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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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Abstract

The organoruthenium complex [(η6-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 [(η6-hmb)Ru(en)(S-SCN)]+ which slowly converts to the thermodynamically favored N-bound complex [(η6-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 μM) 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.

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Acknowledgments

We thank Oncosense Ltd and the Chinese Academy of Sciences (Hundred Talents Programme) for their support for this work, and Emily Jones (Oncosense) for measuring the IC50 of complex 1. We also thank members of EC COST Action D39 for stimulating discussions.

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Authors and Affiliations

  1. Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, 100190, Beijing, China

    Fuyi Wang

  2. Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK

    Abraha Habtemariam, Robert J. Deeth & Peter J. Sadler

  3. School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh, EH9 3JJ, UK

    Fuyi Wang, Abraha Habtemariam, Erwin P. L. van der Geer, Robert Gould, Simon Parsons & Peter J. Sadler

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  1. Fuyi Wang
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  2. Abraha Habtemariam
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  3. Erwin P. L. van der Geer
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  4. Robert J. Deeth
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  5. Robert Gould
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  6. Simon Parsons
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  7. Peter J. Sadler
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Correspondence to Fuyi Wang or Peter J. Sadler.

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Wang, F., Habtemariam, A., van der Geer, E.P.L. et al. Synthesis, characterization, and reaction pathways for the formation of a GMP adduct of a cytotoxic thiocyanato ruthenium arene complex. J Biol Inorg Chem 14, 1065–1076 (2009). https://doi.org/10.1007/s00775-009-0549-x

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  • DOI: https://doi.org/10.1007/s00775-009-0549-x

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