title: Structural factors affecting affinity of cytotoxic oxathiole-fused chalcones toward tubulin.
abstract: Synthesis, in vitro cytotoxic activity, and interaction with tubulin of (E)-1-(6-alkoxybenzo[d][1,3]oxathiol-5-yl)-3-phenylprop-2-en-1-one derivatives (2) are described. Some of the compounds demonstrated cytotoxic activity at submicromolar concentrations, and the activity could be related to interaction with tubulin at the colchicine binding site. Interaction of selected derivatives with tubulin was evaluated using molecular modeling, and two different modes of the interaction were identified. The proposed models demonstrate how particular structural fragments participate in binding to the tubulin and explain the importance of the fragments for cytotoxic activity. It was demonstrated that concerning binding to tubulin, the 6-alkoxybenzoxathiole ring can be considered as structural equivalent of trimethoxyphenyl motif of colchicine, podophyllotoxin or combretastatin A4. The observation opened new ways of rational modifications of several groups of tubulin binders.
authors.affiliation: Department of Chemical Technology of Drugs, Medical University of Gdansk, 80-416 Gdansk, Poland. Electronic address: 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
authors.affiliation: Drug Discovery Department, Adamed Group, 05-152 Czosnow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Pieczykolan
authors.affiliation: Drug Discovery Department, Adamed Group, 05-152 Czosnow, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Strożek
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D045325:HCT116 Cells; D006367:HeLa Cells; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D047188:Chalcones; D006574:Heterocyclic Compounds, 2-Ring; D014404:Tubulin
keywords: Benzoxathiole; Chalcone; Cytotoxic activity; Molecular modeling; Tubulin interaction