Design,Synthesis And Anti-tumor Activity Of 4-phenoxy-6,7-disubstituted Quinolines Possessing(Thio)semicarbazones As C-met Inhibitors

In recent years,significant progress has been made towards developing anti-tumor drugs targeting c-Met receptor tyrosine kinase.c-Met kinase and its inhibitors were introduced in details in this paper.The paper focused on the design,synthesis and anti-tumor activity of 4-phenoxy-6,7-disubstituted quinolines possessing(thio)semicarbazones as c-Met kinase inhibitors.According to the structure-activity relationships(SARs)of the inhibitors bearing quinolines reported in other articles,such as Foretinib,N-acylhydrazone moiety,an important pharmacophore possessed in anti-tumor agent PAC-1,was introduced into 4-phenoxy-6,7disubstituted quinolines on the basis of combination principles and local modification.Thus,three series of quinoline derivates added up to eighty-one novel compounds were designed and synthesized,including(E)-N1-(3-fluoro-4-(6,7-disubstitutedquinolin-4-oxy)phenyl)-N4(substitutedmethylene)semicarbazones(serie Ⅰ),(E)-N1-(3-fluoro-4-(6-methoxy-7-(3(piperidin-l-yl)propoxy)quinolin-4-yloxy)phenyl)-N4-(substitutedbenzylidene)thiosemicarbaz ide(serie Ⅱ)and(E)-N1-(substitutedphenyl)-N4-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yloxy)benzylidene)semicarbazide(serie Ⅲ).The structures of all target compounds were confirmed by MS and 1H NMR,and some were identified by 13C NMR,2D NOESY and IR.All target compounds were evaluated for their anti-tumor activity in vitro against four cancer cell lines including c-Met-addicted human non-small-cell lung cancer cell line A549,human colorectal cancer cell line HT-29,human gastric carcinoma cell line MKN-45 and c-Met-less sensitive human breast cancer cell line MDA-MB-231 by MTT assay,taking Foretinib and PAC-1 as references.Some of compounds were evaluated for c-Met kinase inhibition by HTRF kinase assay,using Foretinib as reference.The results showed that some of compounds displayed preferable c-Met kinase inhibition,and IC50 values reached to nano molar level.Thirty-six compounds of series Ⅰ and Ⅱ showed superior or similar activity to Foretinib against one or more cancer cell lines in vitro,thereinto,the cytotoxicity against A549 and HT-29 of compounds Q-44 and Q-76 was 23.6-and 3.2-fold,18.1-and 6.1-fold than that of Foretinib,respectively.Besides,ten compounds of series Ⅲ exhibited superior or similar activity to Foretinib against one or more cancer cell lines in vitro,thereinto,the cytotoxicity against HT-29 and MKN-45 of compound Q-64 was 8.3-and 1.4-fold than that of Foretinib,respectively.Compounds Q-44,Q-64 and Q-76 with excellent activity in vitro were evaluated for their pharmacokinetics preliminarily,and the optimized compound Q-76 was evaluated for its antitumor activity in vivo preliminarily.The results indicated that compound Q-76 shrank tumor growth significantly in HT-29 xenograft mouse model,and the inhibition ratio was 65.9%(p<0.01)in volume.Furthermore,it was well tolerated with no overt signs of toxicity or changes in body weight in the same xenograft models.In addition,in order to further investigate the mechanism of compounds,compound Q-76 was evaluated for Western blotting and kinase selectivity in the paper.As a result,it exhibited preferable inhibition of phosphorylation of c-Met and kinase selectivity.According to the results of anti-tumor avtivity,the SARs of these novel compounds were discussed preliminarily,which would provide useful information for further study in this field.Therefore,it is worthy of further study in the following work.