- Anti-cancer characteristics and ototoxicity of platinum(II) amine complexes with only one leaving ligand
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Unlike cisplatin, which forms bifunctional DNA adducts, monofunctional platinum(II) complexes bind only one strand of DNA and might target cancer without causing auditory side-effects associated with cisplatin treatment. We synthesized the monofunctional triamine-ligated platinum(II) complexes, Pt(diethylenetriamine)Cl, [Pt(dien)Cl]+, and Pt(N,N-diethyl-diethylenetriamine)Cl, [Pt(Et2dien)Cl]+, and the monofunctional heterocyclic-ligated platinum(II) complexes, pyriplatin and phenanthriplatin, and compared their 5’-GMP binding rates, cellular compartmental distribution and cellular viability effects. A zebrafish inner ear model was used to determine if the monofunctional complexes and cisplatin caused hearing threshold shifts and reduced auditory hair cell density. The four monofunctional complexes had varied relative GMP binding rates, but similar cytosolic and nuclear compartmental uptake in three cancer cell lines (A549, Caco2, HTB16) and a control cell line (IMR90). Phenanthriplatin had the strongest effect against cellular viability, comparable to cisplatin, followed by [Pt(Et2dien)Cl]+, pyriplatin and [Pt(dien)Cl]+. Phenanthriplatin also produced the highest hearing threshold shifts followed by [Pt(dien)Cl]+, [Pt(Et2dien)Cl]+, cisplatin and pyriplatin. Hair cell counts taken from four regions of the zebrafish saccule showed that cisplatin significantly reduced hair cell density in three regions and phenanthriplatin in only one region, with the other complexes having no significant effect. Utricular hair cell density was not reduced by any of the compounds. Our results suggest that placing greater steric hindrance cis to one side of the platinum coordinating center in monofunctional complexes promotes efficient targeting of the nuclear compartment and guanosine residues, and may be responsible for reducing cancer cell viability. Also, the monofunctional compounds caused hearing threshold shifts with minimal effect on hair cell density, which suggests that they may affect different pathways than cisplatin.
- Monroe, Jerry D.,Hruska, Heidi L.,Ruggles, Hannah K.,Williams, Kevin M.,Smith, Michael E.
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- Kinetics and mechanism of the substitution reactions of some monofunctional Pt(II) complexes with heterocyclic nitrogen donor molecules. Crystal structure of [Pt(bpma)(pzBr)]Cl2·2H2O
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Substitution reactions of [Pt(terpy)Cl]+ (terpy?=?2,2′;6′,2′′-terpyridine), [Pt(bpma)Cl]+ (bpma?=?bis(2-pyridylmethyl)amine), [Pt(dien)Cl]+ (dien?=?diethylenetriamine or 1,5-diamino-3-azapentane) and [Pt(tpdm)Cl]+/su
- Kosovi?, Milica,Jovanovi?, Sne?ana,Bogdanovi?, Goran A.,Giester, Gerald,Ja?imovi?, ?eljko,Bugar?i?, ?ivadin D.,Petrovi?, Biljana
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- Nucleophilic Displacement of Halides from Monocationic Platinum(II) Complexes containing Neutral Tridentate Chelating Ligands with Sulfur and Nitrogen Donors: Kinetics and Equilibria
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Kinetic and equilibrium measurements on the displacement of halides from the substrates + with the nucleophiles Cl-, Br- and I- have been carried out in methanol at 25 deg C and constant ionic strength.The results are discussed in terms of the relative stability of the planar ground and five-co-ordinate transition states.The significant differences in kinetic behaviour along the series are related to the presence of ?-interacting pyridine rings as well as to the nature of the donor atoms trans and cis to the repleceable halogen.The equilibrium parameters, the leaving-group effect and the intimate mechanism are also discussed and compared with the literature data.
- Pitteri, Bruno,Marangoni, Giampaolo,Cattalini, Lucio,Bobbo, Tatiana
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p. 3853 - 3860
(2007/10/02)
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- Acidic properties of (dimethyl sulfoxide)(1,5-diamino-3-azapentane)platinum(II) perchlorate and kinetics of the displacement of dimethyl sulfoxide from the conjugate base
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[Pt(dien)(Me2SO)](ClO4)2 (dien = 1,5-diamino-3-azapentane) is a weak acid; pKa = 11.94 ± 0.02 at 25.0 °C and I = 0.10. 1H and °C NMR evidence is presented to show that the proton is removed from the 3-nitrogen. The kinetics of the displacement of Me2SO from the conjugate base by the nucleophiles X = Cl-, Br-, I-, N3-, SCN-, and S2O32- have been studied by working in the presence of 0.50 mol dm-3 NaOH. The displacement of Me2SO by X is followed by the displacement of X by OH-, and in the case of the more weakly bound nucleophiles Cl- and Br-, the second stage is much faster than the first and the reaction appears to be a halide-catalyzed replacement of Me2SO by OH-. The reactions, studied under first-order conditions, follow the simple rate law kobsd = k2[X], and values of k2 for the corresponding reactions of the amine complex in the absence of OH- but at I = 1.0 have also been obtained. Deprotonation leads to a relatively small decrease in reactivity (a factor of ~2 at I = 1.0, extrapolating to a factor of ~8 at I = 0). [Pt(en)(Me2SO)2]2+ (en = 1,2-diaminoethane) undergoes a similar deprotonation in basic solution but, because of its solvolytic lability, the pKa could not be determined. Its amido conjugate base, however, is some 10 times more labile than the amine species.
- Romeo, Raffaello,Minniti, Domenico,Alibrandi, Giuseppe,De Cola, Luisa,Tobe, Martin L.
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p. 1944 - 1947
(2008/10/08)
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- Kinetics of the Displacement of Chloroacetate Ion from cis-Bis(chloroacetato)-bis(isopropylamine)platinum(II) and the (Chloroacetato)(1,5-diamino-3-azapentane)platinum(II) Cation
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The displacement of ClCH2CO2- from cis-iNH2)2(ClCH2CO2)2> and + (dien=1,5-diamino-3-azapentane) by solvent, Cl-, Br-, and SCN- has been studied in aqueous solution at 25.0 deg C.The reactions are catalysed by acid by way of a pre-equilibrium protonation of the carboxylate ligand.In the absence of added acid the cationic monocarboxylato complex exhibits a normal nucleophilic discrimination power, comparable to that of the corresponding chloro complex and the nucleophile-independent pathway makes only a small contribution to the consumption of the substrate.In the uncatalysed reactions of the bis(carboxylato) complex, the nucleophile-independent pathway dominates the substitution by the weak nucleophile, Cl-, and a relatively strong nucleophile, such as SCN-, is required to make the direct substitution pathway important.The unusually large contribution from the nucleophile-independent pathway is discussed.
- Canovese, Luciano,Tobe, Martin L.,Annibale, Giuliano,Cattalini, lucio
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p. 1107 - 1114
(2007/10/02)
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