Design, Synthesis, and Cytotoxic Evaluation of Acyl Derivatives of 3-Aminonaphtho[2,3-b]thiophene-4,9-dione, a Quinone-Based System

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• 作者：Isabel Gomez-Monterrey ; Pietro Campiglia ; Claudio Aquino ; Alessia Bertamino ; Ilaria Granata ; Alfonso Carotenuto ; Diego Brancaccio ; Paola Stiuso ; Ilaria Scognamiglio ; M. Rosaria Rusciano ; Angela Serena Maione ; Maddalena Illario ; Paolo Grieco ; Bruno Maresca ; Ettore Novellino
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：June 23, 2011
• 年：2011
• 卷：54
• 期：12
• 页码：4077-4091
• 全文大小：1134K
• 年卷期：v.54,no.12(June 23, 2011)
• ISSN：1520-4804

文摘

A series of 3-acyl derivatives of the dihydronaphtho[2,3-b]thiophen-4,9-dione system were studied with respect to cytotoxicity and topoisomerase II inhibitory activity. These analogues were designed as electron-deficient anthraquinone analogues with potential intercalation ability. Derivatives 3-(diethylamino)-N-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]thiophen-3-yl)propanamide (11m) and 3-(2-(dimethylamino)ethylamino)-N-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]thiophen-3-yl)propanamide (11p) showed a high efficacy in cell lines that were highly resistant to treatment with doxorubicin, such as MDA-MB435 (melanoma), IGROV (ovarian), and SF-295 (glioblastoma) human cell lines. Both compounds inhibit topoisomerase II mediated relaxation of DNA, while only 11p incites arrest at the S phase in Caco-2 cells, inducing a delay of cell cycle progression and an increase of cell differentiation. The ability of these derivatives to modulate small heat shock proteins and cardiotoxicy effects was also explored. In addition, the DNA-binding properties of these compounds were investigated and discussed.