Studies On Synthesis And Antitumor Activity Of Bis-fluoroquinolone Chalcone-like Derivatives

With the incidence increasing year by year,cancer had been a common and frequently occurring disease threat to human life and health caused by many factors.Although the anti tumor drugs now used had made significant progress in improving survival time and life quality of patients,its clinical application was limit for the shortcomings of serious adverse reactions and the anti tumor drug resistance.Therefore,it was a major ongoing topic among scientists all over the world to seek out better anti tumor drugs.Quinolones was antibiotics with the structure characteristics of quinoline-4-ketone-3- carboxylic acid. On the basis of the mechanistic similarities and sequence homologies for the prokaryotic type II topoisomerases(DNA gyrase and topoisomerase IV) and the eukaryotic type II topoisomerases as the common celluar targets for antibacterial fluoroquinolone agents and many anticancer drugs, antibacterial activity is convertible to antitumor activity. Compounds with potential anti tumor activity was obtained by structural modification of quinolones in recent years, but it could not enter into the clinical research because of the pharmacokinetics and pharmacodynamics problems.Therefore, this study aimed to find a new method of structure modification to obtain high effect and low toxicity lead compound, which lay a foundation for further study.An over expression of topoisomerase(Topo) or protein tyrosine kinase(PTK) plays an important role in the occurrence,development and metastasis of tumors, thus, design and development of DNA TOPO and PTK-targeted inhibitors for the treatment of cancer will be very urgent. In view of more advantages of the multi-targeted drugs over the corresponding single-targeted drugs in cancer clinical trials, so design TOPO or PTK-targeted drugs for the treatment of tumor has the vital significance. Chalcone widespread in the medicinal natural products,was a kind of strong anti-tumor compounds with the basic structural features of 1,3-two phenyl acrylic ketone. In consideration of characteristics of antibacterial fluoroquinolones, chalcone ketones compounds and protein tyrosine kinase inhibitor-sunitinib, by a rational pharmacophore combination-based drug design, a series of antitumor small molecular difluoroquinolone-indole "chalcone-like" derivatives will be skillfully designed and synthesized. Finally, a preliminary structure-activity relationship of new title double fluoroquinolone-chalcones conjugates about effect of fluoroquinolone skeletons, isosteres and their corresponding substituents on activity, toxicity and target sites are summarize to further develop an effective approach for design of antitumor fluoroquinolones or new antitumor tyrosine kinase inhibitors.1 A synthesis of target compoundsa series of antitumor small molecular double fluoroquinolone chalcone-like derivatives linked with a active methylene chain will be synthesized by claisen-Schmidt condensation, fluoroquinolone C3 aldehydes and dihydrofluoro quinolone ketones derived from fluoroquinolone C3 carboxylic acids. The structures of new synthesized compounds were characterized by MS、1H NMR.2 Evaluation of antitumor activityThe in vitro antitumor activity against HGC823 Panc, T24 bladder cancer, gastric cancer, pancreatic cancer, HGC27, PU145, prostate cancer, gastric cancer, and pancreatic cancer cells Capan-1 cell lines was evaluate by a MTT assay method. The results showed that the target compounds had higher antitumor activity than the corresponding parent drugs. Among them, compounds E5, E6, F1, F4, F5, F6 exhibited the most potent activity, with IC50 values of 0.13~0.69 μΜ against Capan-1.3 ConclusionIn this study, 24 double fluoroquinolones chalcone derivatives were synthesized and the structure had been confirmed by spectral data. The results of antitumor activity in vitro showed that the target compounds had higher antitumor activity than the corresponding parent drugs. Therefore, fluoroquinolones aldehydes and two hydrogen fluoroquinolones was linked by activated olefinic methyl to obtain the new double fluoroquinolones chalcone lead compounds whoes anti-tumor activity was better than the corresponding parent drugs, which has the value of further study.