Design,Synthesis And Preliminary Study Of Antitumor Activity Of Novel FLT3/VEGFR2 Dual Inhibitors

Objective:Based on the obtained results of our group,the lead compound QYX-H25was optimized according to the binding modes with FLT3 and VEGFR2.The biological activity of all novel compounds was evaluated,and the structure-activity relationships were summarized preliminarily.Finally,more potent FLT3/VEGFR2 dual inhibitors were obtained.Method:Taking 3-hydroxy-4-methoxyacetophenone as starting material,6a-6f and 6h-6q were prepared through nucleophilic substitution,chlorination,condensation and cyclization reactions,etc.Taking 4-chloro-6,7-dimethoxyquinoline as starting material,6g was prepared through nucleophilic substitution,condensation and cyclization reactions,etc.The structures of target compounds were confirmed by HRMS and ¹HNMR.The inhibitory activities against FLT3 and VEGFR2 were determined by mobility assay.In vitro antitumor activity against human myelomonocytic leukemia cell line MV-4-11 was evaluated by CTG assay.Results:Seventeen novel quinoline derivatives bearing thiazolinone or thiazinone fragments were designed and synthesized,and their structures were confirmed by ¹HNMR and HRMS.The results of biological activity against FLT3 and VEGFR2 indicated that most of the compounds showed a good inhibitory activity.Among them,the compound6m was confirmed as the most potent compound with IC₅₀ of 6.9±0.52 nM and 14.6±0.95 nM against FLT3 and VEGFR2,respectively.Based on the above results,we summarized the preliminary structure-activity relationship of this series of compounds.In vitro antitumor activity results show that some of target compounds have better inhibitory activity on human myeloid monocytic leukemia cells MV-4-11 than Sorafenib.Among them,the most active compound 6m was obtained with an IC₅₀of 12.1±1.1 n M against MV-4-11,which was 26 times better than that of Sorafenib.Conclusion:A series of novel quinoline derivatives containing thiazolinone or thiazinone fragments were designed and synthesized,and their structures were confirmed.Preliminary structure-activity relationships were summarized according to the results of biological evaluation.Most of compounds showed good inhibitory activity against FLT3and VEGFR2,with IC₅₀values reaching the nanomole level.In addition,this series of compounds have excellent in vitro antitumor activity against human myeloid monocytic leukemia cells MV-4-11 which was more potent than that of positive control Sorafenib.