AMPK活性配体-金属配合物的设计合成及性质研究

Metal complexes drugs (cisplatin and its analogues) are vitally important and irreplaceable antcancer drugs in clinic, however, a growing global issue is that these drugs have some serious problems, such as limited target specific selectivity, serious toxic and side effects. An effective solving strategy is to integrate targeted small molecules as ligand with platinum drugs to form targeted antitumor complexes, which exhibit significantly better pharmacological properties than corresponding small molecules or platinum drugs. Therefore, this project will focus on the research of targeted antitumor metal complexes which is not only based on the current research status of adenosine 5'-monophosphate-activated protein kinase (AMPK) inhibitors and metal complex drugs, but also combined the academic frontiers of organic chemistry, medicinal chemistry and computer aided drug design. In addition, the key scientific issues including the rational drug design, antitumor activity, structure-activity relationship, structure optimization of AMPK small molecule inhibitors and their metal complexes with high specificity and activity will be systematically studied. This project is expected to obtain a series of AMPK inhibitors which exhibit both target ability of small molecule AMPK inhibitor and unique property of metal complexes, and establish structure-activity relationship. The results of this project are also hoped to provide theoretical and technological support for revealing the mechanism of AMPK in the process of tumor occurrence and development, and lay the foundation for developing targeted new antitumor metallic drugs.

金属配合物药物（顺铂及其类似物）在临床上是一类非常重要且不可替代的抗癌药物，但该类药物靶向性有限、毒副作用严重等问题已经成为一个全球性课题。一种有效的解决策略是将具有靶向性的小分子配体与铂类药物进行结合形成靶向性抗肿瘤配合物，其药理性质显著优于单纯的小分子化合物或铂类药物。本项目以靶向性抗肿瘤金属配合物为研究对象，结合有机化学、药物化学及计算机辅助药物设计等前沿学科，基于单磷酸腺苷活化蛋白激酶（AMPK）抑制剂与金属配合物的研究现状，系统研究高特异性、低毒性的AMPK小分子抑制剂及其金属配合物的合理设计及合成、抗肿瘤活性、构效关系及结构优化等关键科学问题。项目预期获得一系列兼具小分子靶向性和金属配合物药物独特性质的抗肿瘤化合物并建立构效关系，为揭示AMPK在肿瘤发生及发展过程中的作用机制提供理论和技术支持，为开发新的靶向型抗肿瘤金属药物奠定基础。

金属配合物药物，特别是顺铂及其类似物在临床上非常重要，然而，这类药物从诞生至今发展十分缓慢，目前仅有7个药物用于临床，主要原因是由于该类药物靶向性有限、毒副作用严重等。一种有效的解决策略是将具有靶向性的小分子配体与铂类药物进行结合形成靶向性抗肿瘤配合物，其药理性质显著优于单纯的小分子化合物或顺铂类药物。本项目从AMPK小分子抑制剂的结构优化为起点，不断拓展小分子的结构类型，研究了靶向MetAP2、EGFR及BTK等靶点的4类小分子化合物，进一步合成了2类四价铂配合物，并深入研究这些化合物的抗肿瘤或抗微生物性质。这些研究发现了多类结构新颖的抗肿瘤和抗微生物化合物：噻唑并吡咯类化合物具有靶向MetAP2的潜力，该研究展示了理论计算和活性筛选结合发现先导化合物，并结合二者优势进行结构优化发现高活性分子，并进一步研究深入作用机制的流程。多重键-铂配合物是一类抗肿瘤潜力巨大的化合物，该研究揭示了将多键配体引入到顺铂中形成目标化合物，这种策略不仅增强了化合物的吸收、克服了顺铂耐药性问题，目标化合物还具有靶向线粒体和抑制肿瘤细胞解毒的潜力，该类化合物值得进一步研究和开发。