medium suppressive activity in vivo against rodent malaria.

DOI： 10.1248/cpb.53.653

Synthesis of novel siRNAs having thymidine dimers consisting of a carbamate or a urea linkage at their 3 ' overhang regions and their ability to suppress human RNase L protein expression

Y Ueno, T Naito, K Kawada, A Shibata, HS Kim, Y Wataya, Y Kitade

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 330 ( 4 ) 1168 - 1175 2005.5

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

In order to examine the effect of modifications at the 3' overhang regions of short interfering RNAs (siRNAs) oil their gene-silencing activities, we designed and synthesized novel siRNAs having thymidine dimers consisting of a carbamate or a urea linkage at their 3' overhang regions. Suppression of human RNase L protein expression by these siRNAs was analyzed by immunoblot with RNase L-specific antibody. It was found that, at 24 h post-transfection, the modified siRNAs having the thymidine dimers with the carbamate and urea linkage suppress the protein expression 78 and 37 times more efficiently than that with the natural phosphodiester linkage, respectively. Furthermore, the siRNA containing the carbamate linkage was 37 times more resistant to nucleolytic degradation by snake venom phosphodiesterase than the siRNA consisting of the natural phosphodiester linkage. Thus, the RNA duplexes having the thymidine dimers with the carbamate or urea linkage at their 3' overhang regions will be promising candidates for novel siRNA molecules to down-regulate protein expression. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2005.03.100

Synthesis of 5′-methylenearisteromycin and its 2-fluoro derivative with potent antimalarial activity due to inhibition of the parasite S-adenosylhomocysteine hydrolase

Chieko Takagi, Makoto Sukeda, Hye-Sook Kim, Yusuke Wataya, Saori Yabe, Yukio Kitade, Akira Matsuda, Satoshi Shuto

Organic and Biomolecular Chemistry 3 ( 7 ) 1245 - 1251 2005.4

Language：English Publishing type：Research paper (scientific journal)

5′-Methylenearisteromycin (5) and its 2-fluoro derivative 6, which were designed as antimalarial agents because of their AdoHcy hydrolase inhibition, were synthesized from D-ribose, using a stereoselective intramolecular radical cyclization as the key step to construct the carbocyclic structure. These compounds were evaluated as AdoHcy hydrolase inhibitors with the recombinant human and malarial parasite enzymes. Although 5 and 6 were both potent inhibitors of the malarial parasite AdoHcy hydrolase, the 2-fluoro derivative 6 proved to be superior due to its lower inhibitory effect on the human enzyme. In addition, 6 was identified as a potent antimalarial agent using an in vitro assay system with Plasmodium falciparum. © The Royal Society of Chemistry 2005.

DOI： 10.1039/b418829b

Inhibitory mechanisms of 1-(3-C-ethynyl-beta-D-RIBO-pentofuranosyl)uracil (EUrd) on RNA synthesis

T Yokogawa, T Naito, H Kanda, S Takatori, K Takenaka, T Sasaki, A Matsuda, M Fukushima, HS Kim, Y Wataya

NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 24 ( 3 ) 227 - 232 2005

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS INC

1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)uracil (EUrd) is an antimetabolite that strongly inhibits RNA synthesis and shows a broad antitumor activity in vitro and in vivo. In mouse mammary tumor FM3A cells, EUrd is sequentially phosphorylated to its 5-triphosphate, EUTP, a major metabolite, and the RNA synthesis is inhibited proportionally to its intracellular accumulation. To study the inhibitory mechanisms of EUrd on RNA synthesis, we have performed the kinetic analysis of EUTP on RNA polymerization using isolated nuclei. RNA synthesis was inhibited competitively by EUTP. The inhibition constant, K-i was much lower than the K-m value of UTP (K-i value of EUTP, 84 nM; K-m value of UTP, 13 μ M), indicating that the high affinity of EUTP could contribute to the specific inhibition of RNA synthesis. As a result of RNA synthesis inhibition, EUrd, but not ara-C, induced shrinkage of nucleoli, which are the main sites for RNA synthesis in FM3A cells. Thus, the strong affinity of E UTP to RNA polymerase and specific inhibition of RNA synthesis could contribute to its antitumor effect. EUrd is expected to be a new antitumor drug, possessing a strong inhibitory effect on the synthesis of RNA.

DOI： 10.1081/NCN-200055727

Sequence analysis of the 5 '-flanking regions of human dihydropyrimidine dehydrogenase gene: Identification of a new polymorphism related with effects of 5-fluorouracil

T Hasegawa, HB Kim, M Fukushima, Y Wataya

NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 24 ( 4 ) 233 - 242 2005

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS INC

Dihydropyrimidine dehydrogenase (DPD), known as a rate-limiting metabolic enzyme in the catabolism of 5 fluorouracil (5-FU), degrades more than about 80% of the administered 5-FU in human liver. Since it was reported that the anticancer effects of 5-FU were observed in cancer patients with lower DPD activities, many attempts have been conducted to anticipate the expected anticancer effects of 5-FU based on expression of intracanceral DPD. It have been reported that 39 different mutations and polymorphisms in the coding regions of DPD genes have been identified; however, there is no report on polymorphisms in the 5'-flanking region of DPD genes. We investigated polymorphisms in the 5'-flanking regions (3,058 bp), which are considered to control expression of DPD genes, in genomic DNA extracted from 37 kinds of human cancer cells. As the results, out of 37 cancer cells subjected to analysis, DLD-1 cells had C insertion and 7 strains G deletion, which were hetelozygote. No significant relationship was identified between the DPD activity and the expression levels of DPD mRNA in examined 70 kinds of human cancer cells. However, in DLD-1 cells, which have C-insertion polymorphism in 5'-flanking region of DPD gene, the DPD activity was below detection limit (<= 0.5 pmol/min/mg protein). Furthermore, 50% of cytosine residue on the CpG site generated by the C insertion was methylated at the 5 position. In this study, we have identified novel polymorphism possibly related the cytotoxicity of 5-FU in the 5'-flanking region of DPD gene. It is suggested that newly identified polymorphism of DPD gene might affect transcription of DPD, thereby providing influence on the clinical outcome of cancer patients treated with 5-FU.

DOI： 10.1081/NCN-200059676

Duffy antigen is important for the lethal effect of the lethal strain of Plasmodium yoelii 17XL. Reviewed International journal

Nobuyoshi Akimitsu, Hye-Sook Kim, Hiroshi Hamamoto, Koushirou Kamura, Nobuko Fukuma, Nagisa Arimitsu, Kanako Ono, Yusuke Wataya, Motomi Torii, Kazuhisa Sekimizu

Parasitology research 93 ( 6 ) 499 - 503 2004.8

Language：English Publishing type：Research paper (scientific journal)

We studied the potential role of the Duffy antigen and glycophorin A as receptors for rodent malaria parasite invasion of erythrocytes. Parasitemia increased exponentially after infection with Plasmodium berghei NK65, P. chabaudi, and P. vinckei in Duffy antigen knockout, glycophorin A knockout, and wild-type mice, indicating that the Duffy antigen and glycophorin A are not essential for these malaria parasites. However, parasitemia of the Duffy antigen knockout mice infected with P. yoelii 17XL remained constant from day 5 to 14 after infection, and then decreased, resulting in autotherapy. The treatment of P. yoelii 17XL-infected Duffy antigen knockout mice with anti-CD4 antibody increased the parasitemia 15 days after infection and the mice eventually died, indicating that CD-4-positive cells play an important role in the clearance of P. yoelii 17XL at the late stage of the infection.

