Design and synthesis of resveratrol–salicylate hybrid derivatives as CYP1A1 inhibitors

Abstract

Resveratrol and aspirin are known to exert potential chemopreventive effects through modulation of numerous targets. Considering that the CYP450 system is responsible for the activation of environmental procarcinogens, the aim of this study was to design a new class of hybrid resveratrol-aspirin derivatives possessing the stilbene and the salicylate scaffolds. Using HepG2 cells, we evaluated (a) the inhibition of TCDD-mediated induction of CYP1A1 exerted by resveratrol-aspirin derivatives using the EROD assay, and (b) CYP1A1 mRNA in vitro. We observed significant inhibition (84%) of CYP1A1 activity and a substantial decrease in CYP1A1 mRNA with compound 3, compared to control. Resveratrol did not exert inhibition under the same experimental conditions. This inhibitory profile was supported by docking studies using the crystal structure of human CYP1A1. The potential effect exerted by compound 3 (the most active), provide preliminary evidence supporting the design of hybrid molecules combining the chemical features of resveratrol and aspirin.

Resveratrol-salicylate derivatives as selective DNMT3 inhibitors and anticancer agents

“…In this regard, we have recently reported the chemical synthesis and CYP1A1 inhibitory profile of a new series of hybrid resveratrol-salicylate analogues with promising chemopreventive activity (38); after we re-examined the chemical structures of these derivatives, we recognized a potentially useful pattern: by replacing the central methylene group in NSC14778 for the ethylene (CH=CH) moiety present in stilbenes. It is noteworthy that we identified some structural similarities between NSC14778, and our recently reported salicylate-resveratrol analogues, so that it was reasonable to predict certain degree of DNMT inhibition by our molecules (however, please note that we did not start the design of our salicylate-resveratrol derivatives based on the docking pose of NSC14778).…”

“…To study the in vitro DNMT inhibition exerted by the salicylate-resveratrol analogues reported previously (38), we used a filter paper based Scintillation Proximity Assay (SPA) (42). We used the well-known DNMT inhibitor (altough structurally unrelated) S-adenosyl-L-homocysteine (SAH)(54, 55) as the standard which showed IC 50 = 2 μM on DNMT1.…”

“…We carried out the synthesis of hybrid resveratrol-salicylate derivatives 3 – 12 as described in our previous paper (38). …”

“…By analysing the chemical structure of the scaffold present in methylenedisalicylic acids, and compare it to that of our recently reported resveratrol-salicylate analogues, in which we added a carboxylic acid group to one of the aromatic rings present in the polyphenol (38), we hypothesized that, in addition to the CYP1A1 inhibitory activity reported previously, these hybrid drugs could also inhibit the enzymatic activity of DNMT (Figure 1). …”

Interaction of the CYP1A1 gene polymorphism and smoking in non-small cell lung cancer susceptibility

“…The roles of GSTM1, XRCC1, XRCC3, CYP2D6, and C188T genes have been studied thoroughly. However, the cytochrome P450 (CYP) 1A1 gene has not been studied extensively, and the results so far are confusing (Aldawsari et al, 2014;Wohak et al, 2014). Several studies (Lee et al, 2010;Arinc et al, 2014;Henderson et al, 2014;Wang et al, 2014;Gaspar-Ramirez et al, 2015) have shown that patients with CYP1A1 deletion cannot produce the active enzyme, so that carcinogenic substances cannot be metabolized and excreted.…”