新型雷帕霉素类似物及其前体类似物的生物合成与定向修饰的研究

Cancer has become the deadliest disease in the modern world. Rapamycin, FK506 and some of their analogs are among the most potent immunosuppressive drugs to date. Recently they have also been shown to have strong anti-cancer activities in model organisms and in clinics. Despite the significance of these compounds, it is very difficult to prepare a number of novel analogs due to their complex molecular structures. While semi-synthetic rapamycin analogs have received FDA-approval or been in clinics, the scope and flexibility of this approach is limited with regards to amenable diversification of the rapamycin scaffold. In this proposal, using rapamycin as a model, we plan to make novel rapamycin analogs by a combinatorial approach, using precursor-directed biosynthesis to make a few pre-rapamycin analogs, and then further diversify them by semi-synthesis. We envision that this methodology can be developed to a general strategy in a wide range of other macrolides synthesis, especially FK520 and FK506, which will provide methodology applied to medicine discovery and natural product semi-synthesis.

癌症已经成为现代社会公认的“死亡杀手”。近年来，雷帕霉素，FK506和他们的一些类似物做为最有效的免疫抑制药物而暂露头角。最近的研究显示，雷帕霉素和其类似物在生物测试和临床实验中都表现出高效的抗肿瘤活性。然而这一类重要的化合物，却很难制备出结构新颖复杂的类似物。现阶段已上市或处于临床期的半合成雷帕霉素类似物药物，由于传统方法的限制也仅限于对雷帕霉素的C40位化学修饰而获得的。本项目拟使用雷帕霉素作为模板，通过组合合成方式实现新型雷帕霉素类似物的合成。首先采用前体定向合成的方法，制备一类雷帕霉素前体类似物，再经半合成进一步实现其多样化修饰，获得一系列全新的雷帕霉素类似化合物。这一方法有望为更多的大环内酯类天然产物，特别是FK520和FK506的修饰提供借鉴与指导，也为新药研发和天然产物的半合成提供有力的方法学支持。

研究表明，近60%的已上市小分子药物直接或间接来源于活性天然产物的类似物。因此，利用化学半合成策略开发活性天然产物类似物，具有很好的成药前景。本项目通过理性设计，发展构建以雷帕霉素和平板霉素等天然产物为前体的类似化合物分子库。通过对新型化合物的生物活性构效关系进行系统地分析，我们获得了抗癌活性或抑菌活性很好的新型药物先导化合物，并将重要的活性化合物的扩展到克级规模合成，为以后结构优化和临床前研究做准备。