期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 187, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.111960
关键词
Pyridophenoxazinones; Antiproliferative activity; DNA damage; Topoisomerase II inhibitors; Docking studies
资金
- grants Combattere la resistenza tumorale: piattaforma integrata multidisciplinare per un approccio tecnologico innovativo alle oncoterapie CAMPANIA ONCOTERAPIE of Regione Campania (Italy) [B61G18000470007]
A series of L-lysine-conjugated pyridophenoxazinones 2-5 and 2'-5' were designed and synthesized for developing compounds with multimodal anticancer potentialities. All compounds inhibited the proliferation of a panel of human liquid and solid neoplastic cell lines. 2 and 5 were the most active compounds with IC50 values in the submicromolar range. UV-vis, H-1 NMR, unwinding, and docking experiments demonstrated that they intercalate between the middle 5'-GC-3' base pairs with the carboxamide side chain lying into major groove. Charge-transfer contribution to the complex stability, evaluated by ab initio calculations, was found to correlate with cytotoxicity. Relaxation and cleavage assays showed that 2 and 5 selectively target Topo II alpha, over Topo II beta and stimulate the formation of covalent Topo II-DNA complexes, functioning as poisons. Moreover, compound 5 induced DNA damage and arrested MCF-7 cells at the G2/M phase. Altogether, the work provides interesting structure-activity relationships in the pyridophenoxazinone-L-lysine conjugate series and identifies 5 as a promising candidate for further in vivo evaluation. (C) 2019 Elsevier Masson SAS. All rights reserved.
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