Naslov
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

Autori
Hranjec, Marijana ; Kralj, Marijeta ; Piantanida, Ivo ; Sedić, Mirela ; Šuman, Lidija ; Pavelić, Krešimir ; Karminski-Zamola, Grace

Izvornik
Journal of medicinal chemistry (0022-2623) 50 (2007), 23; 5696-5711

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
benzimidazoles ; amidines ; quinolines ; interaction with ct-DNA ; antitumor evaluation ; inhibition of topoisomerase II

Sažetak
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 two to tenfold 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 towards colon carcinoma cells encourages further development of this compound as a lead.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Biologija, Temeljne medicinske znanosti

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