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

Tumor disease has been a threat to human life and health. For decades, people has been kept exploring in the field of anti-cancer drugs. They were carried out to explore bold and in-depth in some of the key aspects of the tumor, such as angiogenesis inhibitors, telomerase inhibitors, as well as leading tumor suppressor gene. In recent years, with the development of science and technology, especially with the mechanism of tumor study, for Specific target which is in the process of tumor cell growth and proliferation, the molecular targeted drug which can select destruction of tumor cells but not normal tissue has been discovery and using in clinical. Tumor medical treatment is from palliative to radical treatment of the transition. The role of HDAC inhibitors in the pathogenesis of tumor - gene transcriptional regulation of the key aspects of dysfunction, and corrected by suppressing abnormal expression of genes, thereby inducing the stagnation of tumor cell growth, differentiation or apoptosis. It has been found that the combination of HDAC inhibitors and HDLP (HDAC-like protein) are completely different with the combination of TSA and HDLP. Using HDLP to molecular docking for screen HDAC inhibitors The results showed that the former′s target is not Zn2 +, but the two benzene ring which are corresponding to the most narrow active site pockets Phe141 and Phe198. They block the channel which physiological substrate of HDAC (histone N-acetyl-Lys side-chain) into the catalytic center. This shows that benzamides selective inhibitor of the target is significantly better than Zn2+ for the combination of the inhibitor target.Mitsui Chemicals company′s MS-275 is the histone deacetylase inhibition which is the fastest growing research and development in animals with oral anti-cancer activity and low toxicity. Currently the drug is being researched for leukemia and solid tumor in clinical in United States. It has entered clinical phase II. The polyamine analogs have strong anti-tumor activity, because of high-affinity with DNA.We chose MS-275 as lead compound. According to the development progress and the known quantitative structure-activity relationship, and the relationships between drug molecular and the amino acids in activity site .We build a virtual compounds library by using traditional and computer-aided drug designing methods. By molecular docking, a series of compounds have high scores. We have designed and synthesized of a series of compounds. Aim to achieve independent intellectual property rights of HDAC. Compound I was reformed on the basic of 90 compounds which had been synthesized by our laboratory. It retained the benzamide structure. 4-fluorobenzene-1, 2-diamine which was belonged to enzyme inhibition domain was substituted by 4-methoxybenzene-1, 2-diamine.The pyrimidine, a rigidity group, was still induced into the surface recognition domain to instead of flexibility group which was in the MS-275. And the rigidity group could be substituted by (heterocyclic) aryl group. Compound II was changed structure on the basic of Compound I. Pyrimidine was changed from 2, 4 substituted into 4, 6 substituted for test the antitumor activities by the different structure of pyrimidine. We usedρ-aminomethyl benzoic acid reaction with methyl isothiourea in order to synthesis guanidylmethyl-benzoic acid (intermediate5). Then hypnone derivatives and DMFDMA products reacted aldol condensation. Product and intermediate 5 occurred cyclization reaction before admiration. The key intermediate was made by benzene derivatives with 4- formyl-benzonitrile methyl condensation. By the hydrolysis reaction with the intermediate, then react with o-phenylenediamine to synthesis compound I. We adopted 2-methyl-4, 6-dichloro-pyrimidine and 4-aminomethyl benzoic acid methyl ester to generate intermediate nucleophilic substitution and achieved intermediate 4. Then aromatic boric acid react with intermediate 4, Suzuki coupling, after lytic responsethe hydrolysate amidated to synthesize compound II. A total of 20 newly benzamide derivatives were synthesize, and all the structures had been verified by 1H-NMR.We used MCF-7, A549, Hep-G2, HL-60, and HeLa to evaluate target compounds′activities in vitro. The results showed that compound I which was changed from 4-fluorobenzene-1, 2-diamine to 4-methoxybenzene-1, 2-diamine. Its activity was obviously lower. II-1, II-2, II-3, II-5, II-6, and II-8 have a significant anti-tumor activity. Especially, II-1 is better than the MS–275 on various cancer cells pre-test compounds. So it can be further studied again.