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Competition between glutathione and DNA oligonucleotides for ruthenium(ii) arene anticancer complexes
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Wang, Fuyi, Xu, Jingjing, Wu, Kui, Weidt, Stefan K., Mackay, C. Logan, Langridge-Smith, Pat R. R. and Sadler, P. J. (2013) Competition between glutathione and DNA oligonucleotides for ruthenium(ii) arene anticancer complexes. Dalton Transactions, Volume 42 (Number 9). pp. 3188-3195. doi:10.1039/c2dt32091f ISSN 1477-9226.
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Official URL: http://dx.doi.org/10.1039/C2DT32091F
Abstract
The organometallic anticancer complex [(η6-bip)Ru(en)Cl]+ (1; bip = biphenyl, en = ethylenediamine) selectively binds to N7 of guanine bases of oligonucleotides and native DNA. However, under physiologically relevant conditions (micromolar Ru concentrations, pH 7, 22 mM NaCl, 310 K), the tripeptide glutathione (γ-L-Glu-L-Cys-Gly; GSH) is kinetically competitive with guanine (as guanosine 3′,5′-cyclic monophosphate, cGMP) for coordination with complex 1, and gives rise to a ruthenium thiolato adduct. This thiolato adduct can subsequently undergo oxidation to a sulfenate intermediate, providing a facile route for the formation of a final cGMP adduct via the displacement of S-bound glutathione by G N7 (F. Y. Wang, J. J. Xu, A. Habtemariam, J. Bella and P. J. Sadler, J. Am. Chem. Soc., 2005, 127, 17734). In this work, the competition between GSH and the single-stranded 14-mer oligonucleotide 5′-TATGTACCATGTAT-3′ (I) and duplex III (III = I + II, II = 5′-ATACATGGTACATA) for complex 1 and its analogue [(η6-tha)Ru(en)Cl]+ (2, tha = tetrahydroanthracene) under physiologically relevant conditions was investigated using conventional ESI-MS and high resolution ESI-FTICR-MS coupled to conventional HPLC and nanoscale HPLC, respectively. The results indicate that whether there was high excess of GSH or not in the reaction mixtures, the reaction of complex 1 or 2 with single-stranded oligonucleotide I always gave rise to mono-ruthenated oligonucleotide, and the reaction of complex 1 or 2 with duplex III gave rise to the mono-ruthenated duplex oligonucleotide. Furthermore, the ruthenation of duplex III by complex 1 showed no significant discrimination between the complementary strands I and II, but complex 2 appeared to bind preferentially to strand II compared to strand I as revealed by the high resolution FTICR-MS analysis. GSH is highly abundant in cells at millimolar concentrations and is well known to be involved in the deactivation of the clinical drug cisplatin and in platinum resistance. Our findings reveal a potentially contrasting role for GSH in the mechanism of action of these ruthenium anticancer complexes that may contribute to the lack of cross-resistance with platinum drugs.
Item Type: | Journal Article | ||||
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||
Journal or Publication Title: | Dalton Transactions | ||||
Publisher: | Royal Society of Chemistry | ||||
ISSN: | 1477-9226 | ||||
Official Date: | 18 October 2013 | ||||
Dates: |
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Volume: | Volume 42 | ||||
Number: | Number 9 | ||||
Page Range: | pp. 3188-3195 | ||||
DOI: | 10.1039/c2dt32091f | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access |
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