DOI： 10.1007/s00436-004-1165-x

Antimalarial Activity of Lavandulyl Flavanones Isolated from the Roots of Sophora flavescens

KIM Youn Chul, KIM Hye-Sook, WATAYA Yusuke, SOHN Dong Hwan, KANG Tai Hyun, KIM Myung Soo, KIM Yong Man, LEE Geon-Mok, CHANG Jong-Duk, PARK Hyun

Biological and Pharmaceutical Bulletin 27 ( 5 ) 748 - 750 2004.5

Language：English Publisher：The Pharmaceutical Society of Japan

Four lavandulyl flavanones, (2S)-2′-methoxykurarinone (1), sophoraflavanone G (2), leachianone A (3), and (−)-kurarinone (4), which are isolated from the roots of Sophora flavescens have been tested for in vitro antimalarial activity against Plasmodium falciparum. Compounds 1—3 showed moderate antimalarial activities with EC50 values of 2.4×10−6, 2.6×10−6, and 2.1×10−6 M, respectively. These compounds did not show selective toxicity against P. falciparum in the toxicity test on mouse mammalian tumor cells, however, it is suggested that the position of methoxyl groups in flavanone skeleton plays an important role on antimalarial activity.

DOI： 10.1248/bpb.27.748

Other Link： https://jlc.jst.go.jp/DN/JALC/00237416056?from=CiNii

π-Delocalized β-carbolinium cations as potential antimalarials Reviewed

K. Takasu, T. Shimogama, C. Saiin, H.-S. Kim, Y. Wataya, M. Ihara

Bioorganic and Medicinal Chemistry Letters 14 ( 7 ) 1689 - 1692 2004

Genetic analysis of mefloquine-resistant mechanism of Plasmodium falciparum. International journal

Yuko Nishiyama, Yohei Okuda, Hye-Sook Kim, Takahisa Huruta, Mikio Kimura, Yusuke Wataya

Nucleic acids symposium series (2004) ( 48 ) 163 - 4 2004

Language：English Publishing type：Research paper (scientific journal)

We studied DNA sequence polymorphism, expression level of pfmdr1 gene and sensitivity of major antimalarial drugs in both mefloquine sensitive and resistant strains to elucidate mechanism of mefloquine resistance. Mefloquine-resistant 523a R/24 strain exhibited decreased susceptibility to mefloquine, artemisinin and halofantrine whereas increased susceptibility to chloroquine. We found a novel point mutation in pfmdr1 gene of 523a R/24 strain. Moreover, overexpression of mRNA of pfmdr1 has been observed in this strain. In addition, functional analysis by pfmdr1 antisense revealed correlation of mefloquine sensitivity with expression level of pfmdr1. We suggest that gene mutation and overexpression of pfmdr1 may be associated with mechanism of mefloquine resistance.

Antimalarial activity of herbal extracts used in traditional medicine in Korea

H Park, MS Kim, BH Jeon, TK Kim, YM Kim, J Ahnn, DY Kwon, Y Takaya, Y Wataya, HS Kim

BIOLOGICAL & PHARMACEUTICAL BULLETIN 26 ( 11 ) 1623 - 1624 2003.11

Language：English Publishing type：Research paper (scientific journal) Publisher：PHARMACEUTICAL SOC JAPAN

Aqueous extracts of 6 traditional Korean medicines used to treat malaria were tested in vitro for their antimalarial activity against Plasm odium falciparum. The EC50 values for the herbal extracts were in the range 1.4-8.1 mug/ml. Significant antimalarial activity was observed with Coptis japonica (EC50 = 1.4 mug/ml), but it demonstrated no selective toxicity (selectivity = 1). In contrast, Kalopyanax pictus showed antimalarial activity (EC50 = 4.6 mug/ml) and higher selective toxicity (>4). This indicated that K. pictus may be potent for a new antimalarial agent.

DOI： 10.1248/bpb.26.1623

Synthesis of 2-fluoronoraristeromycin and its inhibitory activity against Plasmodium falciparum S-adenosyl-L-homocysteine hydrolase

Y Kitade, H Kojima, F Zulfiqur, HS Kim, Y Wataya

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 13 ( 22 ) 3963 - 3965 2003.11

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Palladium-coupling reaction of (IS, 4 R)-cis-4-acetoxy-2-cyclopenten-1-ol with sodium salt of 2-fluoroadenine resulted in the formation of (IS,4R)-4-(6-amino-2-fluoro-9H-purin-9-yl)cyclopent-2-en-1-ol. Subsequent oxidation was carried out with osmium tetraoxide (OsO4) in the presence of 4-methylmorpholine N-oxide (NMO) to give 2-fluoronoraristeromycin, possessing significant inhibitory activity against recombinant Plasm odium falciparum SAH hydrolase. (C) 2003 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2003.08.074

Unique properties of respiratory chain in Plasmodium falciparum mitochondria

Fumika Mi-Ichi, Satoru Takeo, Eizo Takashima, Tamaki Kobayashi, Hye Sook Kim, Yusuke Wataya, Akira Matsuda, Motomi Torii, Takafumi Tsuboi, Kiyoshi Kita

Advances in Experimental Medicine and Biology 531 117 - 133 2003.9

75(P-65) Creation of New Antimalarials Based on the Quinazoline Alkaloid Febrifugine and Its Metabolites

Kikuchi Haruhisa, Hirai Shingo, Yamamoto Keisuke, Miyazawa Yuriko, Oshima Yoshiteru, Kim Hye-Sook, Wataya Yusuke

Symposium on the Chemistry of Natural Products, symposium papers ( 45 ) 443 - 448 2003.9

Language：Japanese Publisher：Symposium on the chemistry of natural products

Quinazolinone-type alkaloids, febrifugine (1) and isofebrifugine (2), isolated from Dichroa febrifuga roots, show powerful antimalarial activity against Plasmodium falciparum. Unfortunately, their emetic effect and other undesirable side effects have precluded their clinical use in malaria. Due to their antimalarial potency, analogues were searched for, with the goal of preserving the strong antimalarial activity, while dramatically reducing side effects. We expected that compounds useful in drug development would exist in metabolites derived from 1 and Df-1 (3), the condensation product of 1 with acetone, by mouse liver S9. Feb-A and B (5 and 6) were isolated as the major metabolites of 1. In addition to 5 and 6, feb-C and D (7 and 8) were also purified from the metabolic mixture of 3.5 and 6 were compounds oxidized at C-6 and C-2 of the quinazolinone ring of 1, respectively. Compounds 7 and 8, derived from 3, also bear febrifugine-type structures in which 1 were oxidized at C-4" and C-6", respectively. In vitro antimalarial and cytotoxic tests using synthetically obtained racemic 5-7 and enantiomerically pure 8 demonstrated that 5 and 7 had antimalarial activity against P. falciparum, of similar potency to that of 1, with high selectivity. Antimalarial activity of 6 and 8, however, was dramatically decreased in the test. The results suggest that basicity of both the 1 and 1"-nitrogen atoms of 1 is crucial in conferring powerful antimalarial activity. Racemic 5 and 7 exhibited powerful in vivo antimalarial activity against mouse malaria P. berghei, and especially no serious side effects were observed with 5 and 7. Thus, the metabolites 5 and 7 appear to be promising lead compounds for development of new types of antimalarial drugs.

