title: Antiproliferative activity of a series of cisplatin-based Pt(IV)-acetylamido/carboxylato prodrugs.
abstract: We report studies of a novel series of Pt(IV) complexes exhibiting an asymmetric combination of acetylamido and carboxylato ligands in the axial positions. We demonstrate efficient synthesis of a series of analogues, differing in the alkyl chain length and hence lipophilicity, from a stable acetylamido/hydroxido complex formed by reaction of cisplatin with peroxyacetimidic acid (PAIA). NMR spectroscopy and X-ray crystallography confirm the identity of the resulting complexes, and highlight subtle differences in the structure and stability of acetylamido complexes compared to the equivalent acetato complexes. Reduction of acetylamido complexes, whether achieved chemically or electro-chemically, is significantly more difficult than that of acetate complexes, resulting in lower antiproliferative activity for shorter-chain complexes. For those with longer chains and hence greater cell uptake, this difference is negated and acetylamido complexes are as active as acetato analogues, both exhibiting antiproliferative potency (1/IC50) against A2780 ovarian cancer cells similar to that of cisplatin.
authors.affiliation: Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale, Viale Teresa Michel 11, 15121 Alessandria, Italy. domenico.osella@uniupo.it.
authors.forename: Mauro
authors.initials: M
authors.lastname: Ravera
authors.affiliation: Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale, Viale Teresa Michel 11, 15121 Alessandria, Italy. domenico.osella@uniupo.it.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Gabano
authors.affiliation: Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale, Viale Teresa Michel 11, 15121 Alessandria, Italy. domenico.osella@uniupo.it.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Zanellato
authors.affiliation: Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale, Viale Teresa Michel 11, 15121 Alessandria, Italy. domenico.osella@uniupo.it.
authors.forename: Federico
authors.initials: F
authors.lastname: Fregonese
authors.affiliation: Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze, 17/A, 43124 Parma, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Pelosi
authors.affiliation: School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Platts
authors.affiliation: Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale, Viale Teresa Michel 11, 15121 Alessandria, Italy. domenico.osella@uniupo.it.
authors.forename: Domenico
authors.initials: D
authors.lastname: Osella
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D002945:Cisplatin / Q000737:chemistry*; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D018360:Crystallography, X-Ray; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D010984:Platinum / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D011355:Prodrugs; D010984:Platinum; D002945:Cisplatin