9-Benzylidene-naphtho[2,3-b]thiophen-4-ones as Novel Antimicrotubule AgentsSynthesis, Antiproliferative Activity, and Inhibition of Tubulin Polymerization

• Published in: Journal of medicinal chemistry Vol. 49; no. 26; pp. 7816 - 7825
• Main Authors: Zuse, Anne, Schmidt, Peter, Baasner, Silke, Böhm, Konrad J, Müller, Klaus, Gerlach, Matthias, Günther, Eckhard G, Unger, Eberhard, Prinz, Helge
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.12.2006; Amer Chemical Soc
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Cycle - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemistry, Medicinal; Colchicine - pharmacology; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Flow Cytometry; General aspects; Humans; Inhibitory Concentration 50; K562 Cells - drug effects; Leukemia P388 - drug therapy; Life Sciences & Biomedicine; Medical sciences; Mice; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; Tubulin - chemistry; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; Tumor Cells, Cultured; KETO-ENOL TAUTOMERISM; ANTITUBULIN AGENTS; ANTIMITOTIC AGENTS; ACTIVITY IN-VIVO; CELL-GROWTH; MICROTUBULE DYNAMICS; THIOPHENE ANALOGS; DERIVATIVES; BINDING; CANCER; Antineoplastic agent; Human; Lung; Gut; Central nervous system; Antitubulin; Uterine cervix; In vitro; Hela cell line; Biological activity; Ovary; Cell line; Glioma; Cell cycle; G2 Phase; Phenols; Colon; Chemical synthesis; Antimitotic; Tumor cell
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0605031

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.