Side-on binding of p-sulphonatocalix[4]arene to the dinuclear platinum complex trans-[{PtCl(NH3)2}2mu-dpzm]2+ and its implications for anticancer drug delivery.

Abstract

The utility of p-sulphonatocalix[4]arene (s-CX[4]) as a drug delivery vehicle for multinuclear platinum anticancer agents, using trans-[{PtCl(NH(3))(2)}(2)mu-dpzm](2+) (di-Pt; where dpzm=4,4'-dipyrazolylmethane) as a model complex, has been examined using (1)H nuclear magnetic resonance, electrospray ionisation mass spectrometry, molecular modelling and in vitro growth inhibition assays. s-CX[4] binds di-Pt in a side-on fashion in a ratio of 1:1, with the dpzm ligand of the metal complex located within the s-CX[4] cavity with binding further stabilised by ion-ion interactions and hydrogen bonding between the metal complex am(m)ine groups and the s-CX[4] sulphate groups. Partial encapsulation of di-Pt within the cavity does not prevent binding of 5'-guanosine monophosphate to the metal complex. When bound to two individual guanosine molecules, di-Pt also remains partially bound by s-CX[4]. The cytotoxicity of free di-Pt and s-CX[4] and their host guest complex was examined using in vitro growth inhibition assays in the A2780 and A2780cis human ovarian cancer cell lines. Free di-Pt has an IC(50) of 100 and 60 microM, respectively, in the cell lines, which is significantly less active than cisplatin (1.9 and 8.1 microM, respectively). s-CX[4] displays no cytotoxicity at concentrations up to 1.5mM and does not affect the cytotoxicity of di-Pt, probably because its low binding constant to the metal complex (6.8 x 10(4)M(-1)) means the host-guest complex is mostly disassociated at biologically relevant concentrations.

DOI: 10.1016/j.jinorgbio.2008.12.011

Cite this paper

@article{Wheate2009SideonBO, title={Side-on binding of p-sulphonatocalix[4]arene to the dinuclear platinum complex trans-[\{PtCl(NH3)2\}2mu-dpzm]2+ and its implications for anticancer drug delivery.}, author={Nial J. Wheate and Gr{\'a}inne M Abbott and Rothwelle J. Tate and Carol Jean Clements and Ruangelie Edrada-Ebel and Blair F. Johnston}, journal={Journal of inorganic biochemistry}, year={2009}, volume={103 3}, pages={448-54} }