DOI： 10.24496/tennenyuki.45.0_443

Synthesis of antimalarial yingzhaosu a analogues by the peroxidation of dienes with Co(II)/O-2/Et3SiH

T Tokuyasu, S Kunikawa, M Abe, A Masuyama, M Nojima, HS Kim, K Begum, Y Wataya

JOURNAL OF ORGANIC CHEMISTRY 68 ( 19 ) 7361 - 7367 2003.9

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER CHEMICAL SOC

Co(II)-catalyzed peroxidation of dienes including (S)-limonene in the presence of molecular oxygen and triethylsilane provided in each case the corresponding 2,3-dioxabicyclo[3.3.1] nonane derivatives via the intramolecular cyclization of the unsaturated peroxy radical intermediates. The product composition was remarkably influenced by the structure of the dienes, the nature of the solvents, and the concentration of the substrates and the catalyst. Some of the yingzhaosu A analogues obtained in this study showed notable antimalarial activities in vitro.

DOI： 10.1021/jo030107

Metabolites of febrifugine and its synthetic analogue by mouse liver S9 and their antimalarial activity against Plasmodium malaria parasite

S Hirai, H Kikuchi, HS Kim, K Begum, Y Wataya, H Tasaka, Y Miyazawa, K Yamamoto, Y Oshima

JOURNAL OF MEDICINAL CHEMISTRY 46 ( 20 ) 4351 - 4359 2003.9

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER CHEMICAL SOC

Quinazolinone type alkaloids, febrifugine (1) and isofebrifugine (2), isolated from Dichroa febrifuga roots, show powerful antimalarial activity against Plasmodium falciparum. Unfortunately, their emetic effect and other undesirable side effects have precluded their clinical use for malaria. Because of their antimalarial potency, analogues were searched for, with the goal of preserving the strong antimalarial activity, while dramatically reducing side effects. We expected that compounds useful in drug development would exist in metabolites derived from I and Df-1 (3), the condensation product of 1 with acetone, by mouse liver S9. Feb-A and -B (4 and 5) were isolated as the major metabolites of 1. In addition to 4 and 5, feb-C and -D (6 and 7) were also purified from the metabolic mixture of 3. Compounds 4 and 5 were compounds oxidized at C-6 and C-2 of the quinazolinone ring of 1, respectively. Compounds 6 and 7, derived from 3, also bear febrifugine type structures in which the 4"- and 6"-positions of the piperidine ring of 1 were oxidized. In vitro antimalarial. and cytotoxic tests using synthetically obtained racemic 4-6 and enantiomerically pure 7 demonstrated that 4 and 6 had antimalarial activity against P. falciparum, of similar potency to that of 1, with high selectivity. The antimalarial. activity of 5 and 7, however, was dramatically decreased in the test. The in vitro antimalarial activity of analogues 22 and 43, which are stereoisomers of 4 and 6, was also evaluated, showing that 22 is active. The results suggest that basicity of both the 1- and the 1"-nitrogen atoms of 1 is crucial in conferring powerful antimalarial activity. Racemic 4 and 6 exhibited powerful in vivo antimalarial activity against mouse malaria P. berghei, and especially, no serious side effects were observed with 4. Thus, the metabolite 4 appears to be a promising lead compound for the development of new types of antimalarial drugs.

DOI： 10.1021/jjm0302086

In vitro antimalarial activity of metalloporphyrins against Plasmodium falciparum

K Begum, HS Kim, Kumar, V, Stojiljkovic, I, Y Wataya

PARASITOLOGY RESEARCH 90 ( 3 ) 221 - 224 2003.6

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER-VERLAG

The in vitro antimalarial activity against Plasmodium falciparum and heme polymerization were evaluated for ten metalloporphyrins: gallium protoporphyrin IX (GaPPIX), sodium salt of gallium protoporphyrin IX, silver protoporphyrin IX, palladium protoporphyrin IX, cobalt protoporphyrin IX, manganese protoporphyrin IX, tin protoporphyrin IX (SnPPIX), chromium protoporphyrin IX, gallium deuteroporphyrin IX (GaDPIX) and gallium hematoporphyrin IX. Metalloporphyrins inhibited parasite growth with 50% inhibitory concentrations (IC50) ranging from 15.5 muM to 190 muM. In trophozoite lysate-mediated heme polymerization assays, SnPPIX, GaPPIX and GaDPIX exerted potent inhibitory activity similar to that of artemisinin and chloroquine.

DOI： 10.1007/s00436-003-0830-9

In vitro antiplasmodial activity of antimalarial medicinal plants used in Vietnamese traditional medicine

Q Le Tran, Y Tezuka, JY Ueda, NT Nguyen, Y Maruyama, K Begum, HS Kim, Y Wataya, QK Tran, S Kadota

JOURNAL OF ETHNOPHARMACOLOGY 86 ( 2-3 ) 249 - 252 2003.6

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Among 42 extracts, prepared from 14 medicinal plants used in Vietnamese traditional medicine to treat malaria, 24 were found to have antiplasmodial activity by inhibiting the growth of the chloroquine-resistant Plasmodium falciparum strain FCR-3 with EC50 values less than 10 mug/ml. Each medicinal plant possessed at least one active extract. The methanol extract of Coscinium fenestratum had the strongest antiplasmodial activity with EC50 value of 0.5 mug/ml. Activity-guided fractionation led to identification of berberine as the major active constituent. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.

DOI： 10.1016/S0378-8741(03)00045-X

Parallel synthesis of antimalarial rhodacyanine dyes by the combination of three components in one pot

K Takasu, H Terauchi, H Inoue, HS Kim, Y Wataya, M Ihara

JOURNAL OF COMBINATORIAL CHEMISTRY 5 ( 3 ) 211 - 214 2003.5

Antimalarial activity of novel 1,2,5,6-tetraoxacycloalkanes and 1,2,5-trioxacycloalkanes

HS Kim, E Begum, N Ogura, Y Wataya, Y Nonami, T Ito, A Masuyama, M Nojima, KJ McCullough

JOURNAL OF MEDICINAL CHEMISTRY 46 ( 10 ) 1957 - 1961 2003.5

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER CHEMICAL SOC

Photooxygenation of 2-phenylnorbornene 1 in the presence of 30% aqueous hydrogen peroxide afforded 1,2-bishydroperoxide 3, which could be cycloalkylated on treatment with silver oxide and a 1,omega-diiodoalkane to provide the tricyclic peroxides 12. Trimethylsilylation of 3 followed by TMSOTf-catalyzed cyclocondensation with carbonyl compounds led to the formation of the tricyclic peroxides 14 containing a 1,2,4,5-tetroxepane structure. Photooxygenation of 1 in the presence of either unsaturated hydroperoxides or unsaturated alcohols followed by bis(collidine)iodine hexafluorophosphate promoted cyclization gave the corresponding cyclic peroxides 15-17. Several of these cyclic peroxides showed substantial antimalarial activity particularly in vitro.

