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Search for and molecular design of bioactive taxoids

生物活性紫杉烷的搜索和分子设计

基本信息

批准号：
10557204
负责人：
KOBAYASHI Jun'ichi
金额：
$ 7.36万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

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.

在本研究项目中，对具有生物活性的紫杉烷进行了搜索和分子设计。来自日本红豆杉Taxus cuspidata Sieb。等祖克。在札幌收集的紫杉烷中，分离出十种新的紫杉烷和相关二萜类化合物紫杉吡啶 B 〜 H 和 J 〜 L，并根据光谱数据和化学方法阐明了结构。紫杉吡啶 G 和 H 增加了多重耐药细胞中长春新碱的积累，而紫杉醇则没有表现出这种活性，并且紫杉吡啶 G 和 H 没有表现出细胞毒性。 Taxuspine C 是一种来自红豆杉的已知紫杉烷，可增强长春新碱 (VCR) 对 P388/VCR 小鼠的化疗效果。这些结果表明一些紫杉烷可能成为有用的先导化合物来克服肿瘤细胞的多药耐药性。另一方面，紫杉吡啶 K 和 L 显着抑制 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，尽管紫杉吡啶 K 和 L 缺乏与紫杉醇中这种独特活性相关的氧杂环丁烷环和 N-酰基苯基异丝氨酸部分。 Taxuspine D 是一种来自红豆杉的已知紫杉烷，可诱导有丝分裂纺锤体的异常形状变化，如紫杉醇。通过进一步研究本研究中获得的新化合物的构效关系，可能会发现更强大、更特异的 MDR 修饰剂。