2. Academic Validation
  3. Novel amidino substituted benzimidazole and benzothiazole benzo[b]thieno-2-carboxamides exert strong antiproliferative and DNA binding properties

Novel amidino substituted benzimidazole and benzothiazole benzo[b]thieno-2-carboxamides exert strong antiproliferative and DNA binding properties

  • Eur J Med Chem. 2017 Aug 18:136:468-479. doi: 10.1016/j.ejmech.2017.05.014.
Maja Cindrić 1,  Samy Jambon 2,  Anja Harej 3,  Sabine Depauw 2,  Marie-Hélène David-Cordonnier 4,  Sandra Kraljević Pavelić 3,  Grace Karminski-Zamola 1,  Marijana Hranjec 5
Affiliations

Affiliations

  • 1 Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, P. O. Box 177, HR-10000 Zagreb, Croatia.
  • 2 INSERM UMR-S1172, Jean-Pierre Aubert Research Centre (JPARC), Université de Lille, Hospital Centre of Lille (CHU), Institut pour la Recherche sur le Cancer de Lille (IRCL), Place de Verdun, F-59045 Lille cedex, France.
  • 3 Department of Biotechnology, Centre for High-throughput technologies, University of Rijeka, Radmile Matejčić 2, HR-51000 Rijeka, Croatia.
  • 4 INSERM UMR-S1172, Jean-Pierre Aubert Research Centre (JPARC), Université de Lille, Hospital Centre of Lille (CHU), Institut pour la Recherche sur le Cancer de Lille (IRCL), Place de Verdun, F-59045 Lille cedex, France. Electronic address: marie-helene.david@inserm.fr.
  • 5 Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, P. O. Box 177, HR-10000 Zagreb, Croatia. Electronic address: mhranjec@fkit.hr.
PMID: 28525845 DOI: 10.1016/j.ejmech.2017.05.014
Abstract

Within this manuscript design, synthesis of novel 2-imidazolinyl substituted benzo[b]thieno-2-carboxamides 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 μM. 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.

Keywords

Amidines; Antiproliferative activity; Benzimidazoles; Benzothiazoles; DNA binding; Topoisomerase poisoning; benzo[b]thieno-2-carboxamides.

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