Design,Synthesis And Anticancer Activity Study Of Benzamide And Cinnamamide Derivatives As Histone Deacetylases Inhibitors

Cancer has become the second killer of humen health following the heart disease. It is caused by diverse reasons which include environmental pollution, chemical pollution, ionizing radiation, microorganism, hereditary capacity, unbalance of internal secretion. Because of the development of science and the damage of environment, humen now are likely to be hurt by these cancerogen, and the rate of cancer has been increasing year by year. Just as the characterizes of diverse pathogenesis and recurrence of cancer, cure of cancer has become the biggest puzzle for humen. Now methods for cancer are mainly about operation, radiate, chemistry and prevention. As a chemist, we mainly design and synthesize new compounds on the base of relevant cancer target spot, and then value their antitumor activities. HDAC which is regared as intracellular metalloprotease has been regarded as a new target and hot point for cancer. HDAC plays an important role for gene expression and posttranscriptional modification. In tumor cells overexpression of HDACS increases hyperdeacetylation of histone which causes hypercombination of histone and DNA, at last transcription is suppressed. So inhibition of HDAC can inhibit the proliferation of tumor and cause apoptosis.With the development of computer, Computer Aided Drug Design(CADD) has been used for screening and design compounds. It can improve the rationality of compounds design, and enhance the activity of compounds, above all efficiency of compounds has been improved by CADD. My topic mainly pays attention to compounds of hydroxamate, we studied the structure activity relationship on the base of previous work about phenylpropanamide derivatives, one compound was designed and synthesized from leading compound.The activities of rigidity and flexibility were compared by means of reduction of cinnamamide fragment double bond. We also studied the structure activity relationship of cinnamamide compounds synsized by the way of CADD. A series of compounds characterized with hydroxamate were designed from the raw materials L-Trp on the base of LBH-589which has been studied in phase â…¢. Firstly valproate which was reported with anticancer activity was introduced into amino of Trp,and its pharmacokinetics was studied. Diverse structurally amino acids were introduced into amino, about twenty compounds reported first time were synthesized. The structures have been certified by high resolution mass spectrum (HRMS) and1H nuclear magnetic resonance (1H-NMR).At last activities of compounds were assessed with enzyme and cell. Rigidity of phenylpropanamide derivatives showed better activity of enzyme and cell in vitro. Cinnamamide derivatives were firstly assessed with Hela extract and secondly assessed by HCT116and MDA-MB-23in vitro, and then were assessed with athymic. At last the best compound was choosed to study pharmacokinetics, but the result disappointed us. The work above provides important theory and practice for future development of HDACi.