Design, Synthesis And Antitumor Activities Of Benzamide Derivatives As Novel Histone Deacetylase Inhibitors

Design, Synthesis and Antitumor Activities of Benzamide Derivatives as Novel Histone Deacetylase InhibitorsFor decades, mankind has been kept exploring in the field of anticancer drugs.However , the differentiation and complexity of tumor mechanism make the same anticancer drugs in the treatment of various tumors play different outcomes.Targeting specific elements anticancer drugs of R & D is the current and future research directions.As a new type of anticancer drugs, histone deacetylase (HDAC) inhibitor has distinctive features and advantages compared with the traditional cytotoxic anticancer drugs group. Histones are important components of eukaryotic nuclear chromosome composition,the belannce between histone acetylation and deacetylation is an important process of gene expression regulation and is the key modification of the transcriptional process. The stu- dies show that histone acetylation and deacetylation have a close relationship with tum- or occurrence and development. Histone deacetylases involve in tumor development and progression by removing acetyl groups with other transcriptional regulation.Xie Aihua et.al used the HDLP (histone deacetylase-like protein) for molecular docking screening of HDAC inhibitors and found that the MS-275-a benzamides histone deace- tylase inhibitors may have a novel combining methods with the enzyme, docking results showed that the former didn't bind to Zn²⁺ for the target, but had the effect on the narrowest part of the activity pocket, blocking the physiological substrate of HDAC (histone acetylation N-Lys side chains) stretched to catalytic center of the channel. Therefore, the target selectivity of Benzamide Inhibitors is better than Zn²⁺ for the binding target protein. This seems to explain the low toxicity features of MS-275,which provides a new idea for designing and screening of HDAC inhibitors. The structure of MS-275 is devided into enzyme binding region , the link area and the inhibition zone. Because Polyamine analogues have the high-affinity targets producing strong anti-tumor activity, we keep more amino part to enhance the anticancer activity of compounds; reserve the structure benzamide of MS-275to to reduce toxic compounds and improve selectivity; combining of HDAC inhibitor ben-124 studied by our research group, the design of the introduction of pyrimidine groups in the enzyme binding region is retained.This total eight new target compounds were not reported, and its structure identified by 1H-NMR spectroscopy. Using the MTT of the compounds was Determined on different cancer cell proliferation ability. The evaluation results show that the biological activity, of which one compounds (I-4) showed good inhibitory activity compared with the positive control close to MS-275, to be selected as a lead compound for further study.