Search for and molecular design of bioactive taxoids

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In this research project, search for and molecular design of bioactive taxoids were carried out.From the Japanese yew Taxus cuspidata Sieb. Et Zucc. collected at Sapporo, ten new taxoids and related diterpenoids, taxezopidines B 〜 H and J 〜 L, were isolated and the structures were elucidated on the basis of spectroscopic data and chemical means. Taxezopidines G and H increased accumulation of vincristine in multidrug-resistant cells, while taxol did not show such activity and taxezopidines G and H exhibited no cytotoxicity. Taxuspine C, a known taxoid from the yew, enhanced the chemotherapeutic effect of vincristine (VCR) in P388/VCR-bearing mice. These results suggest that some taxoids may become useful lead compounds to overcome multidrug resistance in tumor cells. On the other hand, taxezopidines K and L markedly inhibited 2+ Ca -induced depolymerization of microtubules and the potency corresponded to half to one third of that of taxol, although taxezopidines K and L lack both the oxetane ring and N-acylphenylisoserine moiety which are associated with this unique activity in taxol. Taxuspine D, a known taxoid from the yew, induced unusual shape change of mitotic spindles like taxol. More powerful and specific MDR modifiers may be found through further studies of structure-activity relationships on the new compounds obtained in this study.