新型端粒酶TERT抑制剂：手性吡唑-香豆素-色酮新骨架的优化设计合成及构效关系

Telomerase is a highly effective tumor marker, in order to confirm the site-specific of telomerase, novel highly selective inhibitors used as the key active site of telomerase TERT protein will be designed and synthesized. Based on structure-activity relationships of chiral pyrazole with anticancer activity and the telomerase TERT protein crystal structure, considering the three key residues ASP360, LYS480 and LYS358 of preliminary research found, using 50 crystal structure conformations of aryl chiral pyrazole of applicant containing, the training was set and a reasonable molecular will be designed.The structures will be optimized in this proposal. Basis for the molecular design of the structure needs, substituted aldehyde, ketone used as raw materials, the coumarin-aryl chiral pyrazole-multihydroxy chromone skeleton will be builded. All title compounds will be clearly characterized, a variety of biological activity of cancer cells and telomerase TERT protein will be evaluated. Cocrystallization complex of the active molecules with telomerase TERT protein will be cultivated and resolved. Combined with molecular design results, in-depth to explore the structure-activity relationship,the active site will be determine and find out high activity inhibitors against telomerase TERT. These results would be much helpful for rational design of more efficient telomerase inhibitors for chemotherapy and provide theoretical support for the improvement of such inhibitors.

端粒酶是一种高效的肿瘤标志物，为了确证端粒酶作为肿瘤标志物的部位特异性，拟设计基于端粒酶关键活性部位TERT蛋白为靶标的高效、高选择性抑制剂。该研究在申请者已有的手性吡唑-抗癌活性初步构效关系的基础上，基于端粒酶TERT蛋白晶体结构, 利用申请者前期获得的50个芳基手性吡唑X-Ray优势构象建立训练集，参考预研发现的三个关键残基ASP360，LYS480及LYS358，进行合理的分子设计及结构优化。依据分子设计的结构需要，拟以简单取代醛、酮为原料，构建香豆素-手性吡唑-多羟基色酮骨架；对合成的目标化合物进行结构表征，各种癌细胞及端粒酶TERT蛋白生物活性评价； Cocrystallization培养活性分子与蛋白复合物的晶体结构并解析，结合分子设计成果，深入探讨构效关系，确定活性位点，以期筛选出高效的端粒酶TERT抑制剂。通过课题的实施有助于丰富新型端粒酶TERT抑制剂筛选的科学内函。

端粒酶是一种高效的肿瘤标志物，为了确证端粒酶作为肿瘤标志物的部位特异性，拟设计基于端粒酶关键活性部位TERT 蛋白为靶标的高效、高选择性抑制剂。该研究在申请者已有的手性吡唑-抗癌活性初步构效关系的基础上，基于端粒酶TERT 蛋白晶体结构,利用申请者前期获得的50 个芳基手性吡唑X-Ray 优势构象建立训练集，参考预研发现的三个关键残基ASP360，LYS480 及LYS358，进行合理的分子设计及结构优化。依据分子设计的结构需要，拟以简单取代醛、酮为原料，构建香豆素-手性吡唑-多羟基色酮骨架；对合成的目标化合物进行结构表征， 各种癌细胞及端粒酶TERT 蛋白生物活性评价；Cocrystallization 培养活性分子与蛋白复合物的晶体结构并解析，结合分子设计成果，深入探讨构效关系，确定活性位点，以期筛选出高效的端粒酶TERT 抑制剂。通过课题的实施有助于丰富新型端粒酶TERT 抑制剂筛选的科学内函。