Rational design, synthesis, biological evaluation and molecular modeling of histone deacetylase inhibitors as anti-breast cancer stem cell agents

Abstract

Introduction: Histone deacetylases (HDACs) are overexpressed in cancer and their inhibition show promising results in cancer therapy. Computational drug design is an effective strategy for accelerating and economizing drug discovery process. Aims: The aims of current work were rational design, synthesis and biological evaluation of selective HDAC1-3 inhibitors as potential anticancer agents.Methods: Using three HDACIs as template structures and a fragment library, a chemical space was generated and filtered. The selected structures were docked on HDAC1 and ranked using binding affinity. The designed compounds were synthesized and characterized. Class I HDAC inhibitory potencies of the compounds as well as their in vitro antiproliferative activities were evaluated against two breast cancer cell lines. Molecular docking study was conducted for predicting the binding mode of the designed compounds towards HDAC enzyme. A quantitative structure-activity relationship (QSAR) analysis was performed to correlate the observed antiproliferative potencies of the studied derivatives to their structures by deriving group contribution values for different structural components. These group contribution values were used to propose novel potent compounds. Results: Top ranked structure in terms of predicted binding affinity was selected and after some structural modifications involving carbamate to amide conversion and homologation, twelve novel benzamide-based HDACIs (the structure is shown below) were designed and synthesized. Investigation of in vitro HDAC inhibitory activity of the derivatives revealed that four compounds were active. Furthermore, antiproliferative activity showed that two groups of compounds with NH2 and Me functional groups in R2 position exhibited strong activity with IC50 in micromolar range. Molecular docking showed that those compounds inhibiting HDAC enzyme could bind well to the active site of the enzyme. Based on the calculated group contribution values for different structural elements obtained by QSAR analysis, two new derivatives with improved antiproliferative potencies were proposed. Conclusions: Collectively, the current study presents in silico design of a series of novel benzamide-based selective HDAC1-3 inhibitors, their synthesis as well as biological evaluations. Among the synthesized compounds, 3j (R1: Me, R2: NH2, n:0) showed selective HDAC1-3 inhibitory activity at submicromolar concentration with strong antiproliferative activity.