کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1397240 1501114 2015 11 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Design and synthesis of 2-phenylnaphthalenoids and 2-phenylbenzofuranoids as DNA topoisomerase inhibitors and antitumor agents
کلمات کلیدی
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Design and synthesis of 2-phenylnaphthalenoids and 2-phenylbenzofuranoids as DNA topoisomerase inhibitors and antitumor agents
چکیده انگلیسی


• Eight 2-phenylnaphthalenoids and twenty four 2-phenylbenzofuranoids were synthesized.
• 2-Phenylnaphthalenoids were TopoIIα poisons.
• 2-Phenylbenzofuranoids were TopoIIα catalytic inhibitors rather than poisons.
• Scaffold hopping is useful to medicinal chemistry evolution of TopoIIα inhibitors.

Eight 2-phenylnaphthalenoids (2PNs) (3a–h) and twenty four 2-phenylbenzofuranoids (2PBFs) (4a-–4j, 5a–5j, 6a, 6f–6h) were successfully designed, synthesized and their antiproliferative and in vitro DNA topoisomerase inhibitory activities were evaluated. Nine compounds (four 2PNs and five 2PBFs) showed either TopoI or TopoIIα inhibitory activities. Six compounds (four 2PNs and two 2PBFs) exhibited potent cytotoxicity with IC50 values for 72 h exposure ranging from 0.3 to above 20 μM against MDA-MB-231, MDA-MB-435, HepG2 and PC3 cell lines. The two 2PBFs displayed comparable and even better antiproliferative as well as TopoIIα inhibitory activities than 2PNs. Interestingly, the active 2PBFs displayed different mechanisms of TopoIIα inhibition from that of 2PNs, suggesting that the chromophore scaffold replacement may result in a change of the binding site of inhibitors to TopoIIα. Furthermore, the mechanisms of antiproliferation on MDA-MB-231 cells indicate that compounds 5a and 5f are promising for further development of anticancer agents. The results of this study reveal that the evolutionary strategy of medicinal chemistry through scaffold hopping is a promising strategy for structure optimization of TopoIIα inhibitors.

Compounds 5a and 5f selectively inhibit TopoIIα, induce DNA damage and apoptosis in MDA-MB-231 cells.Figure optionsDownload as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Medicinal Chemistry - Volume 102, 18 September 2015, Pages 277–287
نویسندگان
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