American Chemical Society
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Reactions of a Ruthenium(II) Arene Antitumor Complex with Cysteine and Methionine

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journal contribution
posted on 2002-07-26, 00:00 authored by Fuyi Wang, Haimei Chen, John A. Parkinson, Piedad del Socorro Murdoch, Peter J. Sadler
The Ru(II) organometallic antitumor complex [(η6-biphenyl)RuCl(en)][PF6] (1) reacts slowly with the amino acid l-cysteine (l-CysH2) in aqueous solution at 310 K. Reactions were followed over periods of up to 48 h using HPLC, electronic absorption spectroscopy, LC-ESI-MS, and 1D or 2D 1H and 15N NMR spectroscopy. Reactions at a 1 mM/2 mM (Ru/l-CysH2) ratio were multiphasic in acidic solutions (pH 5.1) and appeared to involve aquation as the first step. Initially, 1:1 adducts involving substitution of Cl by S-bound or O-bound l-CysH2, [(η6-biphenyl)Ru(S-l-CysH)(en)]+ (4a) and [(η6-biphenyl)Ru(O-l-CysH2)(en)]2+ (4b) formed, followed by the cystine adduct [(η6-biphenyl)Ru(O-Cys2H2)(en)]2+ (3), and two dinuclear complexes from which half or all of the chelated ethylenediamine had been displaced, [(η6-biphenyl)Ru(H2O)(μS,N-l-Cys)Ru(η6-biphenyl)(en)]2+ (5) containing one bridging cysteine, and [(η6-biphenyl)Ru(O,N-l-Cys-S)(S-l-Cys-N)Ru(η6-biphenyl)(H2O)] (6) containing two bridging cysteines. The unusual cluster species {(biphenyl)Ru}8 (7a) was also detected by MS and was more prevalent in reactions at higher l-CysH2 concentrations. Complex 5 was the dominant product at pH 2−5, but overall, only ca. 50% of 1 reacted with l-CysH2 in these conditions. The reaction between 1 and l-CysH2 was suppressed in 50 mM triethylammonium acetate solution at pH > 5 or in 100 mM NaCl. Only 27% of complex 1 reacted with l-methionine (l-MetH) at an initial pH of 5.7 after 48 h at 310 K and gave rise to only one adduct [(η6-biphenyl)Ru(S-l-MetH)(en)]2+ (8).