Department of Pharmaceutical and Toxicological Chemistry, University of Naples Federico II, Naples, Italy.
J Med Chem. 2011 Jun 23;54(12):4077-91. doi: 10.1021/jm200094h. Epub 2011 May 23.
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.
研究了一系列二氢萘并[2,3-b]噻吩-4,9-二酮体系的 3-酰基衍生物，以评估其细胞毒性和拓扑异构酶 II 抑制活性。这些类似物被设计为具有潜在嵌入能力的缺电子蒽醌类似物。衍生物 3-(二乙氨基)-N-(4,9-二氧代-4,9-二氢萘并[2,3-b]噻吩-3-基)丙酰胺（11m）和 3-(2-(二甲氨基)乙基氨基)-N-(4,9-二氧代-4,9-二氢萘并[2,3-b]噻吩-3-基)丙酰胺（11p）在对阿霉素治疗高度耐药的细胞系中表现出高效，如 MDA-MB435（黑色素瘤）、IGROV（卵巢）和 SF-295（神经胶质瘤）人细胞系。这两种化合物都抑制拓扑异构酶 II 介导的 DNA 松弛，而只有 11p 在 Caco-2 细胞中引起 S 期停滞，诱导细胞周期进程延迟和细胞分化增加。还研究了这些衍生物调节小分子热休克蛋白和心脏毒性的能力。此外，还研究和讨论了这些化合物的 DNA 结合特性。
