Design, Synthesis And Preliminary Activity Assay Of Boronic Acid Histone Deacetylases Inhibitor

It is estimated that there are more than7.0million patients died of cancer every year and1.8million of them from China. The incidence of cancer in our country is similar to the United Kingdom, United States of America, France and increases year by year. However, the cure rate is less than13%. At present, most anticancer medicines display high side effects but low efficacy. Hence, the exploitation of novel drugs with high selectivity and efficacy become priorities in anti-tumor medicine research.Histone deacetylases (HDACs) as a epigenetic anticancer target offered a new approach for discovering high specified and efficacious medicine. Over the last decade, histone deacetylase inhibitors attracted considerable attention due to its important role in the regulation of histone acetylation and deacetylation from normal and cancer cell. HDACi demonstrated anti-tumor efficacy in clinical treatment by inducing histone hyperacetylation, regulating gene transcriptional activity, inhibiting cancer cell proliferation, inducing differentiation and apoptosis. SAHA was the first HDACi drug approved by FDA for treatment of T-cell lymphoma. The model pharmacophore for HDAC inhibitors consist of surface recognition domain with hydrophobic group, linker and the Zn2+binding group. HDACi can be classified as short-chain fatty acids, hydroxamic acids, benzamides, cyclic peptides, thiols, electrophilic Ketones and so on. Suzuki reported novel HDAC inhibitors using boronic acid as its Zn2+binding group, which displayed good inhibitory activity to HDAC1, HDAC2, HDAC6and HDAC8. Meanwhile, HDAC inhibitors with boronic acid showed better antiproliferative activity than SAHA to cancer cell, such as HBC-5、SNB-78、DMS114、LOX-IMVI、SK-OV-3、MKN45、PC-3.Our group has been investigated boronic acid compounds as chemesensors and protease inhibitors for many years. In our ongoing studies, two series of HDAC inhibitors have been designed and synthesized with the scaffold of benzenesulfonamide, alkyl phenyl boronic acid. To the first series, we synthesized14 new compounds and half of them were target compounds. Compound1g showed good inhibitor activity to HCT116and PC-3. The second series were designed mainly depending on leader compound R306465which was in phase I trial. The design replaced phenyl boronic acid with pyridine hydroxamic acids to get13target compounds and14intermediates. Compounds2f、2g、2j、2k、21and2m displayed better inhibitor activity than SAHA to HCT116and PC-3. We totally synthesized36new compounds,20novel target compounds and16new intermediates. All these compounds have been identified by1H-NMR and ESI-MS spectra. All these target compounds need enzymes activity test on HDAC and further research on anticancer mechanism is in progress.