期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 136, 期 -, 页码 468-479出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.05.014
关键词
Amidines; Antiproliferative activity; Benzimidazoles; benzo[b]thieno-2-carboxamides; Benzothiazoles; DNA binding; Topoisomerase poisoning
资金
- Croatian Science Foundation [5596]
- Ligue contre le Cancer (Comite du Nord)
- Association Laurette Fugain [ALF/05]
- Institut pour la Recherche sur le Cancer de Lille (IRCL)
- European Regional Development Fund (ERDF)
- University of Rijeka [13.11.1.1.11]
Within this manuscript design, synthesis of novel 2-imidazolinyl substituted benzo[b]thieno-2carboxamides bearing either benzimidazole or benzothiazole subunit and biological activity are presented and described. The antiproliferative activities were assessed in vitro on a panel of human cancer cell lines. Tested compounds showed moderate activity while cytotoxicity on normal fibroblasts was lower in comparison with 5-fluorouracile. The variations of 2-imidazolinyl substituent at heteroaromatic subunits in different positions led to different cytotoxic properties. The strongest selective activity against HeLa cells was observed for the benzothiazole derivative 4d with 2-imidazolinyl group at the benzo[b]thiophene subunit with a corresponding IC50 = 1.16 mu M. Additionally, several biological experiments were performed to explain the mode of biological action. Fluorescence microscopy evidenced nuclear subcellular localization of compounds 3a, 4a and 4c. Additionally, detailed DNA binding studies confirmed a strong DNA groove binding for derivatives 4a and 4c while DNase I footprinting experiments evidenced sequence-selective binding of compound 4c in the A-T rich side. Furthermore, topoisomerase suppressive effect was for compounds 4a-4c. (C) 2017 Elsevier Masson SAS. All rights reserved.
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