Issue 18, 2009
From the journal:

Dalton Transactions

Influence of amineligands on the aquation and cytotoxicity of trans-diamine platinum(ii) anticancer complexes†

Leticia Cubo,a   Adoración G. Quiroga,*a   Junyong Zhang,b   Donald S. Thomas,b   Amancio Carnero,c   Carmen Navarro-Ranninger*a  and  Susan J. Berners-Price*b  

* Corresponding authors

a Departamento de Química Inorgánica, Universidad Autónoma de Madrid, Madrid, Spain
E-mail: carmen.navarro@uam.es, adoracion.gomez@uam.es
Fax: 34 914974833
Tel: 34 914974356

b School of Biomedical, Biomolecular and Chemical Sciences, Chemistry M313, The University of Western Australia, 35, Stirling Highway, Crawley Perth, WA, Australia
E-mail: sue.berners-price@uwa.edu.au
Fax: +61864881005
Tel: +61864883258

c Experimental Therapeutics Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Abstract

Three 15N-labelled trans-Pt(II) amine complexes with isopropylamine (15N-ipa), methylamine (15N-ma) and dimethylamine (15N-dma) have been prepared and characterized. 2D [1H,15N] HSQC NMR spectroscopy was used to obtain the rate and equilibrium constants for the aquation of trans-[PtCl2(15N-ipa)(15N-ma)] (15N-1), trans-[PtCl2(15N-dma)(15N-ma)] (15N-2) and trans-[PtCl2(15N-dma)(15N-ipa)] (15N-3) in 100 mM NaClO4 solutions at 298 K. New 15N shift ranges for H2N–PtII–N and HN–PtII–N groups are reported. Formation of the diaqua complex was not observed for 3 and accounted for <2% of the species at equilibrium for 1 and 2. The first aquation step is significantly faster for 2 (k1 = 14 × 10−5 s−1) than for the two complexes with the bulkier ipa ligand (k1 = 5.5 × 10−5 s−1 (1), 6.1 × 10−5 s−1 (3)), but 2 is the least aquated of the three complexes at equilibrium. The pKa 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-[PtCl2(dma)2], indicating a smaller proportion of more reactive aqua species will exist at physiological pH. The pKa 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-15N-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.

Graphical abstract: Influence of amine ligands on the aquation and cytotoxicity of trans-diamine platinum(ii) anticancer complexes

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Article information

DOI
https://doi.org/10.1039/B819301K
Article type
Paper
Submitted
30 Oct 2008
Accepted
09 Dec 2008
First published
29 Jan 2009

Dalton Trans., 2009, 3457-3466

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Influence of amine ligands on the aquation and cytotoxicity of trans-diamine platinum(II) anticancer complexes

L. Cubo, A. G. Quiroga, J. Zhang, D. S. Thomas, A. Carnero, C. Navarro-Ranninger and S. J. Berners-Price, Dalton Trans., 2009, 3457 DOI: 10.1039/B819301K

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