Antiproliferative potency of 2-amino, 5-amino and 2,5-diamino substituted benzimidazo[1,2-a]quinolines: 3D QSAR study and DNA binding properties

Perin, Nataša; Cindrić, Maja; Bertoša, Branimir; Vušak, Darko; Martin-Kleiner, Irena; Laine, William; Karminski-Zamola, Grace; Kralj, Marijeta; David-Cordonnier, Marie-Helene; Hranjec, Marijana; Nhilli, Raja (2016) Antiproliferative potency of 2-amino, 5-amino and 2,5-diamino substituted benzimidazo[1,2-a]quinolines: 3D QSAR study and DNA binding properties. European Journal of Medicinal Chemistry, 122 . pp. 530-536. ISSN 0223-5234

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Abstract

This manuscript describes the synthesis, 3D-derived QSAR, antiproliferative activity and DNA binding properties of 2-amino, 5-amino and 2,5-diaminosubstituted benzimidazo[1,2-a]quinolines prepared by microwave assisted amination. Their antiproliferative effect was assessed on three tumor cell lines against colon, lung and breast carcinoma cell lines in vitro. The activities tested ranged from moderate to very strong. 2-amino-subsituted analogues demonstrated stronger antiproliferative activity compared to 5-amino, or 2,5-diamino substituted derivatives, while N-methyl or 3,5-dimethylpiperazinyl substituted analogues were the most active ones. Their DNA binding abilities and mode of interaction were evaluated using spectroscopic (melting temperature studies, UV/Visible and fluorescence spectra analyses, circular dichroism) and biochemical experiments (topoisomerase I-mediated DNA relaxation and DNase I footprinting experiments). From this series, only two compounds (36 and 37) evidenced strong DNA binding properties. Both 36 and its iodide salt 37 intercalate between adjacent base pairs of the DNA helix but the 37 did not show any effect on tumor cells. Only compound 33 presented a very weak topoisomerase I poisoning activity. 3D-QSAR analysis identified hydrogen bonding properties, hydrophobicity, molecular flexibility, and distribution of hydrophobic regions as the molecular properties with the highest influence on the antiproliferative activity against all three studied cell lines.

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Article

Additional Information:

We greatly appreciate the financial support of the Croatian Science Foundation under the projects 5596 (Synthesis and cytostatic evaluations of novel nitrogen heterocycles library) and 5660 (A multidisciplinary approach to discover selective drugs targeting cancer stem cells: The role of potassium transport - MultiCaST) as well as the bilateral Hubert Curien partnership between Croatian And French Institutions (Cogito program) as the Egide Project No. 24765 PH. M. H. David-Cordonnier is grateful to the Ligue Nationale Contre le Cancer (Comite du Nord, Septentrion) for grants and to the Institut pour la Recherche sur le Cancer de Lille (IRCL) for post-doctoral fellowship to Raja Nhili and grants. M. H. David-Cordonnier also thanks Sabine DEPAUW for technical expertise and the IMPRT-IFR114 for giving access to the Pharos-PMI equipment (BioRad).

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Subjects:

UNSPECIFIED

Divisions:

Division of Molecular Medicine

Projects:

Project title	Project leader	Project code	Project type
A multidisciplinary approach to discover selective drugs targeting cancer stem cells: The role of potassium transport-MultiCaST	Marijeta Kralj	5660	HRZZ
Synthesis and cytostatic evaluations of novel nitrogen heterocycles library	Silvana Raić-Malić	5596	HRZZ
Egide project	UNSPECIFIED	24765 PH	FP7