title: Novel phenyl and pyridyl substituted derivatives of isoindolines: Synthesis, antitumor activity and DNA binding features.
abstract: Novel phenyl-substituted (3a-3d, 4a, 5, 8a, 8b and 9a) and pyridyl-substituted (3e-3i, 4b, 8c-8e, 9b and 9c) isoindolines were prepared in the reaction of o-phthalaldehyde and corresponding substituted aromatic and heteroaromatic amines by modification of reaction conditions from low to high temperature and from neutral to acidic environment. The antiproliferative activity of chosen substituted isoindolines was assessed on a panel of tumour cell lines and normal human fibroblasts. The majority of tested compounds was active at the highest tested concentrations phenyl-substituted isoindolines 3a and 3b and pyridyl-substituted isoindoline 3g showed a selective effect at micromolar concentrations on HepG2 cell line in comparison with other tested tumour cell lines and normal human fibroblasts. The strongest yet non-selective effect was observed for the pyridyl-substituted isoindoline 8c. These isoindoline derivatives showed diverse mechanism of action on tumour cell death induction as compounds 3a and 8c probably induced mitotic catastrophe while compound 3b induced apoptosis. Indeed, DNA binding properties evidenced that compounds 8a, 8c and 8d bind to DNA as highly potent DNA intercalators. By contrast, compounds 3b, 3e, 3i, 4a and 5 did not target the DNA. At last, the phenyl-substituted compound 8b proved to be a strong DNA binding compound with sequence selective binding and without DNA intercalation profile.
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: Irena
authors.initials: I
authors.lastname: Sović
authors.affiliation: Department of Biotechnology, University of Rijeka, Radmile Matejčić 2, 51000 Rijeka, Croatia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Kraljević Pavelić
authors.affiliation: Department of Biotechnology, University of Rijeka, Radmile Matejčić 2, 51000 Rijeka, Croatia.
authors.forename: Elitza
authors.initials: E
authors.lastname: Markova-Car
authors.affiliation: Department of Biotechnology, University of Rijeka, Radmile Matejčić 2, 51000 Rijeka, Croatia.
authors.forename: Nataša
authors.initials: N
authors.lastname: Ilić
authors.affiliation: INSERM U837-JPARC (Jean-Pierre Aubert Research Center), Team "Molecular and Cellular Targeting for Cancer Treatment", Université Lille Nord de France, IFR-114, 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: INSERM U837-JPARC (Jean-Pierre Aubert Research Center), Team "Molecular and Cellular Targeting for Cancer Treatment", Université Lille Nord de France, IFR-114, Institut pour la Recherche sur le Cancer de Lille, Place de Verdun, F-59045 Lille Cedex, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Depauw
authors.affiliation: INSERM U837-JPARC (Jean-Pierre Aubert Research Center), Team "Molecular and Cellular Targeting for Cancer Treatment", Université Lille Nord de France, IFR-114, 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: gzamola@fkit.hr.
authors.forename: Grace
authors.initials: G
authors.lastname: Karminski-Zamola
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004247:DNA / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011725:Pyridines; C057812:indoline; D004247:DNA; C023666:pyridine
keywords: Antiproliferative activity; DNA binding; Heterocyclic compounds; Intercalator; Phenyl and pyridyl substituted isoindolines; Sequence-selective binding