title: Dioxol and dihydrodioxin analogs of 2- and 3-phenylacetonitriles as potent anti-cancer agents with nanomolar activity against a variety of human cancer cells.
abstract: 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 GI50 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 (GI50 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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Nikhil R
authors.initials: NR
authors.lastname: Madadi
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Ketkar
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Narsimha R
authors.initials: NR
authors.lastname: Penthala
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: April C L
authors.initials: AC
authors.lastname: Bostian
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Eoff
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. Electronic address: pacrooks@uams.edu.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
mesh_terms: D000097:Acetonitriles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D052117:Benzodioxoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004146:Dioxanes / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D062105:Molecular Docking Simulation; D013237:Stereoisomerism; D013267:Stilbenes / Q000494:pharmacology; D050257:Tubulin Modulators / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: C482492:3,4,5,4'-tetramethoxystilbene; D000097:Acetonitriles; D000970:Antineoplastic Agents; D052117:Benzodioxoles; D004146:Dioxanes; D013267:Stilbenes; D050257:Tubulin Modulators
keywords: 3,4-Ethylenedioxycyanostilbenes; 3,4-Methylenedioxycyanostilbenes; Anti-cancer activity; Molecular docking studies; Synthesis of cyanostilbenes