Reactions of a ruthenium(II) arene antitumor complex with cysteine and methionine

The Ru(II) organometallic antitumor complex [(eta(6)-biphenyI)RuCl(en)][PF6] (1) reacts slowly with the amino acid L-cysteine (L-CysH(2)) 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 H-1 and N-15 NMR spectroscopy. Reactions at a 1 mM/2 mM (RU/L-CysH(2)) 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-CysH(2), [(eta(6)-biphenyl)Ru(S-L-CysH)(en)](+) (4a) and [(eta(6)-biphenyl)Ru(O-L-CysH(2))(en)](2+) (4b) formed, followed by the cystine adduct [(eta(6)-biphenyl)Ru(O-CYS2H2)(en)](2+) (3), and two dinuclear complexes from which half or all of the chelated ethylenediamine had been displaced, [(eta(6)-biphenyl)Ru(H2O)(muS,N-L-Cys)Ru(eta(6)-biphenyl)(en)](2+) (5) containing one bridging cysteine, and [(eta(6)-biphenyl)Ru(O,N-L-CYS-S)(S-L-CYS-N)Ru(eta(6)-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-CysH(2) concentrations. Complex 5 was the dominant product at pH 2-5, but overall, only ca. 50% of 1 reacted with L-CysH(2) in these conditions. The reaction between I and L-CysH(2) 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 [(eta(6)-biphenyl)Ru(S-L-MetH)(en)](2+) (8).