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

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).