Cindrić Maja, Jambon Samy, Harej Anja, Depauw Sabine, David-Cordonnier Marie-Hélène, Kraljević Pavelić Sandra, Karminski-Zamola Grace, Hranjec Marijana
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, P. O. Box 177, HR-10000 Zagreb, Croatia.
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.
Eur J Med Chem. 2017 Aug 18;136:468-479. doi: 10.1016/j.ejmech.2017.05.014. Epub 2017 May 4.
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 IC = 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.
在本手稿设计中，介绍并描述了带有苯并咪唑或苯并噻唑亚基的新型2-咪唑啉基取代苯并[b]噻吩-2-甲酰胺的合成及其生物活性。在一组人类癌细胞系上体外评估了抗增殖活性。测试的化合物显示出中等活性，而与5-氟尿嘧啶相比，对正常成纤维细胞的细胞毒性较低。不同位置的杂芳族亚基上2-咪唑啉基取代基的变化导致不同的细胞毒性特性。在苯并[b]噻吩亚基上带有2-咪唑啉基的苯并噻唑衍生物4d对HeLa细胞表现出最强的选择性活性，其相应的IC = 1.16 μM。此外，进行了几项生物学实验以解释其生物作用模式。荧光显微镜检查证明了化合物3a、4a和4c的核亚细胞定位。此外，详细的DNA结合研究证实了衍生物4a和4c与DNA沟的强结合，而DNase I足迹实验证明了化合物4c在富含A-T的一侧具有序列选择性结合。此外，化合物4a-4c具有拓扑异构酶抑制作用。
