靶向识别与抑制碳酸酐酶IX磷光金属配合物的设计与研究

肿瘤细胞中存在特殊功能的蛋白激酶，来维持肿瘤细胞自身快速增殖与代谢等功能，设计与开发相关激酶的抑制剂，成为肿瘤治疗的新型靶点。CAIX是肿瘤细胞中一种重要的跨膜蛋白, 在许多实体瘤中高度表达, 而在正常组织中几乎不表达, 参与调节肿瘤细胞增殖、转移和侵袭等过程，是潜在抗肿瘤新型靶点。本项目拟通过对磷光金属铱配合物分子结构的合理设计，预期得到1）可以特异性识别与抑制CAIX的小分子配体及相应的金属配合物，选择性杀伤肿瘤细胞；2）利用配体的蛋白疏水空腔光开关以及“分子转子”的转动受限导致的磷光强度与寿命变化实现对肿瘤活细胞内CAIX的磷光“开关”成像和检测；3）肿瘤细胞中CAIX被抑制后，探究肿瘤细胞环境中pH与细胞糖酵解水平的变化，能否激活肿瘤细胞的凋亡通路，抑制肿瘤血管生成以及以及小鼠体内肿瘤的生长；项目旨在为发展基于磷光金属抑制剂作为有临床应用前景的抗癌诊疗药物提供重要的理论与实验基础。

There are protein kinases with special functions in tumor cells, which will maintain the rapid proliferation and metabolism of tumor cells, the design and development of inhibitors of relative kinases has become a new target for tumor treatment. CAIX is an important transmembrane protein in tumor cells, which is highly expressed in many solid tumors but hardly expressed in normal tissues. It is involved in the regulation of tumor cell proliferation, metastasis and invasion, and is a potential new anti-tumor target. In this project, the reasonable design of the molecular structure of the phosphorescent metal iridium complex is intended to obtain 1) small molecular ligands and corresponding metal complexes that can specifically identify and inhibit CAIX. 2) the phosphorescence imaging and detection of CAIX in tumor living cells is realized by using the changes in phosphorescence intensity and life span caused by the light switch of the protein hydrophobic cavity of the ligand and the inhibited rotation of the "molecular rotor". 3)When CAIX was inhibited in tumor cells, the changes of pH and glycolytic level in the tumor cell environment were investigated to explore whether the changes could activate the apoptotic pathway of tumor cells, inhibit tumor angiogenesis and tumor growth in mice. Aiming at provides an important theoretical and experimental basis for the development of novel anticancer drugs based on phosphorescent metal inhibitors