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Synthesis, characterization, and reaction pathways for the formation of a GMP adduct of a cytotoxic thiocyanato ruthenium arene complex
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Wang, Fuyi, Habtemariam, Abraha, van der Geer, Erwin P. L., Deeth, Robert J., Gould, Robert O., Parsons, Simon and Sadler, P. J.. (2009) Synthesis, characterization, and reaction pathways for the formation of a GMP adduct of a cytotoxic thiocyanato ruthenium arene complex. Journal of Biological Inorganic Chemistry, Vol.14 (No.7). pp. 1065-1076. ISSN 0949-8257
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Official URL: http://dx.doi.org/10.1007/s00775-009-0549-x
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 (IC50 24 mu M) 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.
| Item Type: | Journal Article |
|---|---|
| Subjects: | Q Science > QD Chemistry R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Faculty of Science > Chemistry |
| Library of Congress Subject Headings (LCSH): | Organoruthenium compounds -- Therapeutic use, Arene compounds -- Therapeutic use, Antineoplastic agents, Thiocyanates, Organometallic chemistry |
| Journal or Publication Title: | Journal of Biological Inorganic Chemistry |
| Publisher: | Springer |
| ISSN: | 0949-8257 |
| Date: | September 2009 |
| Volume: | Vol.14 |
| Number: | No.7 |
| Number of Pages: | 12 |
| Page Range: | pp. 1065-1076 |
| Identification Number: | 10.1007/s00775-009-0549-x |
| Status: | Peer Reviewed |
| Publication Status: | Published |
| Access rights to Published version: | Restricted or Subscription Access |
| Funder: | Oncosense Ltd., Zhongguo ke xue yuan [Chinese Academy of Sciences] |
| URI: | http://wrap.warwick.ac.uk/id/eprint/17290 |
Data sourced from Thomson Reuters' Web of Knowledge
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