琉球列岛来源稀有放线菌中新型抗肿瘤次生代谢产物的研究

近几十年由于新型活性天然产物的发现效率降低，天然产物由来的新抗肿瘤先导化合物以及药物的开发停滞不前。申请人从寻找新资源和提高发现效率两个方面着手，通过（1）使用特殊自然资源（生物多样性高的冲绳微生物库）提升发现几率；（2）结合前沿技术手段（复合培养法）提高发现效率；（3）使用申请人开发的PDSS半合成法简易高效地制备结构相关衍生物，成功发现并报到了多个具有抗肿瘤活性的新型天然产物。本项目基于上述研究基础，专注于未被广泛挖掘的稀有放线菌资源，筛选出具有生产独特的含硫次级代谢物能力的菌株，并得到含硫代谢产物的生合成前体化合物，通过复合培养+半合成PDSS的手段制备了系列新的衍生物，拟进行构效关系和抗肿瘤活性及作用机制的研究。通过结合发掘高出新率的资源与简便的衍生物制备方法，可以最大程度得提高活性天然产物的结构多样性，为新型抗肿瘤天然药物先导化合物的筛选和开发提供化合物基础和支持。

In recent years, because of the low discovery efficiency of new bioactive natural products, the development of new natural product-orient anticancer drug leads remains stagnant. To solve the problem, the applicant focused on both the searching of the new natural resource and the improvement of discovery efficiency. By using the three effective ways including (1) special natural resource with high biodiversity to improve the discovery probability; (2) the application of combined culture for improvement of discovery efficiency; and (3) application of PDSS to semi-synthesize derivatives efficiently, the applicant successfully discovered and reported several new bioactive natural products. Based on the above result, in the research program, the applicant focused on the actinomycetes which has not been widely investigated and finally discovered two strains which that could produce thiol-containing natural products. The technologies of combined culture and semi-synthesis (PDSS) were next applied to produce more derivatives. The anti-cancer activity and mods of actions of the new natural products will be investigated in the near future. The structure-activity relationship will also be summarized. In conclusion, combination of the new natural resource and new technologies including combined culture and PDSS will significantly improve the discovery efficiency of new bioactive natural products and their derivatives, giving strong support to the discovery of new anticancer drug leads.