DOI： 10.1021/jm020387b

New semisynthetic quassinoids with in vivo antimalarial activity

N Murakami, M Sugimoto, M Kawanishi, S Tamura, HS Kim, K Begum, Y Wataya, M Kobayashi

JOURNAL OF MEDICINAL CHEMISTRY 46 ( 4 ) 638 - 641 2003.2

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER CHEMICAL SOC

On the basis of a comparative analysis for stability in mouse serum between 15-O-acetylbruceolide and bruceolide 15-methyl carbonate, several 3,15-dialkyl carbonates of bruceolide were synthesized and their in vitro antimalarial activity was assessed. Methyl, ethyl, and isopropyl carbonates with pronounced in vitro activity were further evaluated for in vivo antimalarial potency. Both the methyl and ethyl carbonates significantly increased the life span of mice as compared with 3,15-di-O-accetylbruceolide and chloroquine.

DOI： 10.1021/jm0201971

Transformation of Cinchona alkaloids into 1-N-oxide derivatives by endophytic Xylaria sp isolated from Cinchona pubescens

H Shibuya, C Kitamura, S Maehara, M Nagahata, H Winarno, P Simanjuntak, HS Kim, Y Wataya, K Ohashi

CHEMICAL & PHARMACEUTICAL BULLETIN 51 ( 1 ) 71 - 74 2003.1

Language：English Publishing type：Research paper (scientific journal) Publisher：PHARMACEUTICAL SOC JAPAN

The microbial transformation of four Cinchona alkaloids (quinine, quinidine, cinchonidine, and cinchonine) by endophytic fungi isolated from Cinchona pubescens was investigated. The endophytic filamentous fungus Xylaria sp. was found to transform the Cinchona alkaloids into their 1-N-oxide derivatives.

DOI： 10.1248/cpb.51.71

Acute disseminated encephalomyelitis following Plasmodium vivax malaria

Tomohiko Koibuchi, Tetsuya Nakamura, Toshiyuki Miura, Tokiomi Endo, Hitomi Nakamura, Takashi Takahashi, Hye-Sook Kim, Yusuke Wataya, Kazushige Washizaki, Kouki Yoshikawa, Aikichi Iwamoto

Journal of Infection and Chemotherapy 9 ( 3 ) 254 - 256 2003

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Japan

A 24-year-old Japanese man showed neurological disturbances 2 weeks after complete recovery from Plasmodium vivax infection. Magnetic resonance (MR) images of the brain showed multiple high-intensity spotty lesions in the left cerebral cortex and subcortex. Cerebrospinal fluid examination, including polymerase chain reaction analysis for viruses, revealed no sign of active infection. Repeated blood smears were negative for malaria. We diagnosed acute disseminated encephalomyelitis (ADEM) following Plasmodium vivax malaria from the clinical course and MR images. ADEM should be regarded as one of the neurological complications after malarial infection.

DOI： 10.1007/s10156-003-0244-8

Synthesis of carbocyclic and acyclic nucleosides possessing 2-fluoroadenine derivatives and their inhibitory activities against Plasmodium falciparum SAH hydrolase.

Yukio Kitade, Hiroharu Kojima, Fazila Zulfiqur, Saori Yabe, Daisuke Yamagiwa, Yasutomo Ito, Masayuki Nakanishi, Yoshihito Ueno, Hye-Sook Kim, Yusuke Wataya

Nucleic acids research. Supplement (2001) ( 3 ) 5 - 6 2003

Language：English Publishing type：Research paper (scientific journal)

Carbocyclic and acyclic nucleosides possessing 2-fluoroadenine, such as 2-fluoronoraristeromycin (6) and 2-fluoro-9-[(2S,3R)-2,3,4-trihydroxy-butyl-1-yl]adenine (8), were synthesized and their inhibitory activities against human and Plasmodium falciparum recombinant SAH hydrolase were investigated.

DOI： 10.1093/nass/3.1.5

Iron(II)-promoted rearrangement of 1,4-diaryl-2,3-dioxabicyclo[2.2.2]oct-5-enes: a mechanism distinct from that postulated previously

M Kamata, C Satoh, HS Kim, Y Wataya

TETRAHEDRON LETTERS 43 ( 46 ) 8313 - 8317 2002.11

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Reactions of 1,4-diaryl-2,3-dioxabicyclo[2.2.2]oct-5-enes 1a-c (la: Ar=p-FC6H4, 1b: Ar=C6H5 1c: Ar=p-MeC6H4) with FeBr2 afforded syn-1,2;3,4-bis(epoxy)-1,4-diarylcyclohcxanes 4a-c and cis-3,6-diaryl-2,3-epoxycyclohexanones 5a-c as major products instead of the previously reported 1-aroyl-3-aryl-2,3-epoxycyclopentanes 2a-c. (C) 2002 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0040-4039(02)02024-5

Antimalarial activity of yingzhaosu A analogues

HS Kim, H Begum, N Ogura, Y Wataya, T Tokuyasu, A Masuyama, M Nojima, KJ McCullough

JOURNAL OF MEDICINAL CHEMISTRY 45 ( 21 ) 4732 - 4736 2002.10

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER CHEMICAL SOC

Iodonium ion mediated cyclization of unsaturated hydroperoxides 1 afforded the expected yingzhaosu A analogues 2. In some cases, however, the corresponding cyclic ethers 5 were formed competitively with the cyclic peroxides 2, the ratios of these two products being a marked function of the structure of the starting materials. Some of the cyclic peroxides 2 showed significant antimalarial activities in vitro and in vivo.

DOI： 10.1021/jm020208q

Potent antimalarial febrifugine analogues against the Plasmodium malaria parasite

H Kikuchi, H Tasaka, S Hirai, Y Takaya, Y Iwabuchi, H Ooi, S Hatakeyama, HS Kim, Y Wataya, Y Oshima

JOURNAL OF MEDICINAL CHEMISTRY 45 ( 12 ) 2563 - 2570 2002.6

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER CHEMICAL SOC

Although febrifugine (1) and isofebrifugine (2), alkaloids isolated from roots of the Dichroa febrifuga plant, show powerful antimalarial activity against Plasmodium falciparum, strong side effects such as the emetic effect have precluded their clinical use against malaria. However, their antimalarial potency makes them attractive substances as leads for developing new types of chemotherapeutic antimalarial drugs. Thus, we have evaluated the in vitro antimalarial activity of the analogues of febrifugine (1) and isofebrifugine (2). The activities of the analogues derived from Df-1 (3) and Df-2 (4), condensation products of 1 and 2 with acetone, respectively, were also obtained. The 3"-keto derivative (7, EC50 = 2.0 x 10(-8) M) of 1 was found to exhibit potential antimalarial activity with high selectivity against P. falciparum in vitro. The in vitro activities of the reduction product (8, EC50 = 2.0 x 10-8 M) of 1 at C-2' and its cyclic derivatives 9 and 10 (EC50 = 3.7 x 10(-9) and 8.6 x 10(-9) M, respectively) were found to be strongly active and selective. Additionally, the Dess-Martin oxidation product of 3 was found to be strongly active with high selectivity against P. falciparum. A structure-activity relationship study (SAR) demonstrates that the essential role played by the 4-quinazolinone ring in the appearance of activity and the presence of a 1"-amino group and C-2', C-3" O-functionalities are crucial in the activity of 1. For 7, 8, and 9, prepared as racemic forms, an in vivo study has also been conducted.

