两类生物碱的全合成及其生物活性与靶点确认的研究

An approach to the total synthesis of chetomin will be described. Upon the completion of the total synthesis, we will use chetomin as a HIF-1 alpha inhibitor combined with PD-L1 mAb to study their antitumor “synergistic effect” in syngeneic mice model. This study will also rely on different genetic tools including RNA-seq, Chip-seq, and so on. This combined therapy could provide a novel approach for cancer immunotherapy. We will also optimize our synthetic routes for the preparations of alstoscholarisine A-like chemical probes. Since alstoscholarisines A-E could significantly promote adult neuronal stem cell proliferation, we will try to identify their potential protein target using ABPP and DARTS techniques. We believe this study will benefit the treatment of neurodegenerative diseases such as Parkinson’s disease, Huntington’s disease and Alzheimer’s disease.

本项目拟完成复杂天然产物chetomin的首次全合成，并同时优化alstoscholarisines A-E的全合成路线以利于类天然小分子探针的制备。在chetomin合成工作的基础上，将利用chetomin作为HIF-1 alpha抑制剂在小鼠模型中观察其与PD-L1单克隆抗体的协同抗肿瘤现象，并以此为基础利用RNA-seq、Chip-seq等技术手段阐明其在肿瘤微环境的调控机制。我们还将利用ABPP和DARTS等技术手段确认alstoscholarisines A-E或天然产物类似物的蛋白靶点，探索其在神经干细胞增殖的调控机制，以期促进干细胞疗法在神经退行性疾病的临床应用。

本项目拟完成复杂天然产物chetomin的首次全合成，并同时优化alstoscholarisine A-E的全合成路线以利于类天然小分子探针的制备。同时，本项目将探索金属Ni催化的C-C键生成，构建类似天然产物骨架。本项目还将利用新的小分子D18探索其与PD-L1单克隆抗体的协同抗肿瘤现象，并以此为基础利用RNA-seq、Chip-seq等技术手段阐明其在肿瘤微环境的协同调控机制。