title: Competitive reactions of a ruthenium arene anticancer complex with histidine, cytochrome c and an oligonucleotide.
abstract: The ruthenium arene anticancer complex [(eta(6)-bip)Ru(en)Cl][PF(6)] (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), (15)N-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 [(1)H, (15)N] 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(TATGTACCATGTAT) 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.
authors.affiliation: School of Chemistry, University of Edinburgh, UK.
authors.forename: Fuyi
authors.initials: F
authors.lastname: Wang
authors.forename: Juraj
authors.initials: J
authors.lastname: Bella
authors.forename: John A
authors.initials: JA
authors.lastname: Parkinson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sadler
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D001483:Base Sequence; D001667:Binding, Competitive; D045304:Cytochromes c / Q000737:chemistry*; D006639:Histidine / Q000737:chemistry*; D015394:Molecular Structure; D009838:Oligodeoxyribonucleotides / Q000737:chemistry*; D011485:Protein Binding; D017975:Ruthenium Compounds / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D009838:Oligodeoxyribonucleotides; D017975:Ruthenium Compounds; D006639:Histidine; D045304:Cytochromes c
references.citation: J Med Chem. 2001 Oct 25;44(22):3616-21
references.pmid: 11606126
references.citation: J Am Chem Soc. 2003 Jan 8;125(1):173-86
references.pmid: 12515520
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3838-40
references.pmid: 12646702
references.citation: Chemistry. 2003 Dec 5;9(23):5810-20
references.pmid: 14673852
references.citation: Br J Cancer. 2002 May 20;86(10):1652-7
references.pmid: 12085218
references.citation: Spectrochim Acta A Mol Biomol Spectrosc. 2000 Dec;56(14):2699-705
references.pmid: 11145336
references.citation: J Biomol NMR. 1994 Mar;4(2):301-6
references.pmid: 8019138
references.citation: J Biol Chem. 1994 Jan 28;269(4):2581-8
references.pmid: 8300587
references.citation: Chem Rev. 1999 Sep 8;99(9):2499-510
references.pmid: 11749488
references.citation: J Mol Biol. 1990 Jul 20;214(2):585-95
references.pmid: 2166170
references.citation: Inorg Chem. 1996 Feb 14;35(4):1065-1072
references.pmid: 11666286
references.citation: Chem Commun (Camb). 2004 Aug 21;(16):1786-7
references.pmid: 15306883
references.citation: Inorg Chem. 2002 Aug 26;41(17):4509-23
references.pmid: 12184769
references.citation: J Am Chem Soc. 2002 Mar 27;124(12):3064-82
references.pmid: 11902898