title: Cyclometalated Iminophosphorane Gold(III) and Platinum(II) Complexes. A Highly Permeable Cationic Platinum(II) Compound with Promising Anticancer Properties.
abstract: New organometallic gold(III) and platinum(II) complexes containing iminophosphorane ligands are described. Most of them are more cytotoxic to a number of human cancer cell lines than cisplatin. Cationic Pt(II) derivatives 4 and 5, which differ only in the anion, Hg2Cl6(2-) or PF6(-) respectively, display almost identical IC50 values in the sub-micromolar range (25-335-fold more active than cisplatin on these cell lines). The gold compounds induced mainly caspase-independent cell death, as previously reported for related cycloaurated compounds containing IM ligands. Cycloplatinated compounds 3, 4, and 5 can also activate alternative caspase-independent mechanisms of death. However, at short incubation times cell death seems to be mainly caspase dependent, suggesting that the main mechanism of cell death for these compounds is apoptosis. Mercury-free compound 5 does not interact with plasmid (pBR322) DNA or with calf thymus DNA. Permeability studies of 5 by two different assays, in vitro Caco-2 monolayers and a rat perfusion model, have revealed a high permeability profile for this compound (comparable to that of metoprolol or caffeine) and an estimated oral fraction absorbed of 100%, which potentially makes it a good candidate for oral administration.
authors.affiliation: †Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, New York 11210, United States.|‡Chemistry Ph.D. Program, The Graduate Center, The City University of New York, 365 Fifth Avenue, New York, New York 10016, United States.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Frik
authors.affiliation: †Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, New York 11210, United States.
authors.forename: Jacob
authors.initials: J
authors.lastname: Fernández-Gallardo
authors.affiliation: §Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, 50009 Zaragoza, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Gonzalo
authors.affiliation: ∥Departamento de Ingeniería, Área Farmacia y Tecnología Farmacéutica, Universidad Miguel Hernández, 03550 San Juan, Alicante, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Mangas-Sanjuan
authors.affiliation: ∥Departamento de Ingeniería, Área Farmacia y Tecnología Farmacéutica, Universidad Miguel Hernández, 03550 San Juan, Alicante, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: González-Alvarez
authors.affiliation: §Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, 50009 Zaragoza, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Serrano del Valle
authors.affiliation: ⊥Chemistry Department, New York University, New York, New York 10003, United States.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Hu
authors.affiliation: ∥Departamento de Ingeniería, Área Farmacia y Tecnología Farmacéutica, Universidad Miguel Hernández, 03550 San Juan, Alicante, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: González-Alvarez
authors.affiliation: ∥Departamento de Ingeniería, Área Farmacia y Tecnología Farmacéutica, Universidad Miguel Hernández, 03550 San Juan, Alicante, Spain.
authors.forename: Marival
authors.initials: M
authors.lastname: Bermejo
authors.affiliation: §Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, 50009 Zaragoza, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Marzo
authors.affiliation: †Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, New York 11210, United States.|‡Chemistry Ph.D. Program, The Graduate Center, The City University of New York, 365 Fifth Avenue, New York, New York 10016, United States.|#Biology Ph.D. Program, The Graduate Center, The City University of New York, 365 Fifth Avenue, New York, New York 10016, United States.
authors.forename: María
authors.initials: M
authors.lastname: Contel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002412:Cations; D002417:Cattle; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D003500:Cyclization; D004247:DNA / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006046:Gold / Q000737:chemistry*; D006801:Humans; D015394:Molecular Structure; D010753:Phosphoranes / Q000737:chemistry*; D010984:Platinum / Q000737:chemistry*; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D002412:Cations; D010753:Phosphoranes; D010984:Platinum; D006046:Gold; D004247:DNA