title: 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.
authors.affiliation: a Faculty of Pharmacy and Pharmaceutical Sciences , University of Alberta , Edmonton , Alberta , Canada .
authors.forename: Fahad S
authors.initials: FS
authors.lastname: Aldawsari
authors.affiliation: a Faculty of Pharmacy and Pharmaceutical Sciences , University of Alberta , Edmonton , Alberta , Canada .
authors.forename: Osama H
authors.initials: OH
authors.lastname: Elshenawy
authors.affiliation: b Experimental Oncology Unit, Department of Oncology , University of Alberta , Edmonton , Alberta , Canada .|c Department of Pharmacognosy, Pharmaceutical Sciences Division , Natural Research Centre , Dokki , Giza , Egypt .
authors.forename: Mohamed A M
authors.initials: MA
authors.lastname: El Gendy
authors.affiliation: d Facultad de Química, Departamento de Farmacia , Universidad Nacional Autónoma de México , México .
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Aguayo-Ortiz
authors.affiliation: e Department of Pediatrics , Oncology and Biochemistry, University of Alberta , Edmonton , Alberta , Canada , and.|f Alberta Inflammatory Bowel Disease Consortium , Alberta , Canada.
authors.forename: Shairaz
authors.initials: S
authors.lastname: Baksh
authors.affiliation: a Faculty of Pharmacy and Pharmaceutical Sciences , University of Alberta , Edmonton , Alberta , Canada .
authors.forename: Ayman O S
authors.initials: AO
authors.lastname: El-Kadi
authors.affiliation: a Faculty of Pharmacy and Pharmaceutical Sciences , University of Alberta , Edmonton , Alberta , Canada .
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Velázquez-Martínez
mesh_terms: D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000077185:Resveratrol; D012459:Salicylates / Q000737:chemistry / Q000494:pharmacology*; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D012459:Salicylates; D013267:Stilbenes; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; D000077185:Resveratrol
keywords: Aspirin; CYP1A1; CYP450; chemoprevention; resveratrol