Ouinazolinone And The Design,Synthesize,Activity Study Of Bromodomain Small Molecule Inhibitors

In many natural products such as febrifugine, tryptanthrin, and luotonin A have quinazolinone structure. This kind of natural products containing quinazolinone skeleton mostly showed excellent anti-tumor, anti-virus, anti-inflammatory and other biological activity. On the other hand, there are already a variety of drugs listed containing quinazolinone derivatives. So the study of quinazolinone derivatives has become the hot spot. In recent years, the present study showed, BRDs is the only specifically recognize acetylated lysine and binding proteins. So BRDs play an important role in the field of regulation of gene expression. The study of BRDs as drug targets has become one of hot research field of medicinal chemistry.This study contains two main parts:Part â… :CuCl-mediated cross dehydrogenation coupling reaction to obtain quinazolinone derivatives. Building reaction system by CuCl, KOtBu, DMSO forms a kind of new CDC method to obtain quinazolinone derivatives. Quinazolinone derivatives are mostly with good yield. This reaction have a mild reaction conditions and good functional group tolerance, broke through the aryl substituent limited and received several aliphatic substituted quinazolinone derivatives. This approach can provide ideas and effective means for the subsequent study of quinazolinone derivatives approach.Part â…¡:We designed and synthesized a class of quinazolinone derivatives of 3,5-dimethyl-isoxazole small molecules for inhibitor BRD4. We make use of the advantage of the functional groups splicing principle, advantage fragment reorganization principle. We obtain 21 small molecule inhibitors for BRD4 which have moderate to good yield. The biological activities of these compounds were tested. The results showed that only a few compounds has a weak inhibitory effect on BRD4. Unfortunately other molecules were inactive. Nevertheless, we still provide new structural basis for follow-up study, provide reference for the subjsequent modification and transformation of the structure.