Novel Cyano- and Amidino-Substituted Derivatives of Styryl-2-Benzimidazoles and Benzimidazo[1,2-a]quinolines. Synthesis, Photochemical Synthesis, DNA Binding, and Antitumor Evaluation, Part 3

Abstract

Synthesis of novel cyano- and amidino-substituted styryl-2-benzimidazoles and benzimidazo[1,2-a]quinolines by condensation reactions and photochemical dehydrocyclization and dehydrohalogenation cyclization is described. Thermal denaturation experiments reveal that cyclic derivatives considerably stabilize DNA double helix, while the effect of their acyclic analogues is negligible. According to the spectroscopic study of the interaction of cyclic derivative 19, we propose intercalation of benzimidazo[1,2-a]quinoline moiety into ct-DNA as a dominant interaction underlying biologically relevant effects of this compound, whereas for its acyclic derivative 11, we propose binding into the minor groove of DNA. All compounds show noticeable antiproliferative effect. Morpholino- and chloro-substituted compound 9 is the most active among all acyclic derivatives. All cyclic compounds were 2- to 10-fold more potent, which is correlated with their property to intercalate into DNA. The most active imidazolyl-substituted compound 19 inhibits topoisomerase II and induces strong G2/M cell cycle arrest, pointing to the impairment in mitotic progression. Its pronounced selectivity toward colon carcinoma cells encourages further development of this compound as a lead.

Differential antiproliferative mechanisms of novel derivative of benzimidazo[1,2-α]quinoline in colon cancer cells depending on their p53 status

“…Novel amidino-substituted derivative of benzimidazo [1,2-a]quinoline was synthesized in the group of Professor Grace Karminski-Zamola (Department of Organic Chemistry, Faculty of Chemical Engineering and Technology in Zagreb) as described previously (1).…”

“…Results were expressed as IC 50 (the concentration that causes 50% growth inhibition) calculated from the dose-response curves using linear regression analysis (1).…”

“…In addition, we established that this compound has an ability to intercalate into ct-DNA via its benzimidazo[1,2-a]quinoline moiety, pointing to its DNA-damaging property. Evaluation of the antitumor effects of quinoline derivative against a panel of five different human cancer cell lines showed this compound to exert highly selective cytostatic activity for SW620 colorectal adenocarcinoma cells (1). This finding has elicited the need to further investigate the chemotherapeutic potential of the aforementioned quinoline derivative for colorectal cancer.…”

Novel biologically active nitro and amino substituted benzimidazo[1,2-a]quinolines

“…14 As a part of our continuing search for potential anticancer agents related to benzimidazole derivatives, we have recently reported on the synthesis, cytostatic evaluation, DNA/RNA interaction study and proteomic profiling of a series of amidino-substituted heterocyclic benzimidazoles and benzimidazo [1,2-a]quinolines. 15,16 Biological study confirmed the anticancer potential of this class of compounds, especially that of positively charged analogues of benzimidazo [1,2-a]quinolines which intercalate into ds DNA or RNA.…”

“…The growth inhibition activity was assessed as described previously [ 7,8,15,16,20 ]. The panel cell lines were inoculated onto a series of standard 96-well microtiter plates on day 0, at 1×10 4 to 3×10 4 cells/mL, depending on the doubling times of a specific cell line.…”