Design,Synthesis And Antitumor Activity Of Histone Deacetylase Inhibitors Based On 5-aminoquinoline

Epigenetics can affect the performance of traits without causing changes in DNA sequence.Its manifestations include DNA methylation,histone modification and chromatin remodeling.Histone acetylation is one of the most widely studied modification ways.Under normal physiological conditions,the degree of histone acetylation remains relatively stable under the co-regulation of histone acetyltransferases(HATs)and histone deacetylases(HDACs).Not only HDACs can affect the acetylation of histones but also non-histone proteins.By regulating the acetylation of different substrates,it can affect various physiological processes including apoptosis,differentiation and metabolism.Studies have shown that it is overexpressed in a variety of cancer cells and is one of the important targets for the treatment of cancer.The design and development of small molecule inhibitors with histone deacetylase inhibitory activity has broad application prospects.At present,a number of histone deacetylase inhibitors have been approved for the treatment of tumors,such as Vorinostat,in addition,there are still some compounds in the clinical research.Drugs containing quinoline structure have been increasingly used in medicinal chemistry,such as anti-malarial and anti-inflammatory.Using quinoline as the main skeleton,on the one hand,can make the compound shows better biological activity,and on the other hand,it is also conducive to make a compound to be a "real drug".Therefore,the quinoline can be introduced into the design of anticancer drugs and become one of the most important skeletons for the development of anticancer drugs.In our previous work,the quinoline was used as the enzyme surface recognition region,and a lot of work was done on the exploration of histone deacetylase inhibitors.Besides,through literature research,we found that introduction of ZBG at the C-5 position or C-8 position of the quinoline ring is beneficial to improve the inhibitory activity.Based on this,this project designed a series of compounds with 5-aminoquinoline as the basic core.The synthetic route was determined through the design and retrosynthetic analysis.In the synthesis process,we use 5-aminoquinoline or 5-amino-8-hydroxyquinoline as the starting material,through the amide condensation catalyzed by HATU,the protection and de-protection of hydroxyl group and reduction of nitro group resulted in a total of 85 new compounds,including 25 target compounds and 60 new intermediates.All of the desired compounds have been subjected to 1H-NMR,13C-NMR and HRMS for structural confirmation.The results of the HDACs activity of the target compounds showed that when the aliphatic chain was used as linker,the inhibitory activity showed a trend of increasing with the extension of the carbon chain.When N-hydroxybenzamide was used as ZBG,the substituents in the para position showed the best inhibitory activity.Among them,compounds XM12,XM14,XM20 and XM22 showed similar activities to the positive drug.The subtype selectivity experiment showed that XM12 showed the best activity.Compared with the positive control drug,SAHA,the activity of XM20 on HDAC8 was increased about 10 times,which was helpful to further develop HD AC 8 inhibitors with better activity and selectivity.In the anti-proliferation experiments on tumor cells in vitro,we selected two solid tumor and two hematological tumor cells as the research objects.The results showed that all the compounds exhibited certain antiproliferative activities on MV4-11 cells,among which XM12 exhibited the best antiproliferative activity,but it still needs further structural modification and optimization,and can be used as a lead compound to provide direction for follow-up research.