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Article

Substituted β-Cyclodextrin and Calix[4]arene As Encapsulatory Vehicles for Platinum(II)-Based DNA Intercalators

Anwen M. Krause-Heuer^†, Nial J. Wheate^†, Michael J. Tilby^‡, D. Graham Pearson^§, Christopher J. Ottley^§ and Janice R. Aldrich-Wright*^†

School of Biomedical and Health Sciences, University of Western Sydney, Locked Bag 1797, Penrith South DC, 1797, NSW, Australia, Northern Institute of Cancer Research, Paul O’Gorman Building, Medical School, Framlington Place, University of Newcastle Upon Tyne, Newcastle Upon Tyne, NE2 4HH, United Kingdom, and Arthur Holmes Isotope Geology Laboratory, Department of Earth Sciences, University of Durham, Science Laboratories, South Road, Durham City, DH1 3LE, United Kingdom

Inorg. Chem., 2008, 47 (15), pp 6880–6888

DOI: 10.1021/ic800467c

Publication Date (Web): July 2, 2008

†

University of Western Sydney.

‡

University of Newcastle Upon Tyne.

University of Durham.

* To whom correspondence should be addressed. E-mail: j.aldrich-wright@uws.edu.au. Phone: +61 2 4620 3218. Fax: +61 2 4620 3025.

Abstract

The encapsulation of three platinum(II)-based anticancer complexes, [(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)platinum(II)]²⁺ (56MESS), [(5,6-dimethyl-1,10-phenanthroline)(1R,2R-diaminocyclohexane)platinum(II)]²⁺ (56MERR), and [(5,6-dimethyl-1,10-phenanthroline)(ethylenediamine)platinum(II)]²⁺ (56MEEN), with carboxylated-β-cyclodextrin (c-β-CD) and p-sulfonatocalix[4]arene (s-CX[4]) has been examined by one- and two-dimensional ¹H nuclear magnetic resonance (NMR) spectroscopy, pulsed gradient spin−echo NMR, ultraviolet spectrophotometry, glutathione degradation experiments, and growth inhibition assays. Titration of any of the three metal complexes with c-β-CD resulted in 1:1 encapsulation complexes with the cyclodextrin located over the intercalating ligand of the metal complexes, with a binding constant of 10⁴−10⁵ M⁻¹. In addition to binding over the phenanthroline ligand of 56MEEN, c-β-CD was also found to portal bind to the ethylenediamine ligand, with fast exchange kinetics on the NMR timescale between the two binding sites. In contrast, the three metal complexes all formed 2:2 inclusion complexes with s-CX[4] where the two metal complexes stacked in a head-to-tail configuration and were capped by the s-CX[4] molecules. Interestingly, the 56MEEN-s-CX[4] complex appeared to undergo a thermodynamically controlled rearrangement to a less soluble complex over time. Encapsulation of the metal complexes in either c-β-CD or s-CX[4] significantly decreased the metal complexes’ rate of diffusion, consistent with the formation of larger particle volumes. Encapsulation of 56MESS within s-CX[4] or c-β-CD protected the metal complex from degradation by reduced L-glutathione, with a reaction half-life greater than 9 days. In vitro growth inhibition assays using the LoVo human colorectal cancer cell line showed no significant change in the cytotoxicity of 56MESS when encapsulated by either s-CX[4] or c-β-CD.