Synthesis And Antitumor Activity Of Fluoroquinolone-3-N-Amide Derivatives

Cancer is a kind of disease that seriously endangers human's health,whose incidence rate is increasing year by year.Although there are many methods for treating cancer in clinical practice,at present,it is still mainly treated by chemotheraphy.However,there are many problems with existing antitumor drugs such as serious toxic side effects and a low therapeutic index which due to poor selectivity and drug resistance.Therefore,the design and development of new antitumor drugs have received extensive attention.The research and development of new drugs begin with the discovery of lead compounds,where rational drug design based on mechanism or structure of it is an effective method for discovering lead compounds,and structural modification of existing drugs is the most cost-effective means.As a widely used antibacterial drug in clinical practice,fluoroquinolone plays a role in killing bacteria by inhibiting bacterial DNA gyrase and Topoisomerase IV and thereby interfering with the normal replication,transcription and expression of DNA.Topoisomerase II,which is similar to DNA gyrase and Topoisomerase IV in the sequence and function,also existing in eukaryotic cells,and overexpression of Topoisomerase II is closely related to the occurrence and development of tumors.Inhibitors of it have become the main antitumor drugs.Therefore,it is possible to convert an antibacterial fluoroquinolone into an antitumor fluoroquinolone by a structural modification method.At the same time,structure-activity relationship studies have shown that fluoroquinolone C-3 carboxyl group is not a necessary pharmacophore for its antitumor activity,and its antitumor activity can be improved by its isosteric substitution,which provide the design of antitumor fluoroquinolone molecule with an idea.However,it is currently unknown that which C-3 carboxyl isostere is a suitable pharmacophore for enhancing its antitumor activity.Considering that the occurrence and development of tumor cells are closely related to protein tyrosine kinases,and significant progress has been made in the study of antitumor drugs based on small molecule protein tyrosine kinase inhibitors(PTKIs),and several compounds of it have been successfully used in targeted therapy of cancer,and has received much attention for showing good results.Among them,PTKIs such as Gefitinib,Imatinib,Dasatinib,Sunitinib,Axitinib,etc.are all owning amide chemical structures.Amido group has become the dominant skeleton of PTKIs,and its binding to tyrosine kinases is a keyfactor in its antitumor effect.Therefore,basing on the skeleton migration principle and drug effect group flattening drug molecular design strategy,this paper use amide group as the bioelectronic isosteres of the C-3 carboxyl group to design and synthesis fluoroquinolone-3-N-amide target compounds.Rationality of structural modification is evaluated by the in vitro antitumor activity screening.The fluoroquinolone carboxylic acid is condensed with carbonyldiimidazole to obtain fluoroquinolone imidazole amide,which is subjected to amidolytic reaction with hydroxylamine to obtain fluoroquinolone hydroxamic acid,and the key intermediate fluoroquinolone C-3 amine is obtained by Lossen rearrangement reaction,and then acylated with acid chloride and obtain the target compound fluoroquinolone-3-N-amide derivatives.The structures of the 22 new target compounds were confirmed by1 H NMR,HRMS and IR.The growth inhibition of target products in vitro on three tumor cells(A549,CT-26 and SMMC-7721)was evaluated by MTT assay.Preliminary results showed that the anti-proliferative activity of the target compounds against the two experimental tumor cells(A549,CT-26)was significantly stronger than that of the raw material ciprofloxacin and enrofloxacin,and the inhibitory activity against A549 cells is the strongest.The structure-activity relationship indicates that the anti-tumor activity of the target product containing a strong electron-withdrawing group(nitro,fluorine)is significantly stronger than that owning a electron-donating group.In particular,the IC50 of 3e,3h,4e and4 h on A549 cells was about 10 ?mol/L,which possessing potential research value.However,the target product had poor antiproliferative activity against SMMC-7721 cells and showed selectivity in some extent.To this end,basing on mechanism and rational drug design strategy based on fluoroquinolone's target topoisomerase is also a important target for antitumor drugs,utilizing pharmacophore bioelectronics isosteric and its flattening and skeleton migration medicinal molecule construction method,this paper using amino group as the bioisostere of the fluoroquinolone C-3 carboxyl group,and fluoroquinolone skeleton as a functional modification group to construct fluoroquinolone-3-N-amide target compounds,and their structures are confirmed by spectral data.The results of in vitro antitumor activity indicated that the target compounds were more active than the parent ciprofloxacin and enrofloxacin,suggesting that replacing the C-3 carboxyl group with an amide group is beneficial to improve the antitumor activity of the quinolones,which provides a new structural modification pathway for transforming antibacterial activity of fluoroquinolone to antitumor activity.