ISBN: 978-83-60043-10-3 - eurobic9

Eurobic9, 2-6 September, 2008, Wrocław, Poland
P21. The Reduction of (ImH)[trans-Ru III Cl4(dmso)(Im)] and Preferential
Reaction of the Reduced Complex with Human Serum Albumin.
M. Brindell, a, b I. Sawoska, a G. Stochel a , R. van Eldik b
a
Department of Inorganic Chemistry, Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060
Krakow, Poland
e-mail: brindell@chemia.uj.edu.pl
b
Inorganic Chemistry, Department of Chemistry and Pharmacy, University of Erlangen-Nürnberg,
Egerlandstrasse 1, 91058 Erlangen, Germany
NAMI-A a novel anti-metastatic Ru(III) complex, viz. (ImH)[trans-RuCl4(dmso)(Im)] has successfully
completed phase I clinical trials and undergoes further stages of clinical tests.[1] It can be administered
intravenously and the pharmacokinetic analysis of the Ru content of blood plasma has revealed that most of the
Ru in blood plasma is accumulated in the protein-bound form (> 97%). Extensive binding of this drug to the
plasma proteins may significantly influence its biodistribution and bioavailability, and therefore the
understanding of this process is of great importance. Considering the physiological conditions in blood plasma
(pH 7.4, 0.1-0.15 M NaCl, 37 o C), it is expected that NAMI-A undergoes relatively fast hydrolysis. It was
proposed that under such conditions the stepwise dissociation of two Cl – and one dmso ligands occurs.[2, 3]
Moreover, one should take into account the redox environment present in the blood. The presence of ascorbic
acid in blood serum can lead to reduction of NAMI-A. [3-6]
Based on this information, we can assume that at least two major transformations of NAMI-A, namely
hydrolysis and reduction, can occur immediately after administration, and they can precede the reaction with
serum proteins. Therefore, the form of the complex that actually reacts with serum albumin can differ
significantly from the complex introduced into the organism. In this context, the question arises if NAMI-A
(Ru(III) complex) really reacts with albumin or rather its reduced form, or maybe even the reduced form of the
hydrolytic derivatives of NAMI-A. This presentation aims to answer this question in the most precise way.
References:
[1] Rademaker-Lakhai, J. M.; van_den_Bongard, D.; Pluim, D.; Beijnen, J. H.; Schellens, J. H. M. Clin. Cancer
Res. 2004, 10, 3717-3727.
[2] Bacac, M.; Hotze, A. C. G.; van_der_Schilden, K.; Haasnoot, J. G.; Pacor