Design, Synthesis And Biological Evaluation Of 1,3,4-Thiadiazole Hydroxamates As Histone Deacetylase Inhibitors

Histone deacetylases (HDACs) which are involved in chromatin remodeling belong to the metalloprotease family in eukaryotic cells.18 HDACs have been identified in the mammalian genome and subdivided into four classes based on their homology to the respective yeast transcriptional control factor sequence. 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.HDACs can be tethered closely to the oncogensis, maintenance and progression of cancer considering overexpression of individual HDACs in broad spectrum neoplasms as well as their active roles in cancer cell cycle arrest, differentiation inhibition, apoptosis, migration, invasion, metastasis and angiogenesis. Histone deacetylase inhibitors (HDACi) induce, to a variable extent, cell cycle and growth arrest, differentiation or apoptosis of malignant cells. With the approval of Vorinostat and Romidepsin by the US Food and Drug Administration (FDA) for treatment of cutaneous T cell lymphoma (CTCL), additional 22 HDACi have been in clinical trials for treatment of hematological malignancies and solid tumors. Therefore, HDACi have emerged as a promising therapy for neoplasic indications.According to the achievement of structural biology and chemical structures of reported HDACi, the structural characteristics of HDACi usually include a zinc binding group, a flexible or rigid linker and a surface recognition motif attached to the linker. Based on the structure of zinc binding group, HDACi can be roughly divided into nine main groups such as hydroxamates,2-aminophenylamides, amides, thiols and thiol derivatives, ketones, a-mercaptoketones, sulfamides, trithiocarbonates and boronic acids.It was reported that substituted aryl-isoxazole hydroxamate derivatives had exhibited good inhibition on HDACs and pancreatic cancer cell growth. In our ongoing studies, we designed a series of 2-amino-1,3,4-thiadiazole hydroxamic acid derivatives because the thiadiazole could be used as a bioisosterism of the isoxazole. The synthetic route was started from different carboxylic acid such as benzoic acid, phenylacetic acid and 3-phenylpropionic acid. They coupled with phosphorous oxychloride and converted to amides and thiadiazoles via a one pot reaction to afford high yields. The key intermediate,2-amino-1,3,4-thiadiazoles, then reacted with different bicarboxylic acids and finally gave the corresponding hydroxamic acids.The 1,3,4-thiadiazole hydroxamate derivatives were studied on their preliminary enzymic activities. The result showed that most of the target compounds exhibited good inhibition on HDACs and especially compounds 6i,6d,6j,6n,6m,6o and 6k demonstrated potent inhibition similar to SAHA. This result suggest that five or six methylene groups are optimal for potency between the 1,3,4-thiadiazole ring and the hydroxamate group. The most active compounds 6i,6d,6j and 6n also showed the inhibition on MDA-MB-231 breast cancer cell lines and K562 chronic myelogenous leukaemia cell lines.