Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 26, Issue 9, Pages 2164-2169Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2016.03.068
Keywords
3,4-Methylenedioxycyanostilbenes; 3,4-Ethylenedioxycyanostilbenes; Synthesis of cyanostilbenes; Anti-cancer activity; Molecular docking studies
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Funding
- NCI/NIH, United States [CA 183895]
- NCI/NIH, United States (COBRE Award) [P20GM109005]
- Arkansas Research Alliance Scholar award
- Office Of The Director
- Office of Integrative Activities [1457888] Funding Source: National Science Foundation
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A small library of (Z)-2-(benzo[d][1,3]dioxol-5-yl) and (Z)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl analogs of 2- and 3-phenylacetonitriles has been synthesized and evaluated for their anti-cancer activities against a panel of 60 human cancer cell lines. The dihydrodioxin analog 3j and dioxol analogs 5e and 7e exhibited the most potent anti-cancer activity of all the analogs synthesized in this study, with GI(50) values of <100 nM against almost all of the cell lines in the human cancer cell panel. Of these three, only compound 3j inhibited tubulin polymerization to any degree in vitro. The binding modes of 3j and the structurally related tubulin-inhibitor DMU-212 were determined by virtual docking studies with tubulin dimer. Compound 3j docked at the colchicine-binding site at the dimer interface of tubulin. The Full-Fitness (FF) score of 3j was observed to be substantially higher than DMU-212, which agrees well with the observed anti-cancer potency (GI(50) values). The mechanism by which dioxol analogs 5e and 7e exert their cytotoxic effects remains unknown at this stage, but it is unlikely that they affect tubulin dynamics. Nevertheless, these findings suggest that both dioxol and dihydrodioxin analogs of phenylacrylonitrile may have potential for development as clinical candidates to treat a variety of human cancers. (C) 2016 Elsevier Ltd. All rights reserved.
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