Search for and molecular design of bioactive taxoids

本课题主要进行了生物活性类taxoids的寻找和分子设计。源自日本紫杉Taxus cuspidata Sieb。调查。从日本札幌地区分离得到10个新的分类类及其相关的二萜类，taxezopidines B ~ H和J ~ L，并通过光谱数据和化学手段对其结构进行了鉴定。Taxezopidines G和H增加了多药耐药细胞中长春新碱的积累，而紫杉醇没有这种活性，Taxezopidines G和H没有细胞毒性。Taxuspine C是一种已知的红豆杉类Taxuspine C，它可以增强长春新碱（VCR）对P388/VCR小鼠的化疗效果。这些结果表明，一些类taxoids可能成为克服肿瘤细胞多药耐药的有用先导化合物。另一方面，taxezopidines K和L显著抑制2+ Ca诱导的微管解聚，其效力相当于紫杉醇的一半到三分之一，尽管taxezopidines K和L缺乏与紫杉醇中这种独特活性相关的氧烷环和n -酰基苯基异丝氨酸片段。紫杉杉素D是一种已知的红豆杉类Taxuspine D，与紫杉醇一样，诱导有丝分裂纺锤体发生不寻常的形状变化。通过对本研究获得的新化合物的构效关系的进一步研究，可能会发现更强效和特异性的MDR改性剂。

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.