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.

Photoactivation of trans diamine platinum complexes in aqueous solution and effect on reactivity towards nucleotides

“…Trans,trans,trans-[PtCl 2 (OH) 2 (dma)(ipa)], 1, and trans-[PtCl 2 (ipa)(ma)], 2, were prepared using previously described procedures [24,25]. Guanosine-5′-monophosphate (GMP), cytidine-5′-monophosphate (CMP) and 9-methyladenine (9MeA) were purchased from Sigma-Aldrich and adenosine-5′-monophosphate (AMP) from Acros Organic.…”

Synthesis, characterization, DNA interaction studies and anticancer activity of platinum–clotrimazole complexes

“…Early structure-activity relationship studies suggested that transplatin complexes would be inactive as antitumour drugs [14]. However, more recent studies, resulting in part from the search for drugs which are active against cisplatin-resistant tumours, have reactivated an interest in trans-isomers [15][16][17][18][19]. Thus, there have been promising reports of trans-platinum complexes containing planar amines [20][21][22] or bulky amine ligands [23,24] which showed cytotoxicity against human tumour cell lines equal to or higher than cisplatin.…”

Understanding trans platinum complexes as potential antitumor drugs beyond targeting DNA

“…What seems surprising is that this complex is also the less aquated in the equilibria, despite the faster aquation, the amount of monoaqua species is lower. If we think that, in general, the most active species is the monoaquo and more importantly, trans-PtCl 2 (ma)(dma) the most cytotoxic of the series in the cell lines checked [25], we can end in that the lower concentration of monoaquo species in the equilibrium must be an advantage. Our interpretation is that this situation favors the monoaquo species not to be kidnapped and erased from the milieu by any molecule before it gets the target.…”