DOI： 10.1021/jm010448q

Synthesis and notable antimalarial activity of acyclic peroxides, 1-(alkyldioxy)-1-(methyldioxy)cyclododecanes

Y Hamada, H Tokuhara, A Masuyama, M Nojima, HS Kim, K Ono, N Ogura, Y Wataya

JOURNAL OF MEDICINAL CHEMISTRY 45 ( 6 ) 1374 - 1378 2002.3

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER CHEMICAL SOC

Of several bis(alkyldioxy)alkanes and the related acyclic peroxides prepared in this study, 1,1-bis(methyldioxy)cyclododecane showed the most notable antimalarial activity particularly in vivo (almost a half of that of artemisinin).

DOI： 10.1021/jm010473w

Synthesis, Fe(II)-induced degradation, and antimalarial activities of 1,5-diaryl-6,7-dioxabicyclo[3.2.2]nonanes: direct evidence for nucleophilic O-1,2-aryl shifts

M Kamata, M Ohta, K Komatsu, HS Kim, Y Wataya

TETRAHEDRON LETTERS 43 ( 11 ) 2063 - 2067 2002.3

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

1,5-Diaryt-6.7-dioxabicyclo[3.2.2]nonanes 1a-d (1a: Ar=p-FC6H4, 1b: Ar=Ph. 1e: Ar=p-MeC6H4. 1d: Ar=pMeOC(6)H(4)) were prepared by a modified method of photo-electron transfer oxygenation. and the reactions of 1 with FeBr2 were investigated under various conditions. The Fe(Il)-induced degradation of 1 afforded various rearrangement products and fragmentation products through competitive single electron transfer (SET) and Lewis acid pathways. Direct evidence for the O-1,2-aryl shift was obtained by the isolation of rearrangement products. 1-aryloxy-5-aryl-8-oxabicyclo[3.2.1]octanes 8. The degradation mechanism was proposed and the in vitro antimalarial activities were also evaluated. (C) 2002 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0040-4039(02)00166-1

New Neplanocin Analogues. 12. Alternative Synthesis and Antimalarial Effect of (6‘R)-6‘-C-Methylneplanocin A, a Potent AdoHcy Hydrolase Inhibitor

Satoshi Shuto, Noriaki Minakawa, Satoshi Niizuma, Hye-Sook Kim, Yusuke Wataya, Akira Matsuda

Journal of Medicinal Chemistry 45 ( 3 ) 748 - 751 2002.1

Fe(II)-mediated fragmentation of 1,4-diaryl-2,3-dioxabicyclo[2.2.2]octanes through competitive single electron transfer pathway and Lewis acid pathway

M Kamata, T Kudoh, J Kaneko, HS Kim, Y Wataya

TETRAHEDRON LETTERS 43 ( 4 ) 617 - 620 2002.1

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Reactions of 1, 4-diaryl-2,3-dioxabicyclo[2.2.2]octanes 1a-d (1a: Ar=p-FC6H4, 1b: Ar=Ph, 1e: Ar=p-MeC6H4, 1d: Ar=p-MeOC6H4) with FeBr2 in THF afforded 1,4-diarylbutan-1,4-diones 2a-d and 1,4-diaryl-7-oxabicyclo[2.2.1]heptanes 3a d. On the other hand, 4-aryl-3-cyclohexenones 4c-d and p-substituted phenols 5c-d were obtained in the reactions of 1c-d with FeBr2 in CH2Cl2. A new fragmentation mechanism involving an electrophilic oxyl radical 1,5-substitution and a nucleophilic O-1,2-aryl shift is proposed based on the product analysis. In addition, the in vitro antimalarial activities of 1a-d were tested. (C) 2002 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0040-4039(01)02201-8

Rhodacyanine dyes as antimalarials. 1. Preliminary evaluation of their activity and toxicity Reviewed

K. Takasu, H. Inoue, H.-S. Kim, M. Suzuki, T. Shishido, Y. Wataya, M. Ihara

Journal of Medicinal Chemistry 45 ( 5 ) 995 - 998 2002

Mechanisms of cell death induced by 5-fluoro-2'-deoxyuridine (FUdR)--necrosis or apoptosis after treated with FUdR.

Yusuke Uchikubo, Takako Hasegawa, Saeko Mitani, Hye-Sook Kim, Yusuke Wataya

Nucleic acids research. Supplement (2001) ( 2 ) 245 - 246 2002

Language：English Publishing type：Research paper (scientific journal)

5-Fluoro-2'-deoxyuridine (FUdR) inhibits thymidylate synthase (TS). The inhibition of TS causes an imbalance of intracellular deoxyribonucleoside triphosphate (dNTP) pools which subsequently induced cell death. We investigated the molecular mechanisms of cell death after treated with FUdR in F28-7 strain (which induced necrosis) and F28-7-A strain (mutant of F28-7 strain which induced apoptosis). After treated with FUdR, we observed different size of DNA fragmentations. F28-7 strain induced DNA cleavaged into 100-200 kbp fragments and F28-7-A strain induced DNA cleavaged into oligonucleosomal sized fragments. In F28-7 strain, FUdR induced the increased mRNA level of c-jun, c-fos and c-myc genes, caspase-3 like protease activity and the changes of mitochondrial membrane potential which were greater and earlier than those of F28-7-A strain. On the other hand, F28-7-A strain induced release of cytochrome c from mitochondrial, but not F28-7 strain. Furthermore, caspase-5 inhibitor was strongly inhibited the cell death of F28-7 strain. We suggest that it is concerned with intensity of intracellular signals in the cell death of F28-7 strain and F28-7-A strain.

DOI： 10.1093/nass/2.1.245

Genomic analysis of mefloquine-resistant Plasmodium falciparum. International journal

Khurshida Begum, Hye-Sook Kim, Yohei Okuda, Yusuke Wataya, Mikio Kimura, Takahisa Huruta

Nucleic acids research. Supplement (2001) ( 2 ) 223 - 4 2002

Language：English Publishing type：Research paper (scientific journal)

We studied sequence polymorphism, expression level of pfmdr1 gene and drug sensitivity in mefloquine sensitive-strain as well as mefloquine-resistant clone/24 to understand underlying drug resistance mechanism. Mefloquine-resistant clone/24 exhibited decreased susceptibility to mefloquine, quinine, halofantrine and artemisinin and increased susceptibility to chloroquine. We analyzed sequence of pfmdr1 gene and found mutation in pfmdr1 on clone/24. Moreover, overexpression of mRNA level of pfmdr1 has been observed in mefloquine-resistant clone/24. Our results explain gene mutation and expression level of pfmdr1 may be associated in mefloquine resistance mechanism.

