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.

Nial J Wheate, Grainne M Abbott, Rothwelle J Tate, Carol J Clements, Ruangelie Edrada-Ebel, Blair F Johnston

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, John Arbuthnott Building, 27 Taylor Street, Glasgow G4 0NR, United Kingdom. nial.wheate@strath.ac.uk

Journal of inorganic biochemistry 2009 Mar

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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.

Citation

Nial J Wheate, Grainne M Abbott, Rothwelle J Tate, Carol J Clements, Ruangelie Edrada-Ebel, Blair F Johnston. 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. Journal of inorganic biochemistry. 2009 Mar;103(3):448-54