Design,Synthesis And Antitumor Activity Study Of Novel Histone Deacetylase Inhibitors Containing Amino Acid Cyclopentyl Ester

Histone deacetylases(HDACs)are a family of metalloproteinase widely expressing in eukaryotes.By catalyzing the removal of acetyl groups from lysine residues in N-terminus of a histone,HDACs could trigger the condensation of chromatin consequently resulting in transcriptional silencing.HDACs play an important role in regulating the expression of oncogenes,therefore,HDACs have been recognized to be closely related with tumorigenesis.To date,18 HDACs have been identified in humans,among which,11 HDACs are zinc dependent HDAC enzymes.Compelling evidences have validated the benefits of UDAC inhibition in various tumor cells,including anti-proliferative,differentiating and pro-apoptotic effects.In the past decades,more and more HDACi candidates have entered clinical trials even been approved by FDA.According to their Structure-activity relationship.we find that most of HDACi consist of three pharmacophore domains,a Zn2+ binding group(ZBG)which could chelate the Zn2+ located in the deep of the active site,a hydrophobic cap group which could be bound to hydrophobic amino acid residues on the surface of the active site and a hydrophobic linker which could concatenate the ZBG and the cap group.Evidence to date,have indicated that the therapeutic and toxic effects of drugs are often generated through effects on different cell lines in the body.Although pharmacological benefits of such drugs are often apparent,their effects on cells which are not involved in the disease process always reslut in toxicity.Therefore,selective delivery of drugs to specific cells or cell lineages would.consequently,have major advantages,in particular,the potential to significantly improve the therapeutic window of an agent.In the present paper,guided by the structure of a monocyte/macrophage targeted HDACi-tefinostat and the pharmacophore of the HDACi.vve designed and synthesized 21 novel compounds by attaching a small esterase-sensitivc chemical motif(ESM)which is selectively hydrolyzed within monocyte-macrophagcs.Subsequently,we evaluated the HDACs inhibition activity and anti-proliferative activity of such targeted compounds by using SAHA and MS275 as the positive control.Among them,4-hydroxybenzamide-based compounds displayed slightly increased HD AC inhibition compared with 3-hydroxybenzamide-based HDACi.Additionally,in in vitro anti-proliferative assay,benzamide HDACi showed greater growth inhibition than hydroxamic acid HDACi,which was exampled by compounds 6a and 6b,exhibiting modest anti-proliferative potency against multiple tumor cell lines such as HEL,K562 and KG-1.Moreover,representative compound 6k exhibited similar HDACs isoform selectivity to SAHA,demonstrating that compound 6k is a pan-HDACi.