Design,Synthesis And Activity Study Of Pyridones Of Bromodomain Protein 4(BRD4) Inhibitor

Although all cells in an individual have a common genetic sequence,the transcription of different genes is not same in different type cells.For example,the function of liver cells is different from that of nerve cells or skin cells.This is an embodiment of epigenetics,and epigenetic processes are currently attracting widespread attention in medicinal chemistry and drug development.Epigenetic changes are stable between cell divisions and do not involve changes in the underlying DNA sequences.This epigenetic regulation is partially mediated by the acetylation of specific lysine residues on histones and other proteins.The large number of lysine acetylations in human cells indicates that lysine acetylation plays an important role in signal networks and transduction.The bromine domain protein BRD,which contains a conserved structural fold,specifically binds to acetyllysine,therefore that promotes gene transcription and other downstream processes.However,in some cancer and inflammatory diseases,dysfunctional epigenetic regulation of gene transcription leads to abnormal expression of growth-promoting genes and pre-inflammatory cytokines.It has been proved that disrupting the interaction between BRD and acetyllysine could effectively prevent cell proliferation in cancer and cytokine production in acute inflammation.In the past decades,with the emergence of some new technologies and the unremitting efforts of scientific researchers,more than a dozen diverse BET / BRD4 inhibitors have entered human clinical trials for the treatment of cancer,central nervous system diseases,inflammation and other diseases.At present,there are many types of BRD4 inhibitors that have been developed,and azepines and pyridones have entered clinical trials.This paper introduced the BRD4 protein and summarized the anticancer mechanism and research progress of several BRD4 inhibitors.ABBV-075 derivatives were designed and synthesized based on small molecule ABBV-075 by means of molecular docking and homologous derivation.This paper mainly includes the following:1.An easy operation route in the laboratory of synthesis of ABBV-075 was designed and optimized.2.Two series of ABBV-075 derivatives were designed and synthesized,and some routes of the intermediate compounds were optimized.3.In vitro activities of the target compounds were analyzed,such as BRD4 BD2 enzyme activity evaluation and antiproliferative activity at the cellular level.