基于人血清白蛋白IB/IIA亚域N-供体氨基酸发展抗肿瘤多靶点先导缩氨基硫脲金属(Fe、Pt、Ru、Au和Os)化合物

如何研发多靶点抗肿瘤药物仍是全球研究热点和难点。一方面金属化合物可能通过多重机制作用肿瘤细胞，另一方面人血清白蛋白载体有助于提高先导金属化合物的成药性。因此，本项目融合无机药物化学、结构生物学、分子药剂学等学科的理论和技术开展以下研究：(1) 合理设计不同系列缩氨基硫脲化合物与金属 (Fe、Pt、Ru、Au、Os) 离子合成新颖的抗肿瘤先导金属化合物；(2) 揭示缩氨基硫脲金属化合物的多靶点抗肿瘤机制；(3) 构建基于人血清白蛋白IB/IIA亚域的特定氨基酸发展先导缩氨基硫脲金属化合物模型。本项目将总结缩氨基硫脲金属化合物的构-效关系，阐明其作用肿瘤细胞的新靶点/机制；验证和阐明人血清白蛋白提高先导金属化合物在体内的生物利用度、靶向能力和降低其副作用的机制。旨在为基于功能蛋白质导向发展新型多靶点抗肿瘤金属药物和靶向治疗肿瘤策略做出基础性和前瞻性工作。

How to develop multi-target anti-tumor drugs is still a global research hotspot and difficulty. On the one hand, metal compounds may act on tumor cells through multiple mechanisms; on the other hand, human serum albumin helps to improve the formation of lead metal compounds. Therefore, the project integrates the theories and technologies of disciplines for inorganic pharmaceutical chemistry, structural biology, molecular pharmaceutics to conduct the following research: (1) Rational design different series of thiosemicarbazones and metal (Fe, Pt, Ru, Au, Os) ions to synthesize novel antitumor lead metal compounds. (2) Explore the multi-target antitumor mechanism of metal thiosemicarbazones complexes. (3) Build a model for developing lead metal thiosemicarbazones compounds based on the specific amino acid(s) of human serum albumin IB/IIA sub-domain. This project will summarize the structure-activity relationships of metal thiosemicarbazone compounds, clarify the potential new target/mechanism of their action against tumor cell, and verify the mechanism of human serum albumin to improve the bioavailability, targeting ability and reduce the side effects of lead metal compounds in vivo. The purpose of our study is to make basic and prospective work for developing the new multi-target anti-tumor metal drug and targeted treatment strategies based on functional protein guidance.