| Co-Investigator(Kenkyū-buntansha) |
TAKEDA Setsuo Taiho Pharmaceutical Co., Laboratory for Chemotherapy Agents, Head, 化学療法剤研究所, 室長
TANAKA Kiyoshi Kyoto University, Institute for Chemical Research, Associate Professor, 化学研究所, 助教授 (50093266)
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| Research Abstract |
Taxol, a highly functional diterpene isolated in 1971 from the Pacific yew tree, Taxus brevifolia (Taxaceae), is currently considered the most exciting lead in cancer chemotherapy, hence called as the anticancer drug of '90s. Some aspects of taxoids, such as their promising antitumor activity, unique structural features, novel mode of action and unusual biogenesis, stimulated the search for new related diterpenoids having similar activity from the widely distributed species of the family Taxaceae as well as natural products. In this project, three Taxaceaes which grow at Yunnan in China, Taxus chinensis, Taxus Yunnansis and Taxus chinensis var. mairei, were chosen as a plant source for a lead compound. From these plants, more than twenty new diterpenes have been isolated in a pure form together with sixteen known taxoids including taxol and 10-deacetyl baccatin III.Among the new diterpenoids, the structures of totally sixteen compounds could be elucidated, in which twelve diterpenoids
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possesses novel 5/7/6/carbon framework and the four an ordinary taxoid skeleton. For structural determination, some 2D NMR techniques, such as Long Range ^<13>C-^1H COSY,ROESY,NOESY,were found to be extremely effective. The final proof on the structures of some new diterpenoids was afforded by X-ray crystallographic analyzes. Particular interest is that the diterpenoids of the former exist as a mixture of conformational isomers in a solution at an ambient temperature. The ratio depends upon the substitution pattern on the B and C ring. Unfortunately, no significant inhibitory activity of the new diterpenoids isolated against tublin depolymerization has been recognized so far. Introduction of the phenyl isoserine moiety, which is known as an essential structural unit for antitumor activity in taxol, into C13 position of the newly isolated 5/7/6 compounds as well as the synthesis of artificially designed compounds based on conformational analysis of active compounds and computationary chemistry, are currently in progress. Less
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