Substituted β-cyclodextrins and calix[4]arene as encapsulatory vehicles for platinum(II)-based DNA intercalators

A.M. Krause-Heuer, Nial J. Wheate, Michael J. Tilby, D. Graham Pearson, Christoper J. Ottley, Janice R. Aldrich-Wright

Research output: Contribution to journalArticle

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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.
Original languageEnglish
Pages (from-to)6880-6888
Number of pages8
JournalInorganic Chemistry
Volume47
Issue number15
DOIs
Publication statusPublished - 2008

Fingerprint

Intercalating Agents
Coordination Complexes
Cyclodextrins
Platinum
vehicles
platinum
deoxyribonucleic acid
Encapsulation
DNA
metals
ethylenediamine
glutathione
nuclear magnetic resonance
ligands
Glutathione
Assays
Nuclear magnetic resonance
degradation
Ligands
Degradation

Keywords

  • β-cyclodextrins
  • calix[4]arene
  • encapsulatory vehicles
  • DNA intercalators
  • inorganic chemistry

Cite this

Krause-Heuer, A. M., Wheate, N. J., Tilby, M. J., Pearson, D. G., Ottley, C. J., & Aldrich-Wright, J. R. (2008). Substituted β-cyclodextrins and calix[4]arene as encapsulatory vehicles for platinum(II)-based DNA intercalators. Inorganic Chemistry, 47(15), 6880-6888. https://doi.org/10.1021/ic800467c
Krause-Heuer, A.M. ; Wheate, Nial J. ; Tilby, Michael J. ; Pearson, D. Graham ; Ottley, Christoper J. ; Aldrich-Wright, Janice R. / Substituted β-cyclodextrins and calix[4]arene as encapsulatory vehicles for platinum(II)-based DNA intercalators. In: Inorganic Chemistry. 2008 ; Vol. 47, No. 15. pp. 6880-6888.
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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.",
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Krause-Heuer, AM, Wheate, NJ, Tilby, MJ, Pearson, DG, Ottley, CJ & Aldrich-Wright, JR 2008, 'Substituted β-cyclodextrins and calix[4]arene as encapsulatory vehicles for platinum(II)-based DNA intercalators', Inorganic Chemistry, vol. 47, no. 15, pp. 6880-6888. https://doi.org/10.1021/ic800467c

Substituted β-cyclodextrins and calix[4]arene as encapsulatory vehicles for platinum(II)-based DNA intercalators. / Krause-Heuer, A.M.; Wheate, Nial J.; Tilby, Michael J.; Pearson, D. Graham; Ottley, Christoper J.; Aldrich-Wright, Janice R.

In: Inorganic Chemistry, Vol. 47, No. 15, 2008, p. 6880-6888.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Substituted β-cyclodextrins and calix[4]arene as encapsulatory vehicles for platinum(II)-based DNA intercalators

AU - Krause-Heuer, A.M.

AU - Wheate, Nial J.

AU - Tilby, Michael J.

AU - Pearson, D. Graham

AU - Ottley, Christoper J.

AU - Aldrich-Wright, Janice R.

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

KW - β-cyclodextrins

KW - calix[4]arene

KW - encapsulatory vehicles

KW - DNA intercalators

KW - inorganic chemistry

UR - http://dx.doi.org/10.1021/ic800467c

U2 - 10.1021/ic800467c

DO - 10.1021/ic800467c

M3 - Article

VL - 47

SP - 6880

EP - 6888

JO - Inorganic Chemistry

JF - Inorganic Chemistry

SN - 0020-1669

IS - 15

ER -