| Abstract
| - Derivatives of β-cyclodextrin and calix[4]arene as hosts for platinum(II)-based DNA intercalators have been investigated by NMR spectroscopy, UV spectrophotometry, and in vitro cytotoxicity studies. c-β-CD forms 1:1 host−guest complexes with the metal complexes, while s-CX[4] forms novel 2:2 complexes, with two molecules of metal complex capped at either end by s-CX[4]. Both macrocycles protect the metal complexes from degradation while not significantly affecting the cytotoxicity of 56MESS in LoVo colorectal cancer cells.
- 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.
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