Simple isoquinoline and benzylisoquinoline alkaloids as potential antimicrobial, antimalarial, cytotoxic, and anti-HIV agents

K Iwasa, M Moriyasu, Y Tachibana, HS Kim, Y Wataya, W Wiegrebe, KF Bastow, LM Cosentino, M Kozuka, KH Lee

BIOORGANIC & MEDICINAL CHEMISTRY 9 ( 11 ) 2871 - 2884 2001.11

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Twenty-six simple isoquinolines and 21 benzylisoquinolines were tested for antimicrobial, antimalarial, cytotoxic, and anti-HIV activities. Some simple isoquinoline alkaloids were significantly active in each assay, and may be useful as lead compounds for developing potential chemotherapeutic agents. These compounds include 13 (antimicrobial), 25, 26, and 42 (antimalarial), 13 and 25 (cytotoxic), and 28 and 29 (anti-HIV). A quaternary nitrogen atom of isoquinolium or dihydroisoquinolinium type may contribute to enhanced potency in the first three types of activities. In contrast, anti-HIV activity was found with tetrahydroisoquinoline and 6,7-dihydroxyisoquinolium salts. (C) 2001 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0968-0896(01)00154-7

Synthesis and antimalarial activity of novel medium-sized 1,2,4,5-tetraoxacycloalkanes

HS Kim, Y Nagai, K Ono, K Begum, Y Wataya, Y Hamada, K Tsuchiya, A Masuyama, M Nojima, KJ McCullough

JOURNAL OF MEDICINAL CHEMISTRY 44 ( 14 ) 2357 - 2361 2001.7

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER CHEMICAL SOC

CsOH- or Ag2O-mediated cycloalkylation of (alkylidene)bisperoxides 3 and 1,n.-dihaloalkanes (n = 3-8) provided the corresponding medium-sized 1,2,4,5-tetraoxacycloalkanes 4-8 in moderate yields. Subsequent evaluation of the antimalarial activity of the cyclic peroxides 4-8 in vitro and in vivo revealed that 1,2,6,7-tetraoxaspiro [7.11]nonadecane 4a has considerable potential as a new, inexpensive, and potent antimalarial drug.

DOI： 10.1021/jm010026g

Yingzhaosu A analogues: synthesis by the ozonolysis of unsaturated hydroperoxides, structural analysis and determination of anti-malarial activity

T Tokuyasu, A Masuyama, M Nojima, KJ McCullough, HS Kim, Y Wataya

TETRAHEDRON 57 ( 28 ) 5979 - 5989 2001.7

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Ozone-mediated cyclization of a series of unsaturated hydroperoxides 7, prepared from dienes 2, afforded the corresponding yingzhaosu A analogues 9 in moderate to high yield. X-Ray crystallographic analysis of two yingzhaosu A analogues, endo-9f and 13, showed that the 2,3-dioxabicyclo[3,3,1]nonane system adopts a chair-boat arrangement. Subsequent treatment of endoperoxides 9 with Ag2O/MeI afforded the expected methyldioxy-substituted cyclic peroxides 14, several of which showed notable anti-malarial activity against P. falciparum in vitro. (C) 2001 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0040-4020(01)00557-9

Synthesis and antimalarial activity of febrifugine derivatives

Y Takeuchi, M Koike, K Azuma, H Nishioka, H Abe, HS Kim, Y Wataya, T Harayama

CHEMICAL & PHARMACEUTICAL BULLETIN 49 ( 6 ) 721 - 725 2001.6

Language：English Publishing type：Research paper (scientific journal) Publisher：PHARMACEUTICAL SOC JAPAN

The regioisomers (2a,b) of the piperidine ring of febrifugine (1a) and isofebrifugine (1b) were synthesized from 4-allyl-3-piperidone (5). Reduction of 5 afforded a mixture of the trans and cis alcohols (6a,b) without diastereoselectivity: this result differentiated it from the reduction of 2-allyl-3-piperidone (14), The antimalarial activity of 2a,b and related compounds was tested.

DOI： 10.1248/cpb.49.721

Antimalarial and cytotoxic activities of bicycle[6.4.0] dodecenones

H Fujishima, H Takeshita, M Toyota, HS Kim, Y Wataya, M Tanaka, T Sasaki, M Ihara

CHEMICAL & PHARMACEUTICAL BULLETIN 49 ( 5 ) 572 - 575 2001.5

Language：English Publishing type：Research paper (scientific journal) Publisher：PHARMACEUTICAL SOC JAPAN

Biological evaluations of bicyclo[6.4.0]dodecenone derivatives on antimalarial activity in vitro against Plasmodium falciparum and cytotoxicity against human KB cells were made. (+/-)-(1R*,4S*,7R*,8S*)-4-tert-Butyl-dimethylsiloxy-5,5-dimethlyl-1-methyl-9-methylene-7-phenylbicyclo[6.4.0]dodec-2,11-dien-10-10-one (15) exhibited potent antimalarial activity, whereas (+/-)-(1R*,7R*,8S*)-1-methyl-9-methylene-7-phenylsulfonybicyclo-[6.4.0]dodec-2,11-dien-10-one (14) showed significant cytotoxic activity in human KB cells. Both 14 and 15 possess, as a structural character, the exo-methylene moiety in their 6-membered ring of the 8-6 fused ring system.

DOI： 10.1248/cpb.49.572

A homologue of N-ethylmaleimide-sensitive factor in the malaria parasite Plasmodium falciparum is exported and localized in vesicular structures in the cytoplasm of infected erythrocytes in the brefeldin A-sensitive pathway

M Hayashi, S Taniguchi, Y Ishizuka, HS Kim, Y Wataya, A Yamamoto, Y Moriyama

JOURNAL OF BIOLOGICAL CHEMISTRY 276 ( 18 ) 15249 - 15255 2001.5

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

N-Ethylmaleimide-sensitive factor (NSF) and its homologues play a central role in vesicular trafficking in eukaryotic cells. We have identified a NSF homologue in Plasmodium falciparum (PfNSF), The reported PfNSF gene sequence (GenBank(TM) accession number CAB10575) indicated that PfNSF comprises 783 amino acids with a calculated molecular weight of 89,133, The overall identities of its gene and amino acid sequences with those of rat NSF are 50.9 and 48.8%, respectively. Reverse transcription-polymerase chain reaction analysis and Northern blotting with total P, falciparum RNA indicated expression of the PfNSF gene. Polyclonal. antibodies against a conserved region of NSF specifically recognized an 89-kDa polypeptide in the parasite cells. After homogenization of the parasite cells, similar to 90% of an 89-kDa polypeptide is associated with particulate fraction, suggesting membrane-bound nature of PfNSF. PfNSF was present within both the parasite cells and the vesicular structure outside of the parasite cells, The export of PfNSF outside of the parasite cells appears to occur at the early trophozoite stage and to terminate at the merozoite stage. The export of PfNSF is inhibited by brefeldin A, with 9 muM causing 50% inhibition. Immuno-electromicroscopy indicated that intracellular PfNSF was associated with organelles such as food vacuoles and that extracellular PfNSF was associated with vesicular structures in the erythrocyte cytoplasm, These results indicate that PfNSF expressed in the malaria parasite is exported to the extracellular space and then localized in intraerythrocytic vesicles in a brefeldin A-sensitive manner. It is suggested that a vesicular transport mechanism is involved in protein export targeted to erythrocyte membranes during intraerythrocytic development of the malaria parasite.

