title: Synthesis and antiproliferative activity of a C,N-cycloplatinated(II) complex with a potentially intercalative anthraquinone pendant.
abstract: The synthesis of the novel anthraquinone platinum derivate [Pt(ppy)Cl(1C3)] (2) [Hppy = N,C-chelating 2-phenylpyridine; 1C3 = 1-[(3-aminopropyl)amino]-anthracene-9,10-dione] and its values of IC(50) against a panel of human tumor cell lines representative of ovarian (A2780 and A2780cisR) and breast cancers (T47D) are reported. At 24 h incubation time, complex 2 was more active than cisplatin (about 9-fold) and the free ligand 1C3 (about 2-fold) in T47-D. The observation that the cisplatin IC(50) falls by about 10-fold from 24 to 72 h, whereas that for 2 changes little, suggests substantial differences in the mode of action. Complex 2 also showed high cytotoxicity against A2780 (about 3-fold greater than cisplatin at 24 h). On the other hand, very low resistance factors (RF) of 2 in A2780cisR at 24-72 h (RF = 1.3) were observed. The interaction of 2 with DNA was followed by electrophoretic mobility and UV-visible spectroscopy, and its reaction with the model nucleobase 9-EtG was studied by (1)H NMR and ESI-MS. Theoretical calculations at the B3LYP/def2-TZVPP//BP86/def2-TZVP level of theory on complex 2 show a labile Pt-Cl bond that allows easy replacement of Cl by N-nucleophiles such as 9-EtG, which forms a stronger Pt-N bond.
authors.affiliation: Departamento de Química Inorgánica, Universidad de Murcia, 30071-Murcia, Spain. jruiz@um.es
authors.forename: José
authors.initials: J
authors.lastname: Ruiz
authors.forename: Consuelo
authors.initials: C
authors.lastname: Vicente
authors.forename: Concepción
authors.initials: C
authors.lastname: de Haro
authors.forename: Arturo
authors.initials: A
authors.lastname: Espinosa
mesh_terms: D000880:Anthraquinones / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry*; D011789:Quantum Theory; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000880:Anthraquinones; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D011725:Pyridines; C058324:2-phenylpyridine