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

Author(s)

Urias, Beatriz Silva ; Pavan, Aline Renata ; Albuquerque, Gabriela Ribeiro ; Prokopczyk, Igor Muccilo ; Ferreira Alves, Tania Mara ; Ferreira de Melo, Thais Regina ; Rodrigues Sartori, Geraldo ; Martins da Silva, Joao Herminio ; Chin, Chung Man ; Dos Santos, Jean Leandro

• Document type: Journal article
• Source: PHARMACEUTICALS; v. 15, n. 10, p. 18-pg., 2022-10-01.

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 mu M and 0.37 mu M 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. (AU)

• FAPESP's process: 18/11079-0 - Synthesis and antitubercular activity of new N-oxide compounds designed to treat multiresistant-tuberculosis
• Grantee: Jean Leandro dos Santos
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/07789-0 - Synthesis of 2-amino-benzamide derivatives designed as fetal hemoglobin inducers
• Grantee: Gabriela Ribeiro Albuquerque
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 18/19523-7 - Design, synthesis and pharmacological evaluation of hydroxyurea derivatives designed as histone deacetylase inhibitors for Sickle Cell Anemia
• Grantee: Aline Renata Pavan
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 15/19531-1 - Targeting histone deacetylase (HDAC-1 and HDAC-2) as mechanisms to induce fetal hemoglobin in sickle cell disease
• Grantee: Jean Leandro dos Santos
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/21252-3 - Synthesis and Pharmacological evaluation of new thalidomide/pomalidomide analogues regulators of epigenetic mechanisms
• Grantee: Aline Renata Pavan
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 19/09456-3 - Synthesis of selective HDAC 1 and 2 inhibitors designed as fetal hemoglobin inducers
• Grantee: Beatriz Silva Urias
• Support Opportunities: Scholarships in Brazil - Scientific Initiation