title: Amino substituted benzimidazo[1,2-a]quinolines: Antiproliferative potency, 3D QSAR study and DNA binding properties.
abstract: We describe the synthesis, 3D-derived quantitative structure-activity relationship (QSAR), antiproliferative activity and DNA binding properties of a series of 2-amino, 5-amino and 2,5-diamino substituted benzimidazo[1,2-a]quinolines prepared by environmentally friendly uncatalyzed microwave assisted amination. The antiproliferative activities were assessed in vitro against colon, lung and breast carcinoma cell lines; activities ranged from submicromolar to micromolar. The strongest antiproliferative activity was demonstrated by 2-amino-substituted analogues, whereas 5-amino and or 2,5-diamino substituted derivatives resulted in much less activity. Derivatives bearing 4-methyl- or 3,5-dimethyl-1-piperazinyl substituents emerged as the most active. DNA binding properties and the mode of interaction of chosen substituted benzimidazo[1,2-a]quinolines prepared herein were studied using melting temperature studies, a series of spectroscopic studies (UV/Visible, fluorescence, and circular dichroism), and biochemical experiments (topoisomerase I-mediated DNA relaxation and DNase I footprinting experiments). Both compound 36 and its bis-quaternary iodide salt 37 intercalate between adjacent base pairs of the DNA helix while compound 33 presented a very weak topoisomerase I poisoning activity. A 3D-QSAR analysis was performed to identify hydrogen bonding properties, hydrophobicity, molecular flexibility and distribution of hydrophobic regions as these molecular properties had the highest impact on the antiproliferative activity against the three cell lines.
authors.affiliation: Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, P.O. Box 177, HR-10000 Zagreb, Croatia.
authors.forename: Nataša
authors.initials: N
authors.lastname: Perin
authors.affiliation: INSERM UMR-S1172, Jean-Pierre Aubert Research Centre (JPARC), Université de Lille, Institut pour la Recherche sur le Cancer de Lille, Place de Verdun, F-59045 Lille cedex, France.
authors.forename: Raja
authors.initials: R
authors.lastname: Nhili
authors.affiliation: Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, P.O. Box 177, HR-10000 Zagreb, Croatia.
authors.forename: Maja
authors.initials: M
authors.lastname: Cindrić
authors.affiliation: Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, HR-10000 Zagreb, Croatia.
authors.forename: Branimir
authors.initials: B
authors.lastname: Bertoša
authors.affiliation: Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, HR-10000 Zagreb, Croatia.
authors.forename: Darko
authors.initials: D
authors.lastname: Vušak
authors.affiliation: Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, P.O. Box 180, HR-10000 Zagreb, Croatia.
authors.forename: Irena
authors.initials: I
authors.lastname: Martin-Kleiner
authors.affiliation: INSERM UMR-S1172, Jean-Pierre Aubert Research Centre (JPARC), Université de Lille, Institut pour la Recherche sur le Cancer de Lille, Place de Verdun, F-59045 Lille cedex, France.
authors.forename: William
authors.initials: W
authors.lastname: Laine
authors.affiliation: Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, P.O. Box 177, HR-10000 Zagreb, Croatia.
authors.forename: Grace
authors.initials: G
authors.lastname: Karminski-Zamola
authors.affiliation: Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, P.O. Box 180, HR-10000 Zagreb, Croatia.
authors.forename: Marijeta
authors.initials: M
authors.lastname: Kralj
authors.affiliation: INSERM UMR-S1172, Jean-Pierre Aubert Research Centre (JPARC), Université de Lille, Institut pour la Recherche sur le Cancer de Lille, Place de Verdun, F-59045 Lille cedex, France.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: David-Cordonnier
authors.affiliation: Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, P.O. Box 177, HR-10000 Zagreb, Croatia. Electronic address: mhranjec@fkit.hr.
authors.forename: Marijana
authors.initials: M
authors.lastname: Hranjec
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D011804:Quinolines; D004247:DNA
keywords: 3D-QSAR; Antiproliferative activity; Benzimidazo[1,2-a]quinolines; Benzimidazoles; DNA binding properties