2001 Fiscal Year Final Research Report Summary
Development of Anti-trypanosomal Drugs Based on Terpene Structure as an Active Unit
| Project/Area Number |
12557199
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Chemical pharmacy
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
KIUCHI Fumiyuki Kyoto University, Graduate School of Pharmaceutical Sciences, Associate Professor, 薬学研究科, 助教授 (60161402)
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| Co-Investigator(Kenkyū-buntansha) |
AOKI Takashi Juntendo University, School of Medicine, Professor, 医学部, 教授 (20053283)
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| Project Period (FY) |
2000 – 2001
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| Keywords | Trypanosoma cruzi / terpenoid / sesquiterpene lactone / Chenopodium ambrosioides / hydroperoxide / Michelea alba / trypanosomiasis / HeLa cell |
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| Research Abstract |
1. Synthesis and Anti-trypanosomal Activity of p-Menthane-type Monoterpene Hydroperoxides
p-Menthane-type monoterpene hydroperoxides and corresponding alcohols were prepared by photo-oxidation and subsequent reduction of optically active limonenes, 4-terpineol and its acetate, etc. The hydroperoxides thus obtained showed strong trypanocidal activity, whereas the alcohols showed no activity up to 400 μM, indicating that the trypanocidal activity was dependent on the hydroperoxide group. Introduction of a hydroxy or an acetoxy group to the hydroperoxides reduced the activity, and a correlation was suggested between the hydrophobicity and the trypanocidal activity of these compounds. The hydroperoxids prepared from limonene strongly inhibited the infection of trypomastigotes of T. crusi to HeLa cells in the HeLa-cell infection assay at 1μg/ml. Stabilization and improved selectivity of trypanocidal activity over cytotoxicity are necessary for further development of these compounds.
2. Anti-trypanosomal Activity of Naturally Occurring Mon- and Sesqui-terpenoids
Four trypanocidal monoterpene hydroperoxides were obtained from Chenopodium ambrosioides, which is known to contain the anthelmintic monoterpene, ascaridole. These hydroperoxides were identified as the same compounds which were obtained by photo-oxidation of l-limonene described above. Twelve terpenoids, including costunolide, dihydrocostunolide, parthenolide, dihydroparthenolide, etc., were isolated from a Malaysian natural medicine, Michelia alba. The sesquiterpene α,β-unsaturated γ-lactones, such as costunolide and parthenolide, showed both trypanocidal activity and cytotoxicity, whereas the lactones without α,β-unsaturation, such as dihydrocostunolide, showed only trypanocidal activity. Thus, the sesquiterpene γ-lactones are possible leads for development of a new anti-trypanosomal drug.
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