Resveratrol is a natural polyphenol with plethora of biological activities. Resveratrol has previously shown to decrease DNA-methyltransferase (DNMT) enzymes expression and to reactivate silenced tumor suppressor genes. Currently, it seems that no resveratrol analogs have been developed as DNMT inhibitors. Recently, we reported the synthesis of resveratrol-salicylate derivatives and by examining the chemical structure of these analogs, we proposed that these compounds could exhibit DNMT inhibition especially that they resembled NSC 14778, a compound we previously identified as a DNMT inhibitor by virtual screening. Indeed, using in vitro DNMT inhibition assay, some of the resveratrol-salicylate analogs we screened in this work that showed selective inhibition against DNMT3 enzymes which were greater than resveratrol. A molecular docking study revealed key binding interactions with DNMT3A and DNMT3B enzymes. In addition, the most active analog, 10 showed considerable cytotoxicity against three human cancer cells; HT-29, HepG2 and SK-BR-3, which was greater than resveratrol. Further studies are needed to understand the anticancer mechanisms of these derivatives.

Resveratrol (3,4,5-Trihydroxy-trans-stilbene) is a naturally occurring polyphenol that exhibits beneficial pleiotropic health effects. It is one of the most promising natural molecules in the prevention and treatment of chronic diseases and autoimmune disorders. One of the key limitations in the clinical use of resveratrol is its extensive metabolic processing to its glucuronides and sulfates. It has been estimated that around 75% of this polyphenol is excreted via feces and urine. To possibly alleviate the extensive metabolic processing and improve bioavailability, we have added segments of acetylsalicylic acid to resveratrol in an attempt to maintain the functional properties of both. We initially characterized resveratrol-aspirin derivatives as products that can inhibit cytochrome P450 Family 1 Subfamily A Member 1 (CYP1A1) activity, DNA methyltransferase (DNMT) activity, and cyclooxygenase (COX) activity. In this study, we provide a detailed analysis of how resveratrol and its aspirin derivatives can inhibit nuclear factor kappa B (NFκB) activation, cytokine production, the growth rate of cancer cells, and in vivo alleviate intestinal inflammation and tumor growth. We identified resveratrol derivatives C3 and C11 as closely preserving resveratrol bioactivities of growth inhibition of cancer cells, inhibition of NFκB activation, activation of sirtuin, and 5’ adenosine monophosphate-activated protein kinase (AMPK) activity. We speculate that the aspirin derivatives of resveratrol would be more metabolically stable, resulting in increased efficacy for treating immune disorders and as an anti-cancer agent.

The carboxylic acid group (–COOH) present in classical NSAIDs is partly responsible for the gastric toxicity associated with the administration of these drugs. This concept has been extensively proven using NSAID prodrugs. However, the screening of NSAIDs with no carboxylic acid at all has been neglected. The goal of this work was to determine if new NSAID derivatives devoid of acidic moieties would retain the anti-inflammatory activity of the parent compound, without causing gastric toxicity. To test this concept, we replaced the carboxylic acid group in ibuprofen, flurbiprofen, and naproxen with three ammonium moieties. We tested the resulting water-soluble NSAID derivatives for anti-inflammatory and ulcerogenic activity in vitro and in vivo. In this regard, we observed that all non-acidic NSAIDs exerted a potent anti-inflammatory activity, suggesting that the acid group in commercial 2-phenylpropionic acid NSAIDs not be an essential requirement for anti-inflammatory activity. These data provide complementary evidence supporting the discontinuation of ulcerogenic acidic NSAIDs.