Studies On Design And Synthesis Of Small Molecule Compounds Based On DNMT Target

DNA methylation is occurred in most prokaryotic and rukaryotic genomes,which has a variety of important biological functions including gene imprinting,regulation of gene expression,X-chromosome inactivation,and preservation of chromosomal integrity.According to the studies,the tumor occurrence and evolution is closely related to the aberrant DNA methylation.It has been confirmed that the tumor can be treated through the inhibition of DNA methylation.DNMT has come into the spotlight as a promising therapeutic target for inhibiting tumor growth and has become one of the leading molecular target in cancer,which have been a particularly active field.In the previous investigations,we occasionally found that RC000 which can inhibit the DNA methylation.We designed and synthesized some novel compounds based on RC000.Hope to find more ideal DNA methylation inhibitors and to lay the foundation for developing DNA methylation inhibitors with clinical application value.This article summarizes the DNA methylation,the classification and function of DNMT and recent research progress in DNA methyltransferases.A series of6-bromo-1-methyl-1H-indole-3-carboxylic acid ester compounds(10 ones)were designed and synthesized by 7 to 10 reactions.The 10 novle compounds,which were not reported,were isolated,purified and characterized by MS and ~1H NMR.All the products were evaluated by DNMT1 half inhibitory concentration test in Shanghai Research Institute of biochemical of China.The results showed that 5 target compounds had the inhibitory effect on DNMT1,In which RC008 and RC010 had stronger with IC50 values of 44?mol/L and 13?mol/L than others.