Synthesis, antiproliferative activity and DNA binding properties of novel 5-aminobenzimidazo[1,2-a]quinoline-6-carbonitriles.
The synthesis of 5-amino substituted benzimidazo[1,2-a]quinolines prepared by microwave assisted amination from halogeno substituted precursor was described. The majority of compounds were active at micromolar concentrations against colon, lung and breast carcinoma cell lines in vitro. The N,N-dimethylaminopropyl 9 and piperazinyl substituted derivative 19 showed the most pronounced activity towards all of the three tested tumor cell lines, which could be correlated to the presence of another N heteroatom and its potential interactions with biological targets. The DNA binding studies, consisting of UV/Visible absorbency, melting temperature studies, and fluorescence and circular dichroism titrations, revealed that compounds 9, 19 and 20 bind to DNA as strong intercalators. The cellular distribution analysis, based on compounds' intrinsic fluorescence, showed that compound 20 does not enter the cell, while compounds 9 and 19 do, which is in agreement with their cytotoxic effects. Compound 9 efficiently targets the nucleus whereas 19, which also showed DNA intercalating properties in vitro, was mostly localised in the cytoplasm suggesting that the antitumor mechanism of action is DNA-independent.
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, P. O. Box 177, HR-10000 Zagreb, Croatia.
Nataša
N
Perin
INSERM U837, Jean-Pierre Aubert Research Centre (JPARC), Team "Molecular and Cellular Targeting for Cancer Treatment", Université Lille 2, IMPRT-IFR-114, Institut pour la Recherche sur le Cancer de Lille, Place de Verdun, F-59045 Lille cedex, France.
Raja
R
Nhili
Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, P. O. Box 180, HR-10000 Zagreb, Croatia.
Katja
K
Ester
INSERM U837, Jean-Pierre Aubert Research Centre (JPARC), Team "Molecular and Cellular Targeting for Cancer Treatment", Université Lille 2, IMPRT-IFR-114, Institut pour la Recherche sur le Cancer de Lille, Place de Verdun, F-59045 Lille cedex, France.
William
W
Laine
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, P. O. Box 177, HR-10000 Zagreb, Croatia.
Grace
G
Karminski-Zamola
Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, P. O. Box 180, HR-10000 Zagreb, Croatia.
Marijeta
M
Kralj
INSERM U837, Jean-Pierre Aubert Research Centre (JPARC), Team "Molecular and Cellular Targeting for Cancer Treatment", Université Lille 2, IMPRT-IFR-114, Institut pour la Recherche sur le Cancer de Lille, Place de Verdun, F-59045 Lille cedex, France. Electronic address: marie-helene.david@inserm.fr.
Marie-Hélène
MH
David-Cordonnier
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, P. O. Box 177, HR-10000 Zagreb, Croatia. Electronic address: mhranjec@fkit.hr.
Marijana
M
Hranjec
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D007364:Intercalating Agents
Amino side chains; Antiproliferative activity; Benzimidazo[1,2-a]quinolines; Cellular distribution; DNA binding properties