Faculty Profiles - KIM Hye-Sook

Papers - KIM Hye-Sook

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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

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