DOI： 10.1074/jbc.M011709200

Synthesis of a novel artemisinin analogue having potent antimalarial activity

K Takasu, R Katagiri, Y Tanaka, M Toyota, HS Kim, Y Wataya, M Ihara

HETEROCYCLES 54 ( 2 ) 607 - + 2001.2

Asymmetric synthesis of (+)-febrifugine and (+)-isofebrifugine using yeast reduction

Y Takeuchi, K Azuma, K Takakura, H Abe, HS Kim, Y Wataya, T Harayama

TETRAHEDRON 57 ( 7 ) 1213 - 1218 2001.2

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

The antimalarial agents febrifugine (D-1) and isofebrifugine (D-2) were synthesized from chiral 3-piperidinol (D-4), which was asymmetrically prepared by the yeast reduction of 3-piperidone derivatives (DL-3), with dynamic optical resolution. (C) 2001 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0040-4020(00)01109-1

P200 Development of new antimalarial drugs : in vitro and in vivo antimalarial activity of endoperoxides

ONO Kanako, OGURA Naoki, KIM HyeSook, BEGUM Khurshida, HAMADA Yoshiaki, NONAMI Yuji, TOKUYASU Takahiro, Masuyama Araki, NOJIMA Masatomo, WATAYA Yusuke

Medical Entomology and Zoology 52 127 - 127 2001

P197W7-6 Antimalarial drug discovery research in Japan

WATAYA Yusuke, KIM HyeSook

Medical Entomology and Zoology 52 127 - 127 2001

69(P-55) Exploring a New Type of Antimalarials Based on the Plant Quinazolinoid, Febrifugine

Takaya Yoshiaki, Tasaka Hidehisa, Hirai Shingo, Oshima Yoshiteru, Iwabuchi Yoshiyasu, Hatakeyama Susumi, Kim Hye-Sook, Wataya Yusuke, Fukushima Masakazu

Symposium on the Chemistry of Natural Products, symposium papers ( 42 ) 409 - 414 2000.10

Language：Japanese Publisher：Symposium on the chemistry of natural products

Febrifugine (1) and isofebrifugine (2), isolated from the roots of Dichroa febrifuga Lour. (Chinese name: Chang Shan) are active principles against malaria. Clinical testing of febrifugine (1) was not successful, and the results of clinical evaluation are not yet available. To reinvestigate the antimalarial activity of these compounds, and to get functional informations to exhibit the activity, we set about studying febrifugine and its analogues. Adducts of febrifugine (1) and isofebrifugine (2) with acetone, Df-1 (3) and Df-2 (4), respectively, were obtained using silica gel and acetone. They showed high activity against P. falciparum malaria in vitro. Structure-activity relationships (SAR) studies on the antimalarial activity of febrifugine-analogues revealed that 4-quinazolinone moiety along with 1'-ketone, 5'-N atom and 9'-O-function are necessary to exhibit antimalarial activity. Moreover, Df-1 (3) was found to be equally effective to P. berghei in vivo as the clinically used drug chloroquine, whereas 4 showed only 1/24 activity of 3. Whole blood concentration of Df-2 (4) decreased more rapidly than that of Df-1 (3). This finding was accounted by the metabolism studies of these compounds by using S-9 mix prepared from mouse liver. Df-2 (4) was readily metabolized in mouse liver. Accordingly, the dose of Df-2 (4) must be higher than that of Df-1 (3) to attain blood levels sufficient for a favorable therapeutic effect.

DOI： 10.24496/tennenyuki.42.0_409

Novel guaiane endoperoxides, nardoguaianone A-D, from Nardostachys chinensis roots and their antinociceptive and antimalarial activities

Y Takaya, Y Takeuji, M Akasaka, O Nakagawasai, T Tadano, K Kisara, HS Kim, Y Wataya, M Niwa, Y Oshima

TETRAHEDRON 56 ( 39 ) 7673 - 7678 2000.9

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Four novel guaianoids, nardoguaianone A, B, C and D, were isolated from Nardostachys chinensis roots. The structures were elucidated by spectral means and chemical transformation. Antinociceptive activities of the constituents of N. chinensis, including some of the above novel compounds, were investigated by the formalin test. As a result, it was revealed that nardoguaianone A and D showed activity at the second phase of pain induced by formalin injection. (C) 2000 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0040-4020(00)00681-5

Synthesis of novel ferrocenyl sugars and their antimalarial activities

T Itoh, S Shirakami, N Ishida, Y Yamashita, T Yoshida, HS Kim, Y Wataya

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 10 ( 15 ) 1657 - 1659 2000.8

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

The synthesis of twelve types of novel ferrocenyl sugars and their biological properties towards the malaria parasite (P. falciparum) and mouse cancer cell (FM3A) are described. (C) 2000 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0960-894X(00)00313-9

Synthesis, crystal structure and antimalarial activity of functionalized spiro-1,2,4,5-tetraoxacycloalkanes from unsaturated hydroperoxy peracetals

Y Nonami, T Tokuyasu, A Masuyama, M Nojima, KJ McCullough, HS Kim, Y Wataya

TETRAHEDRON LETTERS 41 ( 23 ) 4681 - 4684 2000.6

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Treatment of unsaturated hydroperoxy peracetals with bis(sym-collidine)iodine(I) hexafluorophosphate affords a series of iodine-containing spiro-1,2,4,5-tetraoxacycloalkane derivatives in high yield. In addition, ozonolysis of unsaturated hydroperoxy peracetals in AcOH-CH2Cl2 also results in the formation of spirol,2,4,5-tetraoxacycloalkanes. Two of the new compounds, 3-methyl-3-methyldioxy-1,2,6,7-tetraoxaspiro[7.11]nonadecane and dimethyl-4-iodo-1,2,6,7-tetraoxaspiro[7.11]nonadecane, exhibit significant in vitro antimalarial activity against P. falciparum with EC50 values of ca. 10(-7) M. (C) 2000 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0040-4039(00)00688-2

Synthesis and anti-malarial activity of yingzhaosu A analogues from unsaturated hydroperoxy acetals

T Tokuyasu, A Masuyama, M Nojima, HS Kim, Y Wataya

TETRAHEDRON LETTERS 41 ( 17 ) 3145 - 3148 2000.4

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Ozonolysis of a vinyl ether 2, prepared from dihydrocarvone 1 (a 1:4 mixture of cis- and trans-isomer), in methanol gave two isomeric unsaturated hydroperoxy acetals cis- and trans-3. Iodonium ion- or ozone-mediated cyclizations of the hydroperoxide cis-3 gave the corresponding yingzhaosu A analogues 4 and 6 in moderate yields. The peroxide 8, obtained by the Ag2O-mediated methylation of 6, showed notable anti-malarial activity in vitro (IC50=1.0x10(-7) M). (C) 2000 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0040-4039(00)00372-5

Potent in vivo antimalarial activity of 3,15-di-O-acetylbruceolide against Plasmodium berghei infection in mice

Hye-Sook Kim, Yasuharu Shibata, Naoko Ko, Naomi Ikemoto, Yuki Ishizuka, Nobutoshi Murakami, Masanori Sugimoto, Motomasa Kobayashi, Yusuke Wataya

Parasitology International 48 ( 3 ) 271 - 274 2000.1

Language：English

The antimalarial activity of the O-acylated bruceolide derivative, 3,15-di-O-acetylbruceolide, was evaluated against Plasmodium berghei in vivo. The concentration of 3,15-di-O-acetylbruceolide required for 50% suppression (ED50) of P. berghei in mice was 0.46±0.06 mg/kg/day, whereas bruceolide was only half as effective as 3,15-di-O-acetylbruceolide. Two antimalarial drugs used clinically, chloroquine and artemisinin, demonstrated only low activity corresponding to 1/4 and 1/12 of the ED50 value of 3,15-di-O-acetylbruceolide, respectively. These results may be helpful in the design of better chemotherapeutic bruceolides against falciparum malaria. Copyright (C) 2000 Elsevier Science Ireland Ltd.

