Studies On Design, Synthesis And Bioactivity Of Anti-cancer Drugs Based On C-Met Target And Combretastatin A-4Analogues

This dissertation for Ph. D. degree focuses on finding small molecules with highanticancer activity and more active targeting in the enzymic level and/or celluar levelbased on c-Met receptor tyrosine kinase and tumor angiogenesis, respectively. Wecomprehensively employed design based on structure-based design, chemicalsynthesis and evaluations of biological activities to investigate their structure-activityrelationships of BMS777607and Combretastatin A-4. The content of thisdissertation was divided into two parts as follows:1. Design and synthesis of c-Met kinase inhibitors, biological activity evaluationand preliminary structure-activity relationship study.Basing on BMS-777607, a significant Type II c-Met inhibitor discovered byBristol-Myers Squibb, we designed a series of c-Met inhibitors and evaluated theiractivities. According with the structures deconstruction, we disconnected thesubstructure into four units such as Blocks A-D for optimization.1) For Block B (Pyridinone fragment) unit optimization,14compounds weredesigned and synthesized by replacement of pyridinone with sulfonyl amino group,internal sulfonyl amino group and piperidyl-2-one linkages, which showed moderatec-Met inhibitory activity and cellular activity. It is noted that compound72and81arethe best of all, and their c-Met IC50are less than100nM.2) For Block D (3-choloro-2-aminopyridinyl) unit optimization, substitutionsof aminopyrimidine, pyrrolpyrimidine and quinoline structure for3-choloro-2-aminopyridinyl resulted in leads equivalent to or better than BMS-777607. Among thesecompounds, c-Met inhibitory activities for88,89and90are better than BMS-77607,and the cellular levels activities of compounds88and89were less than0.1μM.3) Simultaneous alternation of the structure of Block B and Block D furnished 12compounds, most of which showed c-Met kinase inhibitory activities. It should benoted that compound97is the best of all, which has a c-Met kinase IC50as8.6nM,and significantly inhibited the BaF3-TPR-Met cell proliferation (90.5%/1μM). Furhteroptimization of97led to its α-alkyl-2-piperidone derivatives, which possessessignificant c-Met inhibitory. In addition, we also used scaffold hopping to design fourisoflavones derivatives bearing α-substituted piperidone arm. Their biologicalactivities remain to be evaluated.Based on the above results, structure-activity relationship was further clarified:For Block A unit, substitution on phenyl group show a weak influence; For Block Bunit, the pyridone and α-choloro piperidone connection arm are better than the others,and the cyclic structures are superior to the flexible straight-chain fragments;The hydrogen of amide linkage between Block B and Block C is essential for theactivities; For Block D unit, the quinolyl substitution is the best of all, while the3-chloro-2-aminopyridinyl is slightly weaker than the quinolyl.2. Studies on Design, Synthesis and Bioactivity of Combretastatin A-4analogues.We have designed and synthesized11CA-4analogues which containN-methylation amide, maleimide and2H-1,4-dithiine. The CA-4analoguessynthesized were evaluated against a small panel of tumor cell lines including humanpancreatic tumor (BxPC3), human breast tumor (MCF-7), human lung carcinomas(A549) and human colon tumor (HCT116). Compared with CA-4, Most ofCA-4analogues synthesized are significantly less activitive except226, which was50fold less active than CA-4.