Synthesis And Biological Evaluation Of Novel Hydroximic Analogues As Histone Deacetylase Inhibitor

Histone deacetylases (HDACs) could be considered as a vital target for cancer theraphy. HDAC inhibitors can inhibite the activity of HDACs, in this way, it can affect the acetylation level of histone, change the structure and function of chromatin, and regulate expression level of gene. HDAC inhibitors exert the antitumor effect both in vitro and vivo by various means, including inducing tumor cell apoptosis, growth arrest and differentiation, preventing tumor invasion and metastasis, and inhibiting the formation of tumor blood vessels and lymphatic vessels. Hydroxamic acids are a typical class of HDAC inhibitors. Therefore, we design novel phenyl hydroxamic acids derivatives using o-nitrophenyl acetic acid as the carrier. These derivatives can hardly be reduced in normal cells, but because of low pH and active hydrolase and reductase ester in the environment of tumor cells, these compounds can release the active benzohydroxamic acid which is helpful to the antitumor activity.Using nitrobenzene derivatives as raw material, in the presence of Raney nickel hydrazine, to prepare phenyl hydroxylamine derivatives. Then. N-substituted phenyl hydroxylamine derivatives were reacted with benzoyl chloride. Finally, o-nitrophenyl was esterified at the C position to obtain the target compounds, and 1HNMR, 13CNMR, IR and HRMS were used to confirm the structure of the compounds.The cell proliferation inhibitory activity of the newly synthesized hydroxamic acid derivatives as well as derivatives with o-nitrophenyl acetic acid as the carrier were evaluated by MTT assay. It was shown that compounds 5b and 8b had the best inhibitory effect against three human tumor cell lines, which were superior to vorinostat (SAHA). These compounds exert inhibitory effect on tumor cells through the induction of apoptosis and cell cycle arrest. In vivo antitumor activity study also revealed that toxicity of compounds 5a,5b,8b and 9b was lower than the toxicity of SAHA; The tumor growth inhibition rate of compounds 5b and 8b was significantly higher than SAHA, it means that their selectivity and safety were all improved, compared to SAHA. Hence, in this paper, the designed and synthesised hydroxamic acid derivatives are expected to be developed as novel HDAC inhibitors.