Sulfonate Derivatives of Naphtho[2,3-b]thiophen-4(9H)-one and 9(10H)-Anthracenone as Highly Active Antimicrotubule Agents. Synthesis, Antiproliferative Activity, and Inhibition of Tubulin Polymerization

• Published in: Journal of medicinal chemistry Vol. 50; no. 24; pp. 6059 - 6066
• 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 29.11.2007; Amer Chemical Soc
• Subjects: Anthracenes - chemical synthesis; Anthracenes - chemistry; Anthracenes - pharmacology; Antineoplastic agents; Biological and medical sciences; Cell Cycle - drug effects; Cell Line, Tumor; Chemistry, Medicinal; Colchicine - pharmacology; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; General aspects; Humans; Life Sciences & Biomedicine; Medical sciences; Naphthalenes - chemical synthesis; Naphthalenes - chemistry; Naphthalenes - pharmacology; Nocodazole - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Podophyllotoxin - pharmacology; Science & Technology; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; Tubulin - chemistry; Tubulin - metabolism; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; POTENT ANTIMITOTIC AGENTS; ANALOGS; ANTITUBULIN AGENTS; COMBRETASTATIN A-4; RESISTANCE; LENS ALDOSE REDUCTASE; CELL-GROWTH; MICROTUBULE DYNAMICS; BINDING; CANCER; Antineoplastic agent; Benzene derivatives; Antitubulin; Cytotoxicity; Tricyclic compound; Condensed benzenic compound; Anthracene derivatives; In vitro; Sulfonate; Sulfur heterocycle; Cell line; Structure activity relation; Aromatic compound; Chemical synthesis; Antimitotic; Tumor cell
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0708984

Benzenesulfonate derivatives of naphtho[2,3-b]thiophen-4(9H)-one and 9(10H)-anthracenone were prepared and found to inhibit microtubule formation by an in vitro tubulin polymerization assay. Several analogues showed potent cytotoxic activity in an assay based on K562 leukemia cells with IC50 values of <100 nM. The methylamino analogue 14i was the most active compound in this assay (14i, IC50 K562:  0.05 μM). Antiproliferative activities of selected compounds were additionally evaluated against a panel of 12 tumor cell lines, including multi-drug-resistant phenotypes. All resistant cell lines were sensitive to these compounds. Concentration-dependent flow cytometric studies showed that KB/HeLa cells treated with selected compounds were arrested in the G2/M phases of the cell cycle. In competition experiments, these compounds strongly displaced radiolabeled colchicine from its binding site in the tubulin, showing IC50 values lower than that of colchicine. The results demonstrate that the antiproliferative activity is related to the inhibition of tubulin polymerization.