β-Carboline tethered cinnamoyl 2-aminobenzamides as class I selective HDAC inhibitors: Design, synthesis, biological activities and modelling studies

Abstract The effect of β-carboline motif as cap for HDAC inhibitors containing cinnamic acid as linker and benzamides as zinc binding group was examined in this study. A series of β-carboline-cinnamide conjugates have been synthesized and evaluated for their HDAC inhibitory activity and in vitro cytotoxicity against different human cancer cell lines. Almost all the compounds exhibited superior HDAC inhibitory activity than the standard drug entinostat for in vitro enzymatic assay. Among the tested compounds, 7h displayed a noteworthy potency with an IC50 value of 0.70±0.15 µM against HCT-15 cell line when compared to the standard drug entinostat (IC50 of 3.87±0.62 µM). The traditional apoptosis assays such as nuclear morphological alterations, AO/EB, DAPI, Annexin-V/PI staining revealed the antiproliferative activity of 7h and depolarization of mitochondrial membrane potential by JC-1 was observed in dose-dependent manner. In addition, immunoblot analysis for compound 7h on HCT-15 indicated selective inhibition of the protein expression of HDAC 2 and 3 isoforms of class 1. Cell cycle analysis also unveiled the typical accumulation of cells in G2M phase and sub-G1/S phase arrest. Molecular docking analysis revealed the prominent binding of the most potent compound 7h with the active pocket of the HDAC 2. These finding suggest that the compound 7h can be a promising lead candidate for further investigation in the development of novel anti-cancer drug potentially inhibiting HDACs.