Faculty Profiles - KIM Hye-Sook

Papers - KIM Hye-Sook

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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

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