狗牙花属植物中靶向mTOR抑制的Aspidosperma型生物碱的定向发现及其抗肿瘤作用机制研究

As one of the most commonly activated signaling pathways in human cancer, mTOR signaling pathway is associated with the onset and progression of cancer, which makes mTOR a hot target in anticancer therapy. Previous study indicated that aspidosperma-type alkaloids from Tabernaemontana corymbosa exhibited significant mTOR inhibitory activity, caused cell cycle arrest, autophagic cell death and inhibition of angiogenesis, which suggested that aspidosperma-type alkaloids were potential novel anticancer drugs. However, directed discovery of the aspidosperma-type alkaloids is facing great challenges, which seriously restricts its research process. Based on these findings, this project will be carried out as follows. (i) Directed discovery of active aspidosperma-type alkaloids and analogs from the genus Tabernaemontana according to the strategy of precision discovery "targeted enrichment-accurate identification-fine separation". (ii) Design and synthesis of the derivatives of active aspidosperma-type alkaloids, evaluation of their mTOR inhibitory activity, and illustration of their structure activity relationship. (iii) Evaluation the anticancer activity of the active compounds in vitro and in vivo, and clarification their anticancer mechanism by targeting inhibition of mTOR. The project will not only provide a new strategy for directed discovery of specific type of alkaloids in traditional herbal medicine, but also make basis for the discovery of novel anticancer drugs.

作为肿瘤中最常见的被异常激活的通路之一，mTOR通路与肿瘤的发生发展密切相关，因此靶向mTOR抑制成为抗肿瘤药物的研究热点。申请人前期研究发现，伞房狗牙花中Aspidosperma型生物碱能通过抑制mTOR活性，导致肿瘤细胞周期阻滞、自噬性死亡及新生血管生成抑制等，有望成为新型抗肿瘤药物。目前Aspidosperma型生物碱的定向发现面临巨大挑战，严重制约其研究进程。本项目拟开展：（1）基于“靶向富集-准确识别-精细分离”的精准策略，以mTOR抑制活性为指导，定向发现伞房狗牙花、狗牙花、平脉狗牙花及尖蕾狗牙花等4种狗牙属植物中的Aspidosperma型生物碱；（2）进行结构修饰，研究其构效关系；（3）针对强活性分子，评价其体内外抗肿瘤活性，研究其靶向mTOR抑制的抗肿瘤作用机制。本项目将为中草药中特定骨架类型生物碱的定向发掘提供新思路，对推动新型抗肿瘤药物的研发具有重要意义。

作为肿瘤中最常见的被异常激活的通路之一，mTOR通路与肿瘤的发生发展密切相关，因此靶向mTOR抑制成为抗肿瘤药物研究的热点。狗牙花属植物中Aspidosperma型生物碱有望成为新型靶向mTOR抑制抗的肿瘤药物。目前Aspidosperma型生物碱的定向发现面临巨大挑战，严重制约其研究进程。本研究基于“靶向富集-准确识别-精细分离”的精准策略，以mTOR抑制活性为指导，建立了狗牙花植物中Aspidosperma型生物碱的定向发现方法，从四种狗牙花属植物中分离得到Aspidosperma型生物碱71个，其中新化合物20个，并制备了16个Aspidosperma型生物碱衍生物。同时，深入研究了3个活性Aspidosperma型生物碱的抗肿瘤作用机制，从阻滞细胞周期、诱导自噬性死亡及抑制新生血管生成等方面，阐明了狗牙花属植物中Aspidosperma型生物碱靶向mTOR抑制抗肿瘤作用机制。本项目的研究为中草药中特定骨架类型生物碱的定向发掘提供新思路，同时为新型mTOR抑制剂的创制提供新结构类型的先导化合物，对推动新型抗肿瘤药物的研发具有重要意义。本研究获授权发明专利4项，发表相关SCI论文10篇，超额完成项目预期目标。