title: Design, synthesis and SAR studies of novel 1,2-bis(aminomethyl)cyclohexane platinum(II) complexes with cytotoxic activity. Studies of interaction with DNA of iodinated seven-membered 1,4-diaminoplatinocycles.
abstract: A selected library of nine novel platinum(II) complexes having differently functionalized 1,2-bis(aminomethyl)cyclohexane carrier ligands with a 1,4-diamino framework and iodides as labile ligands have been synthesized and evaluated in vitro for their tumor cell growth inhibitory activity, in front of one pair of human carcinoma cell lines A2780 and A2780cisR. These cell lines were chosen based on studying all the known main mechanisms of resistance of cisplatin. A2780cisR cells are resistant through a combination of reduced drug transport enhanced DNA repair/tolerance and elevated glutathione (GSH) levels with respect to the parental A2780 cells. Most platinum complexes evaluated showed a very low resistant factor, up to 16 times lower than that of cisplatin, which indicates their ability to overcome the cisplatin resistance in ovarian cancer A2780cisR cells. Structure-activity studies have been performed in order to know the influence of the several organic functionalities (CC double bond, free OH group, MeO group, etc.) and the stereochemistry on the cytotoxic activity. Moreover, studies of interaction with DNA of these complexes were performed via three techniques: circular dichroism (CD), electrophoresis on agarose gel (EF) and atomic force microscopy (AFM) in order to evaluate the modifications of secondary and tertiary structure of DNA, induced by platinum complexes. These studies allowed us to correlate the IC50 values of complexes and the intensity of interaction to DNA, the main target for these compounds.
authors.affiliation: Unidad de Química Orgánica Industrial y Aplicada, Departamento de Química Orgánica, Universidad de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain; Institut de Recerca Biomédica, 08028 Barcelona, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Gay
authors.affiliation: Unidad de Química Orgánica Industrial y Aplicada, Departamento de Química Orgánica, Universidad de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain. Electronic address: angel.montana@ub.edu.
authors.forename: Ángel M
authors.initials: ÁM
authors.lastname: Montaña
authors.affiliation: Unidad de Química Orgánica Industrial y Aplicada, Departamento de Química Orgánica, Universidad de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Batalla
authors.affiliation: Escuela Politécnica Superior, Universidad de Santiago de Compostela, Campus de Lugo, 27002 Lugo, Spain.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Mesas
authors.affiliation: Escuela Politécnica Superior, Universidad de Santiago de Compostela, Campus de Lugo, 27002 Lugo, Spain.
authors.forename: María-Teresa
authors.initials: MT
authors.lastname: Alegre
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002942:Circular Dichroism / Q000379:methods; D002945:Cisplatin / Q000031:analogs & derivatives*; D004247:DNA / Q000737:chemistry / Q000648:ultrastructure; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004587:Electrophoresis, Agar Gel / Q000379:methods; D006801:Humans; D018625:Microscopy, Atomic Force / Q000379:methods; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D004247:DNA; D002945:Cisplatin
keywords: 1,4-diamino-ligands; Anticancer agents; Cytotoxicity; Platinum(II) complexes; SAR studies