Design,Synthesis And Anti-tumor Activity Evaluation Of Histone Deacetylase Inhibitor Based On The Scaffold Of 8-substituted Quinoline-2-Carboxamide

Quinoline is a very important organic compound and widely present in nature.It is composed of benzene ring and pyridine ring.Quinoline is widely used in the pharmaceutical industry due to its special biological effects,and has applications in anti-tumor,anti-malaria,and antibacterial.The application of quinoline scaffold as anti-tumor drugs has a very long history.Quinoline alkaloids are a kind of alkaloids with quinoline as the core.Among them,camptothecin is used in traditional Chinese medicine for the treatment of cancer.In addition,the quinoline scaffold is also widely used in small molecule kinase inhibitors and histone deacetylase inhibitors.Besides these applications,quinoline compounds can also inhibit the proliferation of tumor cells through some other mechanisms.We first introduce the application of quinoline compounds in different fields,and conduct research on anti-tumor small molecule compounds based on the quinoline structure.Based on the previous research work of our research group,we found that the compounds wl-9w and cc-4a with quinoline scaffold showed good HDAC inhibitory activity and anti-proliferation activity in vitro.Through the structure-activity relationship analysis,we applied medicinal chemical structure modification strategies and computer-aided drug design methods to modify the structure of compounds wl-9w and cc-4a.We introduce an aromatic group or an alkyl group as enzyme surface recognition region by ether bond at 8 position of quinoline,and a linker group is introduced at the 2 position to connect with a zinc binding group.We designed a series of histone deacetylase inhibitors based on the scaffold of 8-substituted quinoline-2-carboxamide.Based on the above design,we use 2-methyl-8-hydroxyquinoline as the starting material to obtain 8-hydroxy-quinoline-2-carboxylic acid through two-step oxidation reactions.Amide condensation and Williamson reaction were conducted to get the key intermediate methyl ester.Finally,the methyl ester directly converted to hydroxamic acid and get target compounds.A total of 38 target compounds were obtained in this project.All target compounds have been subjected to 1H-NMR,13C-NMR and HRMS for structural confirmation.The result showed that some compounds have better HDACs inhibitory effects compared to Vorinostat in vitro inhibitory assay.The structure-activity relationship analysis found that when linker was methyl or ethyl,compounds showed poor inhibitory activity.Whereas when the linking group is 4-aminomethyl or long-chain aliphatic chain(propyl,butyl or pentyl),it showed good inhibitory activity.Isoform assay proved that the compounds have inhibitory activity against HDAC1,HDAC2 and HDAC6.The results of in vitro anti-proliferative activity experiments showed that compound ZYP-85 had a better inhibitory effect on tumor cells than the positive control Vorinostat.In summary,we designed and synthesized 38 HD AC inhibitors of which the HDACs inhibit activity of ZYP-79,ZYP-81,ZYP-83,ZYP-84 and ZYP-85 have been significantly improved.And ZYP-85 also showed good anti-tumor activity in vitro Based on the results,we can continue to modify and optimize the structure to find compounds with higher selectivity and better anti-tumor activity.