Synthesis And Anti-proliferative Activity Of Fluoroquinolone C3 Urea Derivatives

As a serious threat to human health,cancer causes more than about 1,500 deaths per day.Despite the r ecent advances in cancer treatment technology,and the emergence of anticancer drugs has also improved th e survival of cancer patients.But after the long-term using of anticancer drugs,the drug resistance and side effects and other issues followed.Therefore,the development of new tumor drugs is extremely urgent.The development of new drugs can be obtained from natural products,such as camptothecin,paclitaxel,quinine,artemisinin,etc;or it can also be obtained from structure optimization and modification of lead compounds,thus the active compounds can finally be designed and synthesized.Fluoroquinolones,which are widely used as clinical antibacterial drugs,performed antibacterial effect by inhibiting bacterial gyrase and DNA topoisomerase IV.These two enzymes are belonged to bacteria type II topoisomerase,which is similar in the function and amino acid sequence of eukaryotic topoisomerase II.Thus,it is expected to transform its antibacterial action into the anticancer activity by structure modification,and then develop to new anticancer drugs.Previous studies found that fluoroquinolone C-3 carboxyl is not necessary for antitumor activity and can be replaced with other atoms,which has provided another approach for researchers.Urea compounds,as protein tyrosine kinase inhibitors,have become research focus at present.Over twenty protein tyrosine kinase small molecule inhibitors have become listed,and most of them owe the structures of(-CONH-)and(-NH-CO-NH-).However,the structure of the fluoroquinolones connecting with ureoid groups on its C-3 has never been reported.In this paper,the carbon atom of fluoroquinolones C-3 is replaced by the nitrogen atom,and the structure of urea is introduced into the dominant skeleton of quinolone to realize the splice and activity superposition of pharmacophores.Finally fluoroquinolones C-3 Urea target compounds were designed.To discover novel antitumor lead compounds,a series of fluoroquinolone C-3 urea derivatives(7a-7n,8a-8f)were synthesized with fluoroquinolone amide fluoroquinolone C-3 amine scaffold as a carrier.The structures of twenty-four title compounds were characterized by HRMS,~1H NMR and IR.The anti-proliferative activity against SMMC-7721,Capan-1 cells in vitro was evaluated by MTT assay.20 target compounds were synthesized and their structures confirmed by HRMS,~1H NMR and IR.As the inhibitory activity against Capan-1 cell lines was more potent,their antiproliferative activity against the two cancer cell lines was significantly higher than that of the control substance(ciprofloxacin,norfloxacin).The half inhibitory concentration of 7g,7h,7i,7d,8e,8f against SMMC-7721 cell lines was below10μmol/L,and the values of 7g,7h,8f were lower than the reference substance sunitinib.The inhibitory concentration of target compound 7n against Capan-1 cells was below 10μmol/L and close to sunitinib.In general,the urea derivatives derived from the introduction of urea groups at the C-3 position of fluoroquinolones which have showed potent antitumor activity could be regarded as lead compounds with promising prospects.Moreover,it has an important significance on the study of urea receptor protein tyrosine kinase small molecule inhibitors,but also provide more evidence for the study of the new fluoroquinolones with antitumor activity.