Design, Synthesis And Activity Evaluation Of Hydroximic Analogues As Histone Deacetylase Inhibitor

Histone deacetylase plays a key role in the growth of tumor. It can inhibit the acelylation to acetylize the karyotin futher and activate the gene of cancer cells, leading to the cell growth or dead. Phenylhydroxylamine is the active functional group for antitumor and the o-nitrophenyl acetate as the carrier. Therefor, phenylhydroxylamine derivatives as histone deacetylase inhibitor conjugated with o-nitrophenyl acetate as carrier is hardly cytotoxicitive in normal cell, but highly cytotoxicitive in tumor cell because of the higher activity of ester hydrolase and reductase, and the lower pH value in tumor cell. The release in tumor cell of active phenylhydroxylamine diveratives owed to immediate and stable hexatomic or hepatomic cyclization under higher activity of ester hydrolase lower pH value, and neighboring group assistance of amino preferly translated from nitryl is helpful to the antitumor selectivity.Nitroarene diveratives and hydrate solution catalyzed by Raney nickel to yield the corresponding N-arylhydroxylamines diveratives and the N-arylhydroxylamines is actied with benzoyl chloride diveradives and o-nitrophenoxy acetyic acid respectively under the basic condition yielding the target compounds which were idendificated by1HNMR、13CNMR、IR and HRMS.The experimental model of S180tumor-bearing mice and LD50determination by improved Karber method systematically evaluated the antitumor activities of target compounds. It was in result that LD50of one of them were dramatically lower than the one of cyclophosphamide, and the inhibition rate of five of them was higher than the one of cyclophosphamide. Especially compound a1、b1、b3、b4and b5were considered as potent and selective antitumor agents of a big promise to be further investigated.