Synthesis Process Optimization Of Givinostat And Design,Synthesis And Preliminary Activity Evaluation Of Double-Branched HDACIs

Many epigenetic phenomena have testified that the posttranslational modification(PTM)of histone can cause a functional change in gene expression or chromatin structure,a common form and one of the first discovered is histone acetylation,which could regulate gene expression.The exact number of acetylated lysine residues occurred in histones which are self-perpetuating and heritable in cellular is not clear,but it is known that histone acetylation is an abundant source of potential epigenetic information.Histone acetylation is highly reversible,a lysine residue was acetylated by histone acetyltransferases and deacetylated by deacetylases.There are four classes divided into 18 HDACs,Class I Rpd3-like protein,Class? Had-like protein,Class?sir2-like protein and ClassIV protein.The different structure of ClassI,ClassII and other HDACs homologs from different species share homology with human classical HDACs,and contain active site,they share mechanism of metal-dependent hydrolysis of acetylated substrates.ClassIII use NAD+ as reactant to deacetylate lysine residue of protein substrate and form nicotinamide,the deacetylated product,and the metabolite 2'-O-acetyl-ADP-ribose.Like other cellular enzymes,HDACs modulate various mechanism and pathway such as protein-protein interaction.Disease with multifactorial related to an etiology of epigenetic.The "epigenetic therapy" may offer a new potential way these disease,and one of epigenetic agents is HDACIs.For example,there are more and more efforts to develop the potent anti-cancer agents,but the toxicity and side effects in the treatment various cancers limit their use,the scientists are engaged in developing small molecular targeting abnormal epigenetic factors.The development of safe and potent therapeutic agents with minimal adverse and side effect is still focus on current research work,and subtype selectivity HDACIs may meet the requirements,so the discovery of HDACs is a turning point in treatment cancer.Givinostat(ITF2357)is a pan-HDAC inhibitor developed by Italfarmaco,Italy.Givinostat is currently in phase III clinical study for the treatment of relapsed leukemia and myeloma.Based on the original research route,we optimized the synthesis of Givinostat to be more economical,green and suitable for industrial production.According to the pharmacophore model of Givinostat and HDACIs,a series of double-branched compounds with indoles as cap and hydroxamic acid as ZBG were designed based on the previous compound 12m in the laboratory and the marketed drug LBH-589,and their activities were preliminary evaluated with SAHA and PXD101 as positive controls,the results showed that 7e,7h,7i,7j,71,7r,7s,7t exhibited good HDACs inhibition activity,7h,7i,7j,71,7r good anti-proliferation,71 and 7r had subtype selectivity to HDAC1.In summary,we optimized the synthesis route of Givinostat to make it more economical and green.Meanwhile,we designed,synthesized and preliminary evaluated a series of HDACIs,71 and 7r were selective for HDAC1.Therefore,we hope to further study the double-branched HDACIs to obtain anti-tumor candidate HDACIs.