Design, Synthesis And Antitumor Activity Study Of Novel Histone Deacetylase Inhibitors

Cancer is a class of widespread disease with a high mortality. Conventional antitumor drugs usually result in seriously side effect and in imparing the clinical curative outcome because of lacking targeted therapies. With the development of molecular biological techniques, developing targeted therapeutic drugs has become a hot topic instead of conventional antitumor drugs.HDACs have become promising targets in recent years for cancer therapy. The aberrant expression of histone deacetylases result in hypoacetylation of histones, which is closely related to the occurrence of tumor. Histone deacetylase inhibitors can induce the differentiation and apoptosis of the tumor cells by inhibiting the activity of histone deacetylase. Therefore, searching for HDACs inhibitors as targeted therapy drugs has become a hot topic for cancer treatment.SAHA has been approved by the FDA for the treatment of cutaneous T-cell lymphomas as a histone deacetylase inhibitor. First, we have improved the synthesis of SAHA and have synthesized SAHA through a highly efficient, and environmental benign process method. Second, we have placed appropriate substituents on the phenyl capping group of SAHA in view of enhancing the antitumor potency of inhibitors. For this purpose, we have synthesized a number of derivatives of SAHA-based inhibitors. All the structures of target compounds were confirmed by 1HNMR,13CNMR and HRMS. All target compounds are≥95% pure by HPLC analysis. We have also studied the structure-activity relationship (SAR) of SAHA-based inhibitors by means of computer aided drug design (CADD). We evaluated their anticancer activities in cellular assays. A number of our newly synthesized compounds possess higher inhibition activity than SAHA. Inhibitor B123 that exhibited the highest anti-proliferative activity against A549 human non small cell lung cancer cell (NSCLC) in in-vitro assay was further evaluated in nude mouse xenograft models. It is found at a dose of 25mg/Kg/day inhibitor B123 effectively reduced 90% of final mean tumor volume, compared to the reduction of only 66% caused by SAHA at a higher dose of 50mg/kg/day. Further studies of biological evaluations in both in vitro and in vivo of inhibitor B123 are underway.