Design, Synthesis And Bioactivity Study Of Novel Small-molecule Hydroxamates As Histone Deacetylases Inhibitors

Histone deacetylases(HDACs) belong to a class of intracellular metalloproteases which play an important role in regulation of genes transcription by modifcation and remodeling of chromatin.In tumor cells,HDACs are over-expressed resulting in excessive deacetylated histones which packed DNA tightly to form an abnormal "compact structure" of chromatin.In this process, expression of CDKs(Cyclins dependent kinases) suppressor p21^WAF1/CIP1 is blocked and activity of onco-suppressor p53 is decreased,whereas,tumor activators HIF-1(Hypoxia inducible factor-1) and VEGF(Vascular endothelial growth factor) are up-regulated.Inhibition of HDACs could potently inhibit proliferation of tumor cells,cell cycle arrest and apoptosis,which makes HDACs become epigenetic targets for designing anti-cancer agents.Furthermore,the development of HDACi drugs has been recognized as an effectual strategy for cancer therapy.Small molecular hydroximate HDACs inhibitors(HDACi) have achieved significant biological effects in preclinical models of cancer and evoke popularity. In October 2006,the first hydroximate HDACi drug-SAHA(General name: Vorinostat,Trade name:Zolinza) was approved by FDA for treatment of T-cell lymphoma.Subsequently,more and more hydroximate HDACi entered clinical trials for treatment of solid tumor and hematological malignancy. This thesis contains two parts:Part A:Design and synthesis of novel cinnamamide class of HDACi.In this research,HDAC was used as target and the hydroximate HDACi with the scaffold of cinnamamide containing excellent antineoplastic activity both in vitro and in vivo was used as lead compound.Aided by computer aid drug design(CADD) software Sybyl 7.0,a novel series of cinnamamide hydroximates were designed and synthesized by means of isosteric principle.Totally 20 new compounds were synthesized through reactions of esterification,Williamson reaction,saponification and condensation,their chemical structures were identified by IR,1HNMR,ESI-MS.Among them,two compounds(4d and 4n) showed good inhibitory potency against HDACs and anti-proliferative activities to inhibit human colonic cancer cells growth.Part B:SAR study on the phenylpropanamide derivatives as HDACi:According to the structural features of the catalytic site of HDACs target and SAR information of known HDACi,rational drug design was performed.Phenylpropanoic acid derivatives were linked to glycin(Gly),β-alanine(β-Ala),γ-aminobutyric acid(GABA),para-aminobenzoic acid(PABA) and meta-aminobenzoic acid(MABA) according to the splicing principle.The -COOH group in these amino acids can be converted to be -CONHOH group,thus a new series of phenylpropanamide hydroxymates(10 compounds) were designed and synthsized. Inhibitory activity assays found that para-position substituted benzamide HDACi-9d and 9i showed good potency.The scaffold of 9d and 9i is N-hydroxy -4-(3-phenylpropanamido)benzamide(HPPB).Furtherly a novel series of HPPB derivatives were designed and synthesized,and among them two compounds(14h and 14r) exhibited higher potency against HDACs and human colonic cells growth than the control drug Vorinostat and the lead compounds 9d/9i.