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.
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.
Hranjec
Marijana
M
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, Post Office Box 177, HR-10000 Zagreb, Croatia,
Kralj
Marijeta
M
Piantanida
Ivo
I
Sedić
Mirela
M
Suman
Lidija
L
Pavelić
Kresimir
K
Karminski-Zamola
Grace
G
D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002942:Circular Dichroism; D003500:Cyclization; D004247:DNA / Q000737:chemistry*; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010777:Photochemistry; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013343:Styrenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000578:Amidines; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D009570:Nitriles; D011804:Quinolines; D013343:Styrenes; D004247:DNA; D004250:DNA Topoisomerases, Type II