Development of Anti-trypanosomal Drugs Based on Terpene Structure as an Active Unit

以萜烯结构为活性单元的抗锥虫药物的研制

基本信息

批准号：
12557199
负责人：
KIUCHI Fumiyuki
金额：
$ 1.22万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

1. Synthesis and Anti-trypanosomal Activity of p-Menthane-type Monoterpene Hydroperoxidesp-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-terpenoidsFour 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.

1。p-室型单苯二烷氢过氧化物P-Ementhane-type单一型单苯乙烯氢过氧化物和相应的醇的合成和抗肌体活性通过光氧化和随后的降低光学活性的limonenenes，4-替代酚和其乙酰乙酸的氧化剂，从而制备了杂醇，从而降低了hydropineal的运动，从而降低了hydropineal anderanty。醇的活性最大为400μm，表明锥虫活性取决于氢过氧化物基团。将氢氧化物或乙酰氧化基团引入氢过氧化物，从而降低了活性，并提出了这些化合物的疏水性与锥虫活性之间的相关性。从柠檬烯制备的氢过氧化物强烈抑制了T. crusi的锥虫感染，以1μg/mL的HeLa细胞感染测定中的HeLa细胞感染。对于进一步开发这些化合物，必须稳定和提高锥虫活性对细胞毒性的选择性。2。自然存在的单胞素和塞斯基 - 特苯二固醇锥虫单一型单二苯氢过氧化物的抗肌体活性是从安布西氏菌的，已知含有驱虫单智能单二烯的chenopodium abrosioides。这些氢过氧化物被鉴定为相同的化合物，这些化合物是通过上述L-二烯烯的光氧化获得的。从马来西亚天然医学（Michelia Alba）中分离出萜类化合物，包括Costunolide，Dihydrocostunolide，Dihydroparthenolide等。倍半萜，β-β-不饱和的γ-乳酮（例如Costunolide和Parthenolide）既显示锥虫活性和细胞毒性均表现出，而没有α，β-非饱和的内酯（例如二氢可替诺酚）仅显示锥虫活性。这，倍半萜γ-内酮是开发新的抗肌体药物的可能导致的。