Search for new compounds to overcome multidrug resistance from natural sources

在本研究项目中，我们研究了从天然来源中寻找新的抗多药耐药（MDR）化合物。源自日本紫杉Taxus cuspidata Sieb。调查。从日本札幌地区分离得到22个新的紫杉类及其相关的二萜类，紫杉杉A-H和J-W，并通过光谱数据和化学方法对其结构进行了鉴定。Taxuspines B、C和J增加了多药耐药细胞中长春新碱的积累，而紫杉醇没有表现出这种活性。这些新的类taxoids在小鼠体内没有细胞毒性，也没有毒性。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，taxuspine D显著抑制Ca^<2+>-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taxuspine D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。Taxuspine E具有氧烷环，但不含n -酰基苯基异丝氨酸部分，对KB肿瘤细胞表现出强大的细胞毒性。通过对本研究获得的新化合物的构效关系的进一步研究，可以发现更强效和特异的MDR改性剂。

In this research project, we investigated on search for new compounds to overcome multidrug resistance (MDR) from natural sources.From the Japanese yew Taxus cuspidata Sieb.et Zucc.collected at Sapporo, 22 new taxoids and related diterpenoids, taxuspines A-H and J-W,were isolated and the structures elucidated on the basis of spectroscopic data and chemical means. Taxuspines B,C,and J increased accumulation of vincristine in multidrug-resistant cells, while taxol did not show such activity. These new taxoids exhibited no cytotoxicity and were not toxic for mice in vivo. These results suggest that some taxoids may become useful lead compounds to overcome multidrug resistance in tumor cells. On the other hand, taxuspine D markedly inhibited Ca^<2+>-induced depolymerization of microtubules and the potency corresponded to half to one third of that of taxol, although taxuspine D lacks both the oxetane ring and N-acylphenylisoserine moiety which are associated with this unique activity in taxol. Taxuspine E,having the oxetane ring but not containing the N-acylphenylisoserine moiety, exhibited potent cytotoxicity against KB tumor cells. More powerful and specific MDR modifiers may be found through further studies of structure-activity relationship on the new compounds obtained in this study.