基于海洋天然产物Terpestacin的结构优化与靶向UQCRB蛋白抗肿瘤活性研究

发展新机制的创新药物是克服肿瘤耐药与药物毒副作用，实现肿瘤有效治疗的重要途径。泛醇细胞色素c还原酶结合蛋白（UQCRB）是近年发现的介导HIF-1信号通路抗肿瘤新靶点。文献报道海洋天然产物Terpestacin能靶向UQCRB，下调HIF-1α与VEGF表达，抑制血管生成而发挥抗肿瘤作用，但其活性较弱，结构需进一步优化。前期研究表明，含组氨酸或精氨酸残基末端寡肽修饰的Terpestacin衍生物具有较强的抑制HIF-1α活性与HUVEC形成管腔能力。基于此发现及活性分子结构特点，并结合UQCRB蛋白作用口袋与通道形状，本项目拟设计在Terpestacin上连接一类能增加与通道相互作用的氨基酸或寡肽侧链，构建结构多样性新型衍生物库。通过活性筛选与构效关系研究，发现高活性先导分子；验证并研究其作用靶点与分子机制；评价其体内外抗肿瘤活性与急性毒性，为新型高效的靶向抗肿瘤先导化合物的开发奠定基础。

Development of novel type of antitumor drugs with new mechanism is an important approach for efficient tumor treatment in avoidance of tumor resistance and drug’s side effects. Recent studies showed that Ubiquinol-cytochrome c reductase binding protein (UQCRB) could be used as a new target for tumor treatment in hypoxia-inducible factor (HIF)-mediated angiogenesis during tumor developing, and also showed that the marine-derived Terpestacin could bind to UQCRB and mediate HIF-1α signaling pathway by down-regulating the expression of HIF-1α and VEGF, thus resulting in the inhibition of tumorgenesis. However, the bioactivity of Terpestacin is so poor and further structural optimization is needed in order to obtain new derivatives with high activity. Our previous synthesized Terpestacin derivatives with histidine or arginine residue-terminal oligopeptide side chains have strong abilities to inhibit the expression of HIF-1α and tube formation of HUVEC. Inspired by these findings, and based on the structure of the active pocket of UQCRB protein, in this project novel types of Terpestacin-amino acids/oligopeptides, in order to enhance the activity and binding ability of derivatives to UQCRB, will be designed, synthesized, and evaluated for their inhibition on the expression of HIF-1α. Furthermore, the target of the selected active derivatives will be confirmed, the signaling pathway will be investigated, and the antitumor activities both in vitro and vivo will also be evaluated. This work will afford important basis for discovery of new generation of anticancer drugs based on HIF-1α-mediated pathway.