Shchekotikhin Andrey E, Glazunova Valeria A, Dezhenkova Lyubov G, Luzikov Yuri N, Sinkevich Yuri B, Kovalenko Leonid V, Buyanov Vladimir N, Balzarini Jan, Huang Fong-Chun, Lin Jing-Jer, Huang Hsu-Shan, Shtil Alexander A, Preobrazhenskaya Maria N
Gause Institute of New Antibiotics, Moscow, Russian Federation.
Bioorg Med Chem. 2009 Mar 1;17(5):1861-9. doi: 10.1016/j.bmc.2009.01.047. Epub 2009 Jan 27.
We developed the synthesis of a series of thiophene-fused tetracyclic analogues of the antitumor drug ametantrone. The reactions included nucleophilic substitution of methoxy groups in 4,11-dimethoxyanthra[2,3-b]thiophene-5,10-diones with ethylenediamines, producing the derivatives of 4,11-diaminoanthra[2,3-b]thiophene-5,10-dione in good yields. Several compounds showed marked antiproliferative potency against doxorubicin-selected, P-glycoprotein-expressing tumor cells and p53(-/-) cells. The cytotoxicity of some novel compounds for P-glycoprotein-positive cells is highly dependent on N-substituent at the terminal amino group of ethylenediamine moiety. The cytotoxic potency of selected compounds correlated with their ability to attenuate the functions of topoisomerase I and telomerase, strongly suggesting that these enzymes are the major targets of antitumor activity of anthra[2,3-b]thiophene-5,10-dione derivatives.
我们开展了一系列与抗肿瘤药物氨茴环素结构类似的噻吩并四环类似物的合成研究。反应包括用乙二胺对4,11-二甲氧基蒽[2,3-b]噻吩-5,10-二酮中的甲氧基进行亲核取代，高产率地生成4,11-二氨基蒽[2,3-b]噻吩-5,10-二酮的衍生物。几种化合物对阿霉素筛选的、表达P-糖蛋白的肿瘤细胞和p53(-/-)细胞显示出显著的抗增殖能力。一些新型化合物对P-糖蛋白阳性细胞的细胞毒性高度依赖于乙二胺部分末端氨基上的N-取代基。所选化合物的细胞毒性效力与其减弱拓扑异构酶I和端粒酶功能的能力相关，这有力地表明这些酶是蒽[2,3-b]噻吩-5,10-二酮衍生物抗肿瘤活性的主要靶点。
