title: Resveratrol-salicylate derivatives as selective DNMT3 inhibitors and anticancer agents.
abstract: 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.
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: b Departamento de Farmacia, Facultad de Química , Universidad Nacional Autónoma de México , México City , Mexico .
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Aguayo-Ortiz
authors.affiliation: c Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center , New York , NY , USA , and.
authors.forename: Kanishk
authors.initials: K
authors.lastname: Kapilashrami
authors.affiliation: d Life Science Research Institute, Daewoong Pharmaceutical Co., Ltd. , Pogok-Eup , Republic of Korea.
authors.forename: Jakyung
authors.initials: J
authors.lastname: Yoo
authors.affiliation: c Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center , New York , NY , USA , and.
authors.forename: Minkui
authors.initials: M
authors.lastname: Luo
authors.affiliation: b Departamento de Farmacia, Facultad de Química , Universidad Nacional Autónoma de México , México City , Mexico .
authors.forename: José L
authors.initials: JL
authors.lastname: Medina-Franco
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: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D000077185:Resveratrol; D012459:Salicylates / Q000737:chemistry / Q000494:pharmacology*; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D000097584:DNA Methyltransferase 3B
chemical_list: D000970:Antineoplastic Agents; D004248:DNA (Cytosine-5-)-Methyltransferases; D000077185:Resveratrol; D012459:Salicylates; D013267:Stilbenes; D000097584:DNA Methyltransferase 3B
keywords: Aspirin; DNMT; chemoprevention; docking; resveratrol