Influence of amine ligands on the aquation and cytotoxicity of trans-diamine platinum(II) anticancer complexes.
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.
Cubo
Leticia
L
Departamento de Química Inorgánica, Universidad Autónoma de Madrid, Madrid, Spain.
Quiroga
Adoración G
AG
Zhang
Junyong
J
Thomas
Donald S
DS
Carnero
Amancio
A
Navarro-Ranninger
Carmen
C
Berners-Price
Susan J
SJ
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
D000588:Amines; D000970:Antineoplastic Agents; D017671:Platinum Compounds; D014867:Water; C034697:transplatin; D002945:Cisplatin