Design,synthesis And Structure-activity Analysis Of The Conazole Mutant IDH Inhibitors

Isocitrate dehydrogenase(IDH)is one of the key enzymes in tricarboxylic acid cycle in human body.Gain-of-function mutation of IDH not only affects the normal metabolic activity of human cells,but also catalyzes the production of the metabolite 2-hydroxyglutarate(2-HG),which has been proved to be a carcinogenic compound.Previous studies have shown that 2-HG can inhibit the activities of various dioxygenases such as TET protein,histone demethylase and prolyl hydroxylase(PHD),which can lead to the disorder of epigenetic modification of the cellular genome,the blockage of immature cell differentiation and finally the emergence of tumor.It is worth noting that the disorders of human regulation including epigenetic regulation caused by gain-of-function mutation of IDH are reversible.It would be possible to treat the malignant tumor caused by the mutated IDH through inhibiting the activity of the mutant IDH.Based on the above concept,Mutant IDH inhibitors used as drugs for treating mutant IDH tumors have been successfully marketed in the United States recently,but the research of these fields was still blank china.This paper was carried out to explore and develop new IDH inhibitors.With the help of Computer Aided Drug Design(CADD),four Conazole drug molecules that can inhibit IDH1/R132 H activity were screened successfully from the old drug library.According to the inhibitory activity of these four Conazole molecules on IDH1/R132 H,13 Conazole compounds were designed and synthesized successfully,and they were classified into four categories: A/B/C/D.In the aspect of biological activity test,the inhibitory effects of 17 Conazole compounds on IDH1/R132 H were tested,and 11 of them showed significant inhibitory effects.Through the analysis of the experimental results,the core pharmacodynamic group D1 of Conazole molecule inhibiting IDH1/R132 H was found.The structureactivity relationship of anti-IDH1/R132 H activity of Conazole compounds was revealed preliminarily,which could provide useful experience for the development of novel mutant IDH inhibitors.