Optimization of Resveratrol Used as a Scaffold to Design Histone Deacetylase (HDAC-1 and HDAC-2) Inhibitors

Abstract

Histone deacetylases (HDAC) are epigenetic enzymes responsible for repressing gene expression through the deacetylation of histone lysine residues. Therefore, inhibition of HDACs has become an interesting approach for the treatment of several diseases, including cancer, hematology, neurodegenerative, immune diseases, bacterial infections, and more. Resveratrol (RVT) has pleiotropic effects, including pan-inhibition of HDAC isoforms; however, its ability to interfere with membranes requires additional optimization to eliminate nonspecific and off-target effects. Thus, to explore RVT as a scaffold, we designed a series of novel HDAC-1 and -2 inhibitors containing the 2-aminobenzamide subunit. Using molecular modeling, all compounds, except unsaturated compounds (4) and (7), exhibited a similar mode of interaction at the active sites of HDAC 1 and 2. The docking score values obtained from the study ranged from −12.780 to −10.967 Kcal/mol. All compounds were synthesized, with overall yields ranging from 33% to 67.3%. In an initial screening, compounds (4), (5), (7), and (20)–(26), showed enzymatic inhibitory effects ranging from 1 to 96% and 6 to 93% against HDAC-1 and HDAC-2, respectively. Compound (5), the most promising HDAC inhibitor in this series, was selected for IC50 assays, resulting in IC50 values of 0.44 µM and 0.37 µM against HDAC-1 and HDAC-2, respectively. In a panel of selectivity against HDACs 3–11, compound (5) presented selectivity towards Class I, mainly HDAC-1, 2, and 3. All compounds exhibited suitable physicochemical and ADMET properties as determined using in silico simulations. In conclusion, the optimization of the RVT structure allows the design of selective HDAC inhibitors, mainly targeting HDAC-1 and HDAC-2 isoforms.

The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods

“…Given the recognized pan-HDAC inhibition activity of resveratrol, a combination of scaffold hopping, molecular docking and ADME prediction was utilized to create a set of resveratrol analogs. These prospective inhibitors were subsequently subjected to additional validation via MD simulations and in vitro enzyme inhibition assays targeting HDAC1 and HDAC2 [214,215]. The scaffold hopping strategy was also useful for the discovery of some hybrids bearing 1H-indazol-3-amine and benzohydroxamic acids with dual HDAC/EGFR1 inhibitory activity against breast cancer line MCF-7 [216], and of a novel Aminotetralin Class of HDAC6 and HDAC8 selective inhibitors with potent inhibitory activity against neuroblastoma BE(2)C cells [217].…”

Untargeted LC-MS/MS Metabolomics Study of HO-AAVPA and VPA on Breast Cancer Cell Lines

“…Both HO-AAVPA and VPA also downregulated PC in both cell lines; PE was downregulated in all cases, except in MDA-MB-231 cells treated with VPA; LPC and lysophosphatidylethanolamine (LPE) were also downregulated, but such changes were detected only in MCF-7 cells treated with HO-AAVPA. Resveratrol is considered a pan inhibitor of HDAC [56,57], which has major activity on isoforms 1, 10, 4, and 9 of HDAC [56], all inhibited by VPA as well, except for HDAC10, so this might explain the similarities found between HDACi and VPA and HO-AAVPA [7].…”

A Review on Molecular Docking on HDAC Isoforms: Novel Tool for Designing Selective Inhibitors

“…In this case, the protein structure is distorted, but the binding mode of quisinostat and dacinostat molecules remains unchanged. Silva Urias, B. et al [91] designed, synthesized, and evaluated a series of resveratrol analogues. Resveratrol exhibits inhibitory activity against HDACs but lacks selectivity towards specific isozymes [92,93].…”

“…The researchers investigated the impact of adding an aminobenzamide subgroup to the resveratrol molecule on its activity. A molecular docking analysis was performed using Schrodinger (2019-4) Maestro v12.2, revealing that resveratrol can enter the binding pocket of HDAC1 without directly interacting with the zinc ion, resulting in an interaction Silva Urias, B. et al [91] designed, synthesized, and evaluated a series of resveratrol analogues. Resveratrol exhibits inhibitory activity against HDACs but lacks selectivity towards specific isozymes [92,93].…”

“…Notably, when considering a flexible linker, substituting the carbon atom with either nitrogen or oxygen at the linker site did not appear to have a significant impact on the binding interactions observed. [91] investigated the interactions between resveratrol and its analogues and the HDAC1 enzyme. Hydrogen bond interaction is illustrated by a purple dashed arrow while π-interactions are illustrated with a green line.…”