Title
Novel amidino substituted benzimidazole and benzothiazole benzo[b]thieno-2-carboxamides exert strong antiproliferative and DNA binding properties
Author
Maja Cindrić, Samy Jambon, Anja Harej, Sabine Depauw, Marie-Hélène David-Cordonnier, Sandra Kraljević Pavelić, Grace Karminski-Zamola, Marijana Hranjec
Year
2017
Journal
European Journal of Medicinal Chemistry
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.
Instrument
J-810
Keywords
Circular dichroism, Induced CD, DNA structure, Ligand binding, Biochemistry, Pharmaceutical