Design and Synthesis of Hybrid Compounds as Epigenetic Modifiers

Lopes, Juliana Romano; Prokopczyk, Igor Muccilo; Gerlack, Max; Chin, Chung Man; Santos, Jean Leandro dos

doi:10.3390/ph14121308

Cited by 3 publications

(2 citation statements)

References 42 publications

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“…The fluorescence intensity was measured at an excitation of 360 nm and emission of 460 nm using a Tecan Infinite M1000 microplate reader, and the percentage of activity was calculated using the formula: % activity = (F − Fb) / (Ft − Fb), where F = the intensity of fluorescence in the presence of the compound. In the absence of the test compound, the fluorescent intensity (Ft) in each dataset was defined as 100% activity, while in the absence of HDAC, the fluorescent intensity (Fb) in each dataset was set to 0% activity [ 45 ].…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Methodsmentioning

confidence: 99%

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

et al. 2022

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“…For HIV, Lopes and her research team elucidated the epigenetic modulation through histone deacetylase inhibitors. This approach is being explored in the ‘kick and kill’ strategy, with the aim of reactivating HIV from its reservoirs [ 31 ].…”

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confidence: 99%