title: Influence of S-Oxidation on Cytotoxic Activity of Oxathiole-Fused Chalcones.
abstract: Synthesis, in vitro cytotoxic activity, and interaction with tubulin of oxidized, isomeric 1-(5-alkoxybenzo[d][1,3]oxathiol-6-yl)-3-phenylprop-2-en-1-ones and 1-(6-alkoxybenzo[d][1,3]oxathiol-5-yl)-3-phenylprop-2-en-1-ones are described. Most of the compounds demonstrated cytotoxic activity at submicromolar concentrations. It was found that oxidation of sulfur atom of the oxathiole-fused chalcones strongly influenced activity of the parent compounds, and that depending on relative position of the sulfur atom in the molecule, the activity was either increased or diminished. For isomers with sulfur atom para to the chalcone carbonyl group, oxidation led to increase in activity, while for isomers with sulfur atom meta to the carbonyl the activity dropped down. It was demonstrated that the compounds interact with tubulin at the colchicine binding site, and the interaction was evaluated using molecular modeling. It was concluded that the observed profound influence of oxidation of the sulfur atom on cytotoxic activity cannot be solely related to interaction of the compounds with tubulin.
authors.affiliation: Department of Chemical Technology of Drugs, Medical University of Gdansk, Gen. J. Hallera Street 107, 80-416, Gdansk, Poland. markon@gumed.edu.pl.
authors.forename: Marek T
authors.initials: MT
authors.lastname: Konieczny
authors.affiliation: Department of Organic Chemistry, Medical University of Gdansk, 80-416, Gdansk, Poland.
authors.forename: Anita
authors.initials: A
authors.lastname: Buɬakowska
authors.affiliation: Department of Organic Chemistry, Medical University of Gdansk, 80-416, Gdansk, Poland.
authors.forename: Danuta
authors.initials: D
authors.lastname: Pirska
authors.affiliation: Department of Organic Chemistry, Medical University of Gdansk, 80-416, Gdansk, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Konieczny
authors.affiliation: Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, 80-233, Gdansk, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Skladanowski
authors.affiliation: Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, 80-233, Gdansk, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Sabisz
authors.affiliation: Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, 80-233, Gdansk, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Wojciechowski
authors.affiliation: Drug Discovery Department, Adamed Group, 05-152, Czosnow, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Lemke
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D047188:Chalcones / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D003603:Cytotoxins / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010084:Oxidation-Reduction; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D013455:Sulfur / Q000737:chemistry*
chemical_list: D047188:Chalcones; D003603:Cytotoxins; D013438:Sulfhydryl Compounds; C008730:oxathiol; D013455:Sulfur
keywords: benzoxathiole oxidation; chalcone; cytotoxic activity; molecular modeling; tubulin interaction