Synthesis, characterization, and reaction pathways for the formation of a GMP adduct of a cytotoxic thiocyanato ruthenium arene complex.
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.
Wang
Fuyi
F
Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, 100190 Beijing, China. fuyi.wang@iccas.ac.cn
Habtemariam
Abraha
A
van der Geer
Erwin P L
EP
Deeth
Robert J
RJ
Gould
Robert
R
Parsons
Simon
S
Sadler
Peter J
PJ
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
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D013861:Thiocyanates; D012428:Ruthenium; D006157:Guanosine Monophosphate