title: Influence of amine ligands on the aquation and cytotoxicity of trans-diamine platinum(II) anticancer complexes.
abstract: Three (15)N-labelled trans-Pt(ii) amine complexes with isopropylamine ((15)N-ipa), methylamine ((15)N-ma) and dimethylamine ((15)N-dma) have been prepared and characterized. 2D [(1)H,(15)N] HSQC NMR spectroscopy was used to obtain the rate and equilibrium constants for the aquation of trans-[PtCl(2)((15)N-ipa)((15)N-ma)] ((15)N-1), trans-[PtCl(2)((15)N-dma)((15)N-ma)] ((15)N-2) and trans-[PtCl(2)((15)N-dma)((15)N-ipa)] ((15)N-) in 100 mM NaClO(4) solutions at 298 K. New (15)N shift ranges for H(2)N-Pt(II)-N and HN-Pt(II)-N groups are reported. Formation of the diaqua complex was not observed for and accounted for <2% of the species at equilibrium for 1 and 2 . The first aquation step is significantly faster for 2 (k(1) = 14 x 10(-5) s(-1)) than for the two complexes with the bulkier ipa ligand (k(1) = 5.5 x 10(-5) s(-1) (), 6.1 x 10(-5) s(-1) (3)), but 2 is the least aquated of the three complexes at equilibrium. The pK(a) values for the monoaqua adducts of 1-3 are similar (5.98, 5.85 and 5.91, respectively) and 0.4 pH units lower than the related cis complex cis-[PtCl(2)(dma)(2)], indicating a smaller proportion of more reactive aqua species will exist at physiological pH. The pK(a) values for the diaqua adduct of 2 (4.59 and 7.98) are 0.3-0.6 pH units higher than those of 1(4.31 and 7.30) and 3 (4.28 and 7.29), which have very similar values. The speciation profiles of 1-3 , calculated on the basis of the calculated equilibrium and dissociation constants, indicate that <1% hydrolyzed species will exist under physiological conditions in cancer cells. The cytotoxicity of 1-3 (non-(15)N-labelled) was assessed in three cancer lines (SF268, MCF-7 and NCI-H460). The new trans-Pt(ii) diamine complex 2 is more active than 1 and 3 in all cases and is more potent than cisplatin in the MCF-7 adenocarcinoma cell line.
authors.affiliation: Departamento de Química Inorgánica, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: Cubo
authors.forename: Adoración G
authors.initials: AG
authors.lastname: Quiroga
authors.forename: Junyong
authors.initials: J
authors.lastname: Zhang
authors.forename: Donald S
authors.initials: DS
authors.lastname: Thomas
authors.forename: Amancio
authors.initials: A
authors.lastname: Carnero
authors.forename: Carmen
authors.initials: C
authors.lastname: Navarro-Ranninger
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Berners-Price
mesh_terms: D000588:Amines / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D017671:Platinum Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014867:Water
chemical_list: D000588:Amines; D000970:Antineoplastic Agents; D017671:Platinum Compounds; D014867:Water; C034697:transplatin; D002945:Cisplatin