Research And Application Of The Synthetic Process About Histone Deacetylase Inhibitor Vorinostat

Epigenetics involve the wide range of heritable changes in gene expression that do not result from an alteration in the DNA sequence itself. Different from the genetic variation, the epigenetic process is reversible. Phenotypic changes associated with drug resistance generated by epigenetic in tumor cell could be reversed by epigenetic modulators. Due to its lower effect on normal cell or tissues, epigenetic modulators have been used in the clinical treatment of cancer which can be regarded as a breakthrough to improve the efficacy of current investigation. Histone deacetylase inhibitors have made great progress as a class of epigenetic regulation of drugs. With the approval of Vorinostat and Romidepsin by the US Food and Drug Administration (FDA) for treatment of cutaneous T cell lymphoma (CTCL), and lots of HDAC inhibitors been in clinical trials for treatment of hematological malignancies and solid tumors, HDACi has emerged as a promising hotspot for anticancer drug development.Histone deacetylases (HDACs) which are involved in chromatin remodeling belong to the metalloprotease family in eukaryotic cells. Classes I, II and IV HDAC family members are Zn2+dependent while Class III HDACs require NAD+for their enzymic activity. HDACs are responsible for deacetylation of nucleosomal core histones and non-histones in the regulation of gene expression, protein stability and protein-protein interaction. Different subtype of HDACs play important role in the cell cycle arrest, differentiation inhibition, apoptosis, migration, invasion, metastasis and angiogenesis oncogensis in maligent cancer cells.According to the preliminary study about the synthesis method of Vorinostat, the mixed anhydride method was used as a two-step protocol to prepare Vorinostat. In the first step, process of the reaction was optimized by changing the acylating reagent and the yield increased four percentage. In the second step, DMF was used as the solvent without extraction of hydroxylamine. This modification leads to the facil synthetic way without removing solvent and complicated purification. Due to the good solubility of DMF, this method also adapts to prepare the target compounds with poor solubility. In our studies, this method was used to the synthesis of novel base-labile HDACi.Thus, according to the principles of the scaffold hoping, we developed a novel series of saccharin based hydroxamic acids as potent HDAC inhibitors. The preliminary bioactivity studies were performed on the HDAC inhibitory acitivities and antiproliferative activities. Totally,30 new compounds were synthesized, which include 16 target compounds and 14 intermediates. All the new compounds were identified through1H-NMR,13C-NMR, high resolution mass spectrometry, electrospray ionization mass spectrometry or other methods.