抗癌症干细胞天然产物Rakicidin A的合成及构效关系研究

Cancer stem cells(CSCs) are responsible for cancer formation, progress, relapse, metastasis and resistance. But drugs that may selectively ablate CSCs are very limited. Rakicidins is a family of depsipeptides with more than 5 chiral centers, they are natural products isolated from bacteria. The recent research revealed that Rakicidin A can selectively inhibit leukemia stem cell growth.The five absolute configurations of rakicidin have not been assigned, and there is no report on total synthesis of Rakicidin. Based on our experience on asymmetric total synthesis of complex polyketides and tubulysin lipopeptides, we carried on synthesis of rakicidin, which includes construction of fragment C with two chiral centers and combinatorial syntheses of polyketide fragment B with three chiral centers using combinatorial approach. But we preferentially synthesize several stereoisomers, which can be found in other types of depsipeptides with known absolute configuration, or whose conformation predicted from computer modeling is close to that of natural rakicidins. Without the long flexible aliphatic side chain, the main structure A + B + C will have less possible conformation, and then may have higher possibility to form single crystals. The last linkage of aliphatic side chain will lead to the completion of total synthesis of rakicidin A, and may be feasible to prepare other rakicidins and their analogues. This project is expected to determine the absolute configurations of rakicidin A, and to provide the first total synthesis route for rakicidins. Moreover, this project will release the effect of chiral centers to the anti-CSC activities, and provide information for further exploration of pharmacophore and mechanism to targeting CSCs.

癌症干细胞是大多数癌症产生、发展、复发、转移和耐药的根源，目前选择性杀灭癌症干细胞的化合物极少。Rakicidin 是一类有5 个以上手性中心的大环脂肽类天然产物，其中的Rakicidin A 可选择性杀灭癌症干细胞，但Rakicidin 类化合物的绝对构型均未确定。本项目将采用组合化学的策略，分别构建Rakicidin缩酮片段的8个立体异构体，以及3-羟基天冬酰胺片段的4个立体异构体。天然产物类似结构中常见的缩酮异构体，以及计算机模拟构象与文献报道数据最相符的主结构异构体，予以优先合成。缺少柔性侧链的主结构的构象减少，将有获得单晶的几率。 最后链接脂肪侧链可完成Rakicidin A 及其异构体、类似物的合成。本项目通过全合成化合物库，有望确定Rakicidin A 的绝对构型，并将确立各手性中心与侧链对抗癌症干细胞活性的影响，为探索其抗癌症干细胞的药效团与作用靶点奠定基础。

癌症干细胞是大多数癌症产生、发展、复发、转移和耐药的根源，目前选择性杀灭癌症干细胞的化合物极少。Rakicidin是一类有5个以上手性中心的含APD结构（4-氨基-2,4-戊二烯）大环脂肽类天然产物，其中Rakicidin A可选择性杀灭癌症干细胞，但Rakicidin类化合物的手性中心绝对构型均未确定。. 本项目采用组合化学的策略，分别构建Rakicidin缩酮片段的8个立体异构体，以及3-羟基天冬酰胺片段的4个立体异构体。天然产物类似结构中常见的缩酮异构体，以及计算机模拟构象与文献报道数据最相符的主结构异构体，予以优先合成。最终经过37反应，以0.17%的总产率获得37 mg的目标产物，并通过数据对比分析确认了合成的目标产物与天然Rakicidin A结构数据一致，相关工作发表在J. Am. Chem. Soc.上。在完成Rakicidin A的首次全合成并确定其绝对立体构型后，通过改变其某些官能团，初步探索了其构效关系，并获得了活性、化学稳定性、血浆稳定性更好的化合物分子，相关工作发表在J. Med. Chem. 上。同时，在rakicidin A全合成路线基础上，完成了APD-脂肽类化合物vinylamycin和Microtermolide A和B的首次全合成，并确定了其绝对立体构型，相关工作发表在Org. Lett. 和J. Nat. Prod.上。. 综上，项目负责人完成了一系列APD-脂肽类化合物的首次全合成，并确定了其绝对立体构型，初步探索了Rakicidin A的构效关系，并设计了rakicidin A的分子探针。此外，申请人率先开展了APD类天然产物抗癌症干细胞的药物化学。 已发现活性提高、化学稳定性提高、制备更简单的先导化合物，并能够克服imatinib等药物的耐药性，为进一步探索其抗癌症干细胞的药效团与作用靶点奠定基础。