Design,Synthesis And Anti-tumor Activity Study Of Thiazolinone Urea Derivates

Objective:Based on the obtained structure-activity relationship of small molecule c-Met inhibitors bearing quinoline scaffolds,thiazolinone urea fragments with various biological activity was introduced into the structure of aryloxyquinoline,and a series of novel receptor tyrosine kinase inhibitors were designed and synthesized.The structures of target compounds were indentified,and the antitumor activity and mechanism were studied.According to the results of biologaical evaluation,the structure-activity relationship was analyzed.Methods:Taking 4-hydroxy-3-methoxyacetophenone as the starting material,a series of tyrosine kinase inhibitors with thiazolinone urea fragments were synthesized by O-hydrocarbon reaction,nitration,ammonia methylation,intramolecular cyclization,N-alkylation,chlorination,nucleophilic substitution,reduction,acylation,hydrazine hydrolysis and condensation,etc.The structures of target compounds and some intermediates were indentified by HRMS,¹HNMR and ¹³CNMR.The inhibitory activity of the compounds against kinases such as c-Met、IGF-1R、KDR and Ron was determined by mobility assay;in vitro anti-tumor activity against A549,HT-29 and MDA-MB-231 cell lines was assessed by MTT assay.The mechanism was preliminarily uncovered by real-time dynamic living cell imaging,flow cytometry and cell scratch assay,respectively.Results:A series of 41 novel tyrosine kinase inhibitors with thiazolinone urea fragments were designed and synthesized.The structures of the target compounds were indentified by HRMS,¹HNMR and ¹³CNMR.The inhibitory activity of major compounds against tyrosine kinase and tumor cells was comparative to or significantly superior to that of positive drug.According to the results of biological evaluation,the structure-activity relationship of these compounds was basically revealed.CompoundⅫ-35,the most potent compound,showed high inhibitory activity on the kinases such as c-Met,Ron,IGF-1R and c-Kit,with IC₅₀ of 0.015μM、0.0029μM、4.27μM和0.064μM,respectively.The results of in vitro anti-tumor activity indicated that the IC₅₀ values human non-small cell lung cancer cell line A549and human colon cancer cell line HT-29 were 0.35μM and 0.073μM,which was 27times and 157 times than that of the positive drug,respectively.At the concentration of 3.0μg/mL,compoundⅫ-35 showed comparative apoptotic ability as Cabozantinib（5.0μg/mL）.CompoundⅫ-35（0.01μg/mL）and Cabozantinib（10.0μg/mL）showed similar cytotoxity against HT-29 cells at 72 h.When the concentration was 10.0μg/mL,compoundⅫ-35 could remarkably inhibit the proliferation of HT-29 cells within 72 h,and the cell confluence decreased from 28.3%to 24.3%.In addition,compoundⅫ-35 also showed stronger inhibitory effect on tumor cells migration than that of Cabozantinib.Conclusion:The novel compounds bearing thiazolinone urea fragments showed potent in vitro antitumor activity and kinase inhibitory activity.The IC₅₀ values reach to sub-nanomolar to nanomolar level.The cytotoxity and the antiproliferation of compounds were superior to that of Cabozantinib.In addition,compounds could also induce apoptosis and suppression of cancer cell migration in time-and dose-dependent manner.