Synthesis, antitumor activity and DNA binding features of benzothiazolyl and benzimidazolyl substituted isoindolines. Issue 8 (1st May 2018)

• Record Type: Journal Article
• Authors: Sović, Irena; Jambon, Samy; Kraljević Pavelić, Sandra; Markova-Car, Elitza; Ilić, Nataša; Depauw, Sabine; David-Cordonnier, Marie-Hélène; Karminski-Zamola, Grace
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 8(2018)
• Page Start: 1950
• Page End: 1960
• Publication Date: 2018-05-01
• Subjects: Isoindolines -- Benzothiazole -- Benzimidazole -- Antiproliferative activity -- DNA binding -- Topoisomerase I/II inhibition; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.02.045
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Isoindolines substituted with benzimidazole and benzothiazole were prepared. Compounds showed strong to moderate antiproliferative activity. Activation of the intrinsic, mitochondrial apoptotic pathway was determined. All tested compounds showed nuclear localization in the cell. Compounds containing amidino group interact with DNA helix. Abstract: In this paper novel isoindolines substituted with cyano and amidino benzimidazoles and benzothiazoles were synthesized as new potential anti-cancer agents. The new structures were evaluated for antiproliferative activity, cell cycle changes, cell death, as well as DNA binding and topoisomerase inhibition properties on selected compounds. Results showed that all tested compounds exerted antitumor activity, especially amidinobenzothiazole and amidinobenzimidazole substituted isoindolin-1-ones and benzimidazole substituted 1-iminoisoindoline that showed antiproliferative effect in the submicromolar range. Moreover, the DNA-binding properties of selected compounds were evaluated by biophysical and biochemical approaches including thermal denaturation studies, circular dichroism spectra analyses and topoisomerase I/II inhibition assays and results identified some of them as strong DNA ligands, harboring or not additional topoisomerase II inhibition and able to locate in the nucleus as determined by fluorescence microscopy. In conclusion, we evidenced novel cyano- and amidino-substituted isoindolines coupled with benzimidazoles and benzothiazoles as topoisomerase inhibitors and/or DNA binding compounds with potent antitumor activities.