PSMA靶向秋水仙碱结合部位抑制剂的设计、合成与活性评价

Both prostate-specific membrane antigen (PSMA) targeted antitumor agents and colchicine binding site inhibitors (CBSI) have caught increasing attention in recent years, due chiefly to their dual tumor cell/tumor vascular endothelial cell targeting effects and dual proliferation-inhibiting/vascular-disrupting activities, respectively. To overcome the scientific problems including structural rationality of the PSMA targeted agents and targeting efficiency of CBSI in the fields above, a set of PSMA-targeted CBSI, a novel type of targeting antitumor agents, are developed via fragment-based drug design strategy utilizing small-molecule PSMA ligands as the targeting moieties, the PSMA-specific spacers as the linkers, and the CBSI developed by our group as the active moieties. These PSMA-targeted CBSI will be synthesized, purified and characterized. The potential druggability of the PSMA-targeted CBSI, including dual activity, dual targeting effect, mechanism of action, metabolic stability and preliminary toxicity, will be evaluated. The completion of this project will provide some novel “PSMA-targeted CBSI” with potent antitumor activity, high targeting effect and low toxicity, led to a better understanding of the structure-activity relationship, and lay the foundation for the development of next generation of tumor-targeted drugs with independent intellectual property rights.

具有肿瘤细胞/肿瘤血管内皮细胞双重靶向性的前列腺特异性膜蛋白（PSMA）靶向抗肿瘤药物和具有增殖抑制/血管破坏双重活性的微管蛋白秋水仙碱结合部位抑制剂（CBSI）是近年来广受关注的热点研究领域。为解决上述领域中“PSMA靶向化合物结构合理性”和“CBSI靶向性”等科学问题，首次提出“PSMA靶向CBSI”这一原创性概念，采用基于片段的计算机辅助药物设计方法，优选小分子PSMA配体作为靶向基团、PSMA选择性降解链作为连接链、本课题组前期研制的增殖抑制/血管破坏双重活性CBSI作为活性基团，完成“PSMA靶向CBSI”的设计。完成目标化合物的合成、纯化与表征，并考察目标化合物的双重活性、双重靶向性、代谢稳定性、初步毒性等成药特性。发现结构新、活性强、毒性低、靶向性突出的“PSMA靶向CBSI”，阐明“PSMA靶向CBSI”的构效关系，为创制拥有自主知识产权的靶向性抗肿瘤新药奠定基础。

具有增殖抑制/血管破坏双重活性的微管蛋白秋水仙碱结合部位抑制剂（CBSI）和具有肿瘤细胞靶向性的靶向抗肿瘤药物是近年来广受关注的热点研究领域。为解决上述领域中“CBSI靶向性”和“肿瘤细胞靶向化合物结构合理性”等科学问题，本项目采用基于片段的计算机辅助药物设计方法，优选小分子配体作为靶向基团、选择性降解链作为连接链、拥有自主知识产权的增殖抑制/血管破坏双重活性CBSI作为活性基团。完成了不同结构类型共计200余个目标化合物的分子设计、化学合成与成药性研究；发现结构新、活性强、毒性低、靶向性良好的靶向化秋水仙碱结合部位抑制剂，为创新药物研究奠定了实验基础；揭示靶向化秋水仙碱结合部位抑制剂构效关系规律，为后续的深入研究提供了理论依据。