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Competition between glutathione and guanine for a ruthenium(II) arene anticancer complex : detection of a sulfenato intermediate
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Wang, Fuyi, Xu, Jingjing, Habtemariam, Abraha, Bella, Juraj and Sadler, P. J. (2005) Competition between glutathione and guanine for a ruthenium(II) arene anticancer complex : detection of a sulfenato intermediate. Journal of the American Chemical Society, Volume 127 (Number 50). pp. 17734-17743. doi:10.1021/ja053387k ISSN 0002-7863.
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Official URL: http://dx.doi.org/10.1021/ja053387k
Abstract
The organometallic anticancer complex [(η6-bip)Ru(en)Cl]+ (1; bip = biphenyl, en = ethylenediamine) selectively binds to guanine (N7) bases of DNA (Novakova, O.; Chen, H.; Vrana, O.; Rodger, A.; Sadler, P. J.; Brabec, V. Biochemistry 2003, 42, 11544−11554). In this work, competition between the tripeptide glutathione (γ-l-Glu-l-Cys-Gly; GSH) and guanine (as guanosine 3‘,5‘-cyclic monophosphate, cGMP) for complex 1 was investigated using HPLC, LC−MS and 1H,15N NMR spectroscopy. In unbuffered solution (pH ca. 3), the reaction of 1 with GSH gave rise to three intermediates: an S-bound thiolato adduct [(η6-bip)Ru(en)(GS-S)] (4) and two carboxylate-bound glutathione products [(η6-bip)Ru(en)(GSH-O)]+ (5, 6) during the early stages (<6 h), followed by en displacement and formation of a tri-GS-bridged dinuclear RuII complex [((η6-bip)Ru)2(GS-μ-S)3]2- (7). Under physiologically relevant conditions (micromolar Ru concentrations, pH 7, 22 mM NaCl, 310 K), the thiolato complex 4 was unexpectedly readily oxidized by dioxygen to the sulfenato complex [(η6-bip)Ru(en)(GS(O)-S)] (8) instead of forming the dinuclear complex 7. Under these conditions, competitive reaction of complex 1 with GSH and cGMP gave rise to the cGMP adduct [(η6-bip)Ru(en)(cGMP-N7)]+ (10) as the major product, accounting for ca. 62% of total Ru after 72 h, even in the presence of a 250-fold molar excess of GSH. The oxidation of coordinated glutathione in the thiolato complex 4 to the sulfenate in 8 appears to provide a facile route for displacement of S-bound glutathione by G N7. Redox reactions of cysteinyl adducts of these RuII arene anticancer complexes could therefore play a significant role in their biological activity.
Item Type: | Journal Article | ||||
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||
Journal or Publication Title: | Journal of the American Chemical Society | ||||
Publisher: | American Chemical Society | ||||
ISSN: | 0002-7863 | ||||
Official Date: | 21 December 2005 | ||||
Dates: |
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Volume: | Volume 127 | ||||
Number: | Number 50 | ||||
Page Range: | pp. 17734-17743 | ||||
DOI: | 10.1021/ja053387k | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access |
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