title: Structure, solution chemistry, antiproliferative actions and protein binding properties of non-conventional platinum(II) compounds with sulfur and phosphorus donors.
abstract: Twelve Pt(II) complexes with cis-PtP(2)S(2) pharmacophores (where P(2) refers to two monodentate or one bidentate phosphane ligand and S(2) is a dithiolato ligand) were prepared, characterized and evaluated as potential antiproliferative agents. The various compounds were first studied from the structural point of view; afterward, their solubility properties as well as their solution behaviour were analyzed in detail. Antiproliferative properties were specifically evaluated against A2780 human ovarian carcinoma cells, either resistant or sensitive to cisplatin. For comparison purposes similar studies were carried out on four parent cis-dichloro bisphosphane Pt(II)complexes. On the whole, the cis-PtP(2)S(2) compounds displayed significant antiproliferative properties while the cis-PtP(2)Cl(2) (cis-dichloro bisphosphane Pt(II)) compounds revealed quite poor biological performances. To gain further insight into the molecular mechanisms of these bisphosphane Pt(II) compounds, the reactions of selected complexes against the model protein cytochrome c were investigated by ESI-MS and their adduct formation explored. A relevant reactivity with cyt c was obtained only for cis-PtP(2)Cl(2) compounds, whereas cis-PtP(2)S(2) compounds turned out to be nearly unreactive. The obtained results are interpreted and discussed in the frame of the current knowledge of anticancer platinum compounds and their structure-activity-relationships. The observation of appreciable antiproliferative effects for the relatively inert cis-PtP(2)S(2) compounds strongly suggests that these compounds will undergo specific activation within the cellular environment.
authors.affiliation: Institute of Inorganic and Analytical Chemistry, Friedrich-Schiller-University Jena, August-Bebel-Strasse 2, 07743, Jena, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Mügge
authors.forename: Claudia
authors.initials: C
authors.lastname: Rothenburger
authors.forename: Antje
authors.initials: A
authors.lastname: Beyer
authors.forename: Helmar
authors.initials: H
authors.lastname: Görls
authors.forename: Chiara
authors.initials: C
authors.lastname: Gabbiani
authors.forename: Angela
authors.initials: A
authors.lastname: Casini
authors.forename: Elena
authors.initials: E
authors.lastname: Michelucci
authors.forename: Ida
authors.initials: I
authors.lastname: Landini
authors.forename: Stefania
authors.initials: S
authors.lastname: Nobili
authors.forename: Enrico
authors.initials: E
authors.lastname: Mini
authors.forename: Luigi
authors.initials: L
authors.lastname: Messori
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Weigand
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000737:chemistry / Q000633:toxicity; D045304:Cytochromes c / Q000737:chemistry; D005260:Female; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D010051:Ovarian Neoplasms / Q000188:drug therapy; D010720:Phosphines / Q000737:chemistry; D010758:Phosphorus / Q000737:chemistry; D017671:Platinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry*; D011485:Protein Binding; D013056:Spectrophotometry, Ultraviolet / Q000379:methods; D013329:Structure-Activity Relationship; D013455:Sulfur / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D009944:Organoplatinum Compounds; D010720:Phosphines; D017671:Platinum Compounds; D010758:Phosphorus; D013455:Sulfur; D045304:Cytochromes c; C044646:phosphine; D002945:Cisplatin