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Effects of geometric isomerism in dinuclear platinum antitumor complexes on aquation reactions in the presence of perchlorate, acetate and phosphate

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Abstract

The aquation and subsequent reactions of the dinuclear Pt antitumor complexes [{trans-PtCl(NH3)2}2(μ-NH2(CH2)6NH2)]2+ (1,1/t,t) and [{cis-PtCl(NH3)2}2(μ-NH2(CH2)6NH2)]2+ (1,1/c,c) in 15 mM perchlorate, acetate or phosphate solutions were followed at 298 K by [1H,15N] HSQC 2D NMR spectroscopy. Rate and equilibrium constants for the initial reversible aquation and the subsequent reversible reaction with phosphate or acetate are reported. The rate constant for the first aquation step is two-fold lower for 1,1/c,c than 1,1/t,t but the anation rate constants are similar so that the equilibrium lies further towards the chloro form for the 1,1/c,c compound. A pK a value of 6.01±0.03 was determined for the diaquated species [{cis-Pt(NH3)2(H2O)}2(μ-NH2(CH2)6NH2)]4+ (1,1/c,c-3) which is 0.4 units higher than that of the 1,1/t,t compound. The rate constants for the binding of acetate and phosphate to 1,1/t,t are similar, but the rate constant for the reverse reaction is close to ten-fold higher in the case of phosphate so that equilibrium conditions are attained more rapidly (12 h compared with 64 h). On the other hand, for 1,1/c,c the rate constants for the forward and reverse reactions with acetate and phosphate are quite similar so that equilibrium conditions are reached very slowly (80–100 h) and a greater proportion of phosphate-bound species are present. The reduced lability of the bound phosphate for 1,1/c,c is attributed to the formation of a macrochelate phosphate-bridged species which was characterized by 31P NMR and ESI-MS. The speciation profiles of 1,1/t,t and 1,1/c,c under physiological conditions are explored.

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Notes

  1. The equilibrium constants pK n are not true equilibrium constants because no account has been made of the relative contributions of aqua and hydroxo ligation to the total at the given pH. This is also true for the rate constants. However, in all cases the solution pH is lower by 0.1 to 0.6 pH units than the pK a of the coordinated aqua ligand, and so the major form will be the aqua species

Abbreviations

HSQC :

Heteronuclear single-quantum coherence

ESI-MS :

Electrospray ionization mass spectrometry

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Acknowledgements

This work was supported by the Australian Research Council, US National Institutes of Health (R01-CA78754) and the American Cancer Society (RPG89-002-11-CDD). We thank Dr. Alexander Hegmans for the preparation of 15N-1,1/c,c and Drs. Tony Reeder and Lindsay Byrne for the assistance with the mass spectrometry and NMR experiments, respectively.

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Authors and Affiliations

  1. School of Biomedical & Chemical Sciences, University of Western Australia, Crawley, WA, 6009, Australia

    Junyong Zhang, Donald S. Thomas, Murray S. Davies & Susan J. Berners-Price

  2. Department of Chemistry, Virginia Commonwealth University, Richmond, VA, 23284-2006, USA

    Nicholas Farrell

  3. School of Pharmacy and Molecular Sciences, James Cook University, Townsville, QLD, 4811, Australia

    Murray S. Davies

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  1. Junyong Zhang
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  2. Donald S. Thomas
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  4. Susan J. Berners-Price
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  5. Nicholas Farrell
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Correspondence to Susan J. Berners-Price or Nicholas Farrell.

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Zhang, J., Thomas, D.S., Davies, M.S. et al. Effects of geometric isomerism in dinuclear platinum antitumor complexes on aquation reactions in the presence of perchlorate, acetate and phosphate. J Biol Inorg Chem 10, 652–666 (2005). https://doi.org/10.1007/s00775-005-0013-5

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