Design, Synthesis and Biological Evaluation of Small Molecules Targeting Histone Deacetylase (HDAC) as Anti-Cancer Agents

Abstract

Histone deacetylase (HDAC) enzymes are one of the best-characterized epigenetic targets; the aberrant activity of one or more of the 11 zinc-dependent HDAC isoforms has been associated with many different cancers, as well as several other diseases. Some HDAC inhibitors have been proven efficacious in treating cancer; three are FDA approved for treating cutaneous T-cell lymphoma or multiple myeloma. Animal models of other diseases have shown that HDAC inhibitors have potential as therapeutic agents. However, the clinical use of HDAC inhibitors is currently limited by toxicity and side effects, amongst other problems, possibly arising because the inhibitors are not isoform-selective. This thesis focuses on attempts to synthesize novel HDAC inhibitors with increased isoform selectivity. To identify the core scaffold, pharmacophore modeling was carried out with the aid of the GASP module of Sybyl X, which gave four feature pharmacophores which consisted of two hydrophobic features, one acceptor atom, and one donor atom of the receptor protein. Further, this model was validated by GH score analysis. According to the generated pharmacophore model and literature survey, HDAC inhibitors consist of a) Cap group, b) linker group, and c) Zinc binding group. Based on this data, we have designed some fused heterocyclic compounds. Docking studies and in-silico pharmacokinetics and toxicities were predicted for the best-ranked designed compounds. Two different series of compounds with two linker groups were designed, and their synthetic routes were proposed. In-silico ADMET property of the designed compounds was evaluated and was found to be non-toxic. Based on the results of docking studies, in-silico pharmacokinetics prediction, and synthetic feasibility, total 16 molecules were synthesized in series I, and 16 molecules were synthesized in series II. A series of designed molecules were synthesized and tested for inhibition of HDAC isoforms. Compound 69h and 74n were found to be potent molecules in the cell-based and enzyme-based assays. Based on these results, both of these compounds were evaluated for their metabolic stability against HLM and RLM and displayed good metabolic stability. Based on these results, we have designed, and synthesized series-3 molecules consist of 2-amino thiazole as cap group and amino hexanoic acid as linker group. The synthesized molecules were tested for inhibition of HDAC isoforms, but no improvement over vorinostat was found.