Competitive reactions of a ruthenium arene anticancer complex with histidine, cytochrome c and an oligonucleotide

摘要

The ruthenium arene anticancer complex [(eta(6)-bip) Ru( en) Cl][PF6] ( 1) ( bip is biphenyl, en is ethylenediamine) reacted slowly with the amino acid L-histidine (L-His) in aqueous solution at 310 K. Two L-His adducts of 1 were separated by high-performance liquid chromatography and identified by electrospray ionisation mass spectrometry and NMR: an imidazole N-delta-bound complex [(eta(6)-bip) Ru( en)(N-delta-L-His)](2+), and an N-epsilon-bound complex [(eta(6)- bip) Ru(en)(N-epsilon -L-His)](2+). At 310 K, after 24 h only about 22% of complex 1 ( 2 mM) reacted with L-His, and of the unreacted 1, 59% had hydrolysed. In the presence of 100 mM NaCl, approximately 90% of 1 remained unreacted. In aqueous solution or triethylammonium acetate (TEAA) buffer ( pH 7.6), N-15-labelled 1 reacted with cytochrome c to give two monoruthenated protein adducts. The reaction reached equilibrium within 2 h by which time approximately 50% of cytochrome c was ruthenated. On the basis of [H-1, N-15] NMR data, one adduct may have Ru bound to the N-terminus, and the other to a carboxylate group on the protein. In TEAA buffer and at 310 K, more than 90% of the 14-mer oligonucleotide d(TATGTAC-CATGTAT) reacted with 2 mol Eq of 1 to give rise to monoruthenated and diruthenated oligonucleotide adducts. The presence of cytochrome c ( 1 mol Eq) or L-His ( 4 mol Eq) had little effect on the course of the reaction with the oligonucleotide. In cells, DNA ( or RNA) may be a favoured reaction site for this Ru anticancer complex.