title: Synthesis, characterization, and cytotoxic activity of novel potentially pH-sensitive nonclassical platinum(II) complexes featuring 1,3-dihydroxyacetone oxime ligands.
abstract: The reaction of 1,3-dihydroxyacetone oxime with diam(m)minediaquaplatinum(II) under basic conditions produced zwitterionic diam(m)mine(3-hydroxy-2-(oxidoimino)propan-1-olato-κ(2)N,O)platinum(II) complexes featuring the N,O-chelating ligand. Upon reaction with hydrochloric acid, it was possible to isolate either the singly protonated species still exhibiting the intact N,O-chelate or the open-chain chlorido complex. All complexes were characterized in detail with multinuclear ((1)H, (13)C, and (195)Pt) NMR spectroscopy, ESI mass spectrometry, and in one case X-ray diffraction. Cytotoxicity was investigated in three human cancer cell lines (CH1, SW480, and A549). The obtained IC(50) values are in the medium or even low micromolar range, remarkable for platinum complexes having N(3)O or N(3)Cl coordination spheres. To study the solution behavior of the prepared complexes at physiologically relevant proton concentrations, time-dependent (1)H NMR measurements were performed for the ethane-1,2-diamine-containing series at pH values of 7.4, 6.0, and exemplarily 5.0. While the zwitterionic complex proved to be stable at both pH 7.4 and 6.0, the protonated species were deprotonated at pH 7.4, tending toward ring opening in slightly acidic environments, as characteristic for many solid tumors. Finally, the open-chain form stayed intact at pH 6.0, being completely converted into its chelated analogue at pH 7.4. A pH-dependent evaluation of antiproliferative effects of the two latter complexes at pH 7.4 and pH 6.0 revealed an activation under slightly acidic conditions, which might be of interest for further in vivo studies.
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Währinger Strasse 42, A-1090 Vienna, Austria.
authors.forename: Yulia Yu
authors.initials: YY
authors.lastname: Scaffidi-Domianello
authors.forename: Anton A
authors.initials: AA
authors.lastname: Legin
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jakupec
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Arion
authors.forename: Vadim Yu
authors.initials: VY
authors.lastname: Kukushkin
authors.forename: Mathea Sophia
authors.initials: MS
authors.lastname: Galanski
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004098:Dihydroxyacetone / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D010091:Oximes / Q000737:chemistry; D010984:Platinum / Q000737:chemistry* / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; D009944:Organoplatinum Compounds; D010091:Oximes; D010984:Platinum; D004098:Dihydroxyacetone