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.

• Aspirin
• chemoprevention
• DNMT
• docking
• resveratrol

Acknowledgements

The authors acknowledge Prof. Vern Schramm (Albert Einstein College of Medicine) for providing plasmids for heterologous expression of DNMT3A, 3B and DNMT3L, Prof. Dinshaw Patel (Memorial Sloan Kettering Cancer Center) for hDNMT1 plasmid and Glorymar Ibañez for purifying DNMT3A/3B and 3L.

Declaration of interest

The authors report no conflict of interest. The authors alone are responsible for the content and writing of this article. The authors acknowledge the financial support provided by the Saudi Cultural Bureau in Canada, for a graduate scholarship to (F.S.A.), the National Institute of General Medical Sciences (1R01GM096056) (M.L.), the National Institute of Health (NIH) Director's New Innovator Award Program (1DP2-OD007335) (M.L.), the Starr Cancer Consortium (M.L.), and Mr. William H. Goodwin and Mrs. Alice Goodwin, the Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center (M.L.) and the Department of Pharmacy, School of Chemistry at UNAM (Mexico) for their support.