title: 9-Benzylidene-naphtho[2,3-b]thiophen-4-ones as novel antimicrotubule agents-synthesis, antiproliferative activity, and inhibition of tubulin polymerization.
abstract: A novel series of 9-benzylidene-naphtho[2,3-b]thiophen-4-ones and structurally related compounds were synthesized and evaluated for their ability to inhibit tubulin polymerization. The 4-hydroxy-3,5-dimethoxy-benzylidene analogue 15d was identified as a potent cytotoxic agent in an assay based on K562 leukemia cells. Antiproliferative activity of 15d and the 2,4-dimethoxy-3-hydroxy-benzylidene analogue 15e was additionally evaluated against a panel of 12 tumor cell lines, including multidrug resistant phenotypes. All resistant cell lines were sensitive to these compounds. Concentration-dependent flow cytometric studies showed that K562 cells as well as KB/HeLa cells treated by 15d were arrested in the G2/M phases of the cell cycle. Moreover, four compounds strongly inhibited tubulin polymerization with activities higher or comparable to those of the reference compounds. In competition experiments, the most active compounds strongly displaced radiolabeled colchicine from its binding site in the tubulin, showing IC50 values virtually 3- to 4-fold lower than that of colchicine.
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University, Hittorfstrasse 58-62, D-48149 Münster, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Zuse
authors.forename: Peter
authors.initials: P
authors.lastname: Schmidt
authors.forename: Silke
authors.initials: S
authors.lastname: Baasner
authors.forename: Konrad J
authors.initials: KJ
authors.lastname: Böhm
authors.forename: Klaus
authors.initials: K
authors.lastname: Müller
authors.forename: Matthias
authors.initials: M
authors.lastname: Gerlach
authors.forename: Eckhard G
authors.initials: EG
authors.lastname: Günther
authors.forename: Eberhard
authors.initials: E
authors.lastname: Unger
authors.forename: Helge
authors.initials: H
authors.lastname: Prinz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003078:Colchicine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells / Q000187:drug effects; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry*; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D013876:Thiophenes; D014404:Tubulin; D050257:Tubulin Modulators; D003078:Colchicine