title: Synthesis, characterization, and reaction pathways for the formation of a GMP adduct of a cytotoxic thiocyanato ruthenium arene complex.
abstract: The organoruthenium complex [(eta(6)-hmb)Ru(en)(Cl)][PF6] (hmb is hexamethylbenzene, en is ethylenediamine) undergoes facile aquation and then reacts with KSCN in unbuffered solution to give the S-coordinated thiocyanato product [(eta(6)-hmb)Ru(en)(S-SCN)]+ which slowly converts to the thermodynamically favored N-bound complex [(eta(6)-hmb)Ru(en)(N-NCS)]+ (1+). Complex 1 was synthesized and characterized by X-ray crystallography and mass spectrometry. Despite its lack of hydrolysis over 24 h, complex 1 exhibits moderate cytotoxicity (IC(50) 24 microM) towards the human ovarian cancer cell line A2780, comparable with that of the chlorido analogue which is thought to be activated (towards potential target DNA) via a rapid aquation (Wang et. al. in Proc Natl Acad Sci USA 102:18269-18274, 2005). Detailed kinetic studies suggest that complex 1 binds to guanosine 5'-monophosphate (GMP) through direct N7 substitution of the N-bound SCN ligand. In the presence of a high concentration of chloride (104 mM), however, complex 1 may bind partly to GMP via Cl substitution.
authors.affiliation: Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, 100190 Beijing, China. fuyi.wang@iccas.ac.cn
authors.forename: Fuyi
authors.initials: F
authors.lastname: Wang
authors.forename: Abraha
authors.initials: A
authors.lastname: Habtemariam
authors.forename: Erwin P L
authors.initials: EP
authors.lastname: van der Geer
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Deeth
authors.forename: Robert
authors.initials: R
authors.lastname: Gould
authors.forename: Simon
authors.initials: S
authors.lastname: Parsons
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sadler
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D019295:Computational Biology; D018360:Crystallography, X-Ray; D006157:Guanosine Monophosphate / Q000737:chemistry*; D006801:Humans; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012428:Ruthenium / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D013053:Spectrophotometry; D013861:Thiocyanates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D013861:Thiocyanates; D012428:Ruthenium; D006157:Guanosine Monophosphate