DOI： 10.1016/S1383-5769(99)00023-9

Synthesis, crystal structure and antimalarial activity of novel 1,2,5,6-tetraoxacycloalkanes from 2,3-dihydroperoxy-2-phenylnorbornane

Kevin J. McCullough, Yuji Nonami, Araki Masuyama, Masatomo Nojima, Hye-Sook Kim, Yusuke Wataya

Tetrahedron Letters 40 ( 51 ) 9151 - 9155 1999.12

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier Ltd

Photooxygenation of 2-phenylnorbornene 1 in the presence of 30% aqueous hydrogen peroxide in acetonitrile afforded the labile 1,2-bis-hydroperoxide 3 which could be cycloalkylated to provide the tricyclic peroxides 5, albeit in low yield, on treatment with silver oxide and a 1,ω-diiodoalkane. Trimethylsilylation of 3, followed by TMSOTf-catalyzed cyclocondensation with carbonyl compounds led to the formation of the tricyclic peroxides 8 containing a 1,2,4,5-tetroxepane structure. The structures of two novel tricyclic peroxides 5a and 8a were unambiguously determined by the X-ray crystallographic analysis.

DOI： 10.1016/S0040-4039(99)01944-9

Structure-activity relationships of quaternary protoberberine alkaloids having an antimalarial activity

Kinuko Iwasa, Yumi Nishiyama, Momoyo Ichimaru, Masataka Moriyasu, Hye-Sook Kim, Yusuke Wataya, Takao Yamori, Turuo Takashi, Dong-Ung Lee

European Journal of Medicinal Chemistry 34 ( 12 ) 1077 - 1083 1999.12

Catalytic Asymmetric Synthesis of Antimalarial Alkaloids Febrifugine and Isofebrifugine and Their Biological Activity. Reviewed

Shu Kobayashi, Masaharu Ueno, Ritsu Suzuki, Haruro Ishitani, Hye-Sook Kim, Yusuke Wataya

The Journal of Organic Chemistry Vol.64 ( No.18 ) 6833 - 6841 1999.9

New type of febrifugine analogues, bearing a quinolizidine moiety, show potent antimalarial activity against Plasmodium malaria parasite

Y Takaya, H Tasaka, T Chiba, K Uwai, M Tanitsu, HS Kim, Y Wataya, M Miura, M Takeshita, Y Oshima

JOURNAL OF MEDICINAL CHEMISTRY 42 ( 16 ) 3163 - 3166 1999.8

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER CHEMICAL SOC

Febrifugine (1) and isofebrifugine (2), isolated from the roots of Dichroa febrifuga Lour. (Chinese name: Chang Shan), are active principles against malaria. Adducts of 1 and 2 with acetone, Df-l (3) and Df-2 (4), respectively, were obtained using silica gel and acetone. They showed high activity against P. falciparum malaria in vitro. Compound 3 was found to be equally effective against P. berghei in vivo as the clinically used drug chloroquine, whereas 4 showed only 1/24 of the activity of 3. Metabolism studies of these compounds revealed that compound 4 is readily metabolized in mouse liver. Accordingly, the dose of 4 must be higher than that of 3 to attain blood levels sufficient for a favorable therapeutic effect.

DOI： 10.1021/jm990131e

Synthesis and antimalarial activity of cyclic peroxides, 1,2,4,5,7-pentoxocanes and 1,2,4,5-tetroxanes

HS Kim, Y Shibata, Y Wataya, K Tsuchiya, A Masuyama, M Nojima

JOURNAL OF MEDICINAL CHEMISTRY 42 ( 14 ) 2604 - 2609 1999.7

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER CHEMICAL SOC

A variety of 1,2,4,5,7-pentoxocane and 1,2,4,5-tetroxane derivatives were prepared as potential peroxide antimalarial agents. In both series of cyclic peroxides, the steric and electronic effects of the substituents attached to the peroxide ring exert a remarkable influence on the antimalarial activity. For some cyclic peroxides, which were found to be highly effective in vitro, the study in vivo has been also conducted.

DOI： 10.1021/jm990014j

A colorimetric DNA diagnostic method for falciparum malaria and vivax malaria: A field trial in the Solomon Islands

M Arai, K Kunisada, HS Kim, H Miyake, C Mizukoshi, T Kakutani, A Yamane, S Nakagami, S Kawai, H Nakano, F Kawamoto, Y Wataya

NUCLEOSIDES & NUCLEOTIDES 15 ( 1-3 ) 719 - 731 1996

Language：English Publishing type：Research paper (scientific journal) Publisher：MARCEL DEKKER INC

We have developed a colorimetric assay, ''microtiter plate-hybridization'', for the detection of malaria parasites Plasmodium falciparum and P. vivax in human blood, in which the target DNA sequences (18S small subunit ribosomal RNA gene) amplified by polymerase chain reaction (PCR) are hybridized with the species-specific probes immobilized on a microtiter well, This assay system was tested in Guadalcanal, Solomon Islands, where malaria is highly endemic. We obtained blood samples by finger puncture from 130 asymptomatic donors. Among the 130 samples, 30 (23 %) were P. falciparum positive, 28 (22 %) were P. vivax positive, and 8 (6 %) were mixed infections, The results of our DNA diagnostic method showed good correlation with those of acridine orange microscopy.

Species-specific PCR detection of malaria parasites by microtiter plate hybridization: Clinical study with malaria patients

M. Kimura, H. Miyake, H. S. Kim, M. Tanabe, M. Arai, S. Kawai, A. Yamane, Y. Wataya

Journal of Clinical Microbiology 33 ( 9 ) 2342 - 2346 1995

Language：English Publishing type：Research paper (scientific journal)

A simple and convenient PCR method that amplifies the 18S rRNA genes has been developed for the purpose of detecting and differentiating four species causing malaria in humans. The advantage of the assay is that the biotinylated PCR product is visualized following hybridization with specific probes which are immobilized on plate wells (microtiter plate hybridization). This method has been previously evaluated in a field study and was found to be sensitive and specific for the detection of Plasmodium falciparum and Plasmodium vivax. In the current study, the microtiter plate hybridization PCR method was evaluated by using blood specimens from malaria patients. All of 36 cases of falciparum malaria, 26 of 27 cases of vivax malaria, all of 11 cases of ovale malaria, and 2 cases of malariae malaria were diagnosed species specifically by the PCR method. There were four smear-negative, PCR- positive cases that seemed to correspond to the convalescent stage of malaria. In contrast, 30 cases for which the diagnosis of malaria has been excluded on the basis of microscopy and clinical courses showed negative PCR results. By comparing parasite densities and PCR results following antimalarial treatment of some patients, it was revealed that the PCR results largely paralleled the parasite densities and that PCR could detect as few as 10 parasites per μl of blood. We conclude that this PCR method is highly sensitive and specific for the detection of all four parasite species and can serve as a useful supplement to microscopy for the clinical management of malaria.

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