Synthesis of Novel Nitrogen-Containing Heterocycle Bromophenols and Their Interaction with Keap1 Protein by Molecular Docking

Abstract

We previously reported 5,2’-dibromo-2,4’,5’-trihydroxydiphenylmethanoe (LM49), a bromophenol analogue that shows strong protection from oxidative stress injury owing to its superior anti-inflammatory, antioxidant, and anti-apoptotic properties. A series of novel nitrogen-containing heterocycle bromophenols were herein synthesized by introducing substituted piperidine, piperazine, and imidazole to modify 2-position of the lead compound LM49. By further evaluating their cytoprotective activity against H2O2 induced injury in EA.hy926 cells, 14 target bromophenols showed moderate-to-potent activity with EC50 values in the range of 0.9–6.3 μM, which were stronger than that of quercetin (EC50: 18.0 μM), a positive reference compound. Of these, the most potent compound 22b is a piperazine bromophenol with an EC50 value of 0.9 μM equivalent to the LM49. Molecular docking studies were subsequently performed to deduce the affinity and binding mode of derived halophenols toward the Keap1 Kelch domain, the docking results exhibited that the small molecule 22b is well accommodated by the bound region of Keap1-Kelch and Nrf2 through stable hydrogen bonds and hydrophobic interaction, which contributed to the enhancement of affinity and stability between the ligand and receptor. The above facts suggest that 22b is a promising pharmacological candidate for further cardiovascular drug development. Moreover, the targeting Keap1-Nrf2 protein-protein interaction may be an emerging strategy for halophenols to selectively and effectively activate Nrf2 triggering downstream protective genes defending against injury.

Carnosol as a Nrf2 Activator Improves Endothelial Barrier Function Through Antioxidative Mechanisms

“…Nrf2-Keap1 protein-protein interaction (PPI) has been recognized as a key point for regulating Nrf2 activation [37]. Keap1 depends on the interaction with the key tyrosines, namely Tyr525, Tyr574, Arg-415 and Tyr334 [38,39]. We confirmed that Arg415, Tyr334, Tyr525 were key amino acids for the interaction of carnosol with Keap1.…”

Progress of Bromophenols in Marine Algae from 2011 to 2020: Structure, Bioactivities, and Applications

“…When a series of nitrogen-containing heterocycles such as piperidine, piperazine, and imidazole replaced the OH group at the 2-position of 3.22 , the products also showed moderate to potent cytoprotective activity against H 2 O 2 -induced injury in EAhy926 cells with 3.24 ( Scheme 3 ; EC 50 = 0.9 μM) being the most potent compound. A SAR study revealed that the antiradical ability of these analogues strengthened with an increasing number of heterocycles and hydroxyl groups [ 42 ]. Furthermore, a molecular docking study demonstrated that compound 3.24 could interact with Keap1, and thus in turn modulate Keap1-Nrf2 protein–protein interaction in order to activate Nrf2-induced downstream protective genes from oxidative stress damage [ 42 ] (see Section 3 ).…”

“…A SAR study revealed that the antiradical ability of these analogues strengthened with an increasing number of heterocycles and hydroxyl groups [ 42 ]. Furthermore, a molecular docking study demonstrated that compound 3.24 could interact with Keap1, and thus in turn modulate Keap1-Nrf2 protein–protein interaction in order to activate Nrf2-induced downstream protective genes from oxidative stress damage [ 42 ] (see Section 3 ). Some novel synthetic diarylmethanone BPs 3.25–3.31 ( Scheme 3 ) also showed antiradical abilities.…”

“…In those two cases, the bromine does not seem to play a role in the binding. The binding of 3.24 to Keap1-Kelch was studied [ 42 ]. One bromine is pointing toward the hydrophobic region, but the bromines do not seem to play a major role in binding.…”

“…In the last decade, novel BPs and more of their bioactivities have been reported. Moreover, it is worth noting that more studies have focused on the design and synthesis of novel functional derivatives of BPs [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ], as well as on the illustration of the mechanisms underlying their bioactivity, than only focusing on the isolation and testing the biological activity of BPs found in natural products. Therefore, it is necessary to report these new findings, and so in the present review, we mainly focus on the biological activities of newly discovered BPs from marine algae and also on some of BPs’ representative derivatives synthesized in the last ten years.…”