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

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• 作者：Anne Zuse ; Peter Schmidt ; Silke Baasner ; Konrad J. B&ouml ; hm ; Klaus Mü ; ller ; Matthias Gerlach ; Eckhard G. Gü ; nther ; Eberhard Unger ; Helge Prinz
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：November 29, 2007
• 年：2007
• 卷：50
• 期：24
• 页码：6059 - 6066
• 全文大小：171K
• 年卷期：v.50,no.24(November 29, 2007)
• ISSN：1520-4804

文摘

Benzenesulfonate derivatives of naphtho[2,3-b]thiophen-4(9H)-one and 9(10H)-anthracenone were preparedand found to inhibit microtubule formation by an in vitro tubulin polymerization assay. Several analoguesshowed 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 M).Antiproliferative activities of selected compounds were additionally evaluated against a panel of 12 tumorcell 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 compoundswere arrested in the G2/M phases of the cell cycle. In competition experiments, these compounds stronglydisplaced radiolabeled colchicine from its binding site in the tubulin, showing IC₅₀ values lower than thatof colchicine. The results demonstrate that the antiproliferative activity is related to the inhibition of tubulinpolymerization.