Search for and molecular design of bioactive taxoids

本研究以东北红豆杉为原料，进行了生物活性紫杉类化合物的寻找和分子设计。Et Zucc.从札幌市分离得到10个新的紫杉类化合物及其相关的二萜类化合物，分别为紫杉烷B~H和J~L，其结构经波谱和化学方法确证。紫杉醇G和H增加长春新碱在多药耐药细胞中的蓄积，而紫杉醇没有这种活性，紫杉醇G和H对长春新碱无细胞毒性。红豆杉中已知的紫杉类化合物紫杉碱C可增强长春新碱(VCR)对P388/VCR荷瘤小鼠的化疗效果。这些结果表明，一些紫杉类化合物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，尽管紫杉醇中没有氧杂环己烷和N-酰基苯异丝氨酸基团，但紫杉醇K和L可显著抑制2+Ca诱导的微管解聚，其抑制作用相当于紫杉醇的一半到三分之一。紫杉醇是红豆杉中已知的一种紫杉醇类化合物，它诱导有丝分裂纺锤体的形状发生异常变化。通过进一步研究本研究中得到的新化合物的构效关系，可能会发现更有效和更特异的MDR修饰剂。

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.