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Issue 40, 2015
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Albumin binding and ligand-exchange processes of the Ru(iii) anticancer agent NAMI-A and its bis-DMSO analogue determined by ENDOR spectroscopy

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Abstract

The ruthenium anticancer compound NAMI-A, imidazolium [trans-RuCl4(1H-imidazole)(DMSO-S)], is currently undergoing advanced clinical evaluation. As with other Ru(III) chemotherapeutic candidates, interactions with human serum albumin (HSA) have been identified as a key component of the speciation of NAMI-A following intravenous administration. To characterize coordination to HSA, we have performed electron paramagnetic resonance (EPR) and electron nuclear double resonance (ENDOR) spectroscopic analysis of deuterium-labelled isotopologues of both NAMI-A and its bis-DMSO analogue, [(DMSO)2H][trans-RuCl4(DMSO-S)2] (Ru-bis-DMSO). Samples were prepared using phosphate buffered saline, in the presence of HSA, and with the individual amino acids histidine, cysteine, and alanine. Analysis of 1H ENDOR spectra shows characteristic hyperfine interactions from DMSO, water, and imidazole ligands. Furthermore, coordination of imidazole ligands was confirmed from diagnostic 14N ENDOR signals. Combined with the EPR data from the complexes following incubation in the presence of histidine, the ENDOR data demonstrate that both complexes bind to HSA via histidine imidazoles. Furthermore, the protein-bound species are shown to have water ligands and, in the case of Ru-bis-DMSO, one species has a remaining coordinated DMSO.

Graphical abstract: Albumin binding and ligand-exchange processes of the Ru(iii) anticancer agent NAMI-A and its bis-DMSO analogue determined by ENDOR spectroscopy

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Supplementary files

Article information


Submitted
28 May 2015
Accepted
02 Jul 2015
First published
03 Jul 2015

Dalton Trans., 2015,44, 17482-17493
Article type
Paper
Author version available

Albumin binding and ligand-exchange processes of the Ru(III) anticancer agent NAMI-A and its bis-DMSO analogue determined by ENDOR spectroscopy

M. I. Webb and C. J. Walsby, Dalton Trans., 2015, 44, 17482
DOI: 10.1039/C5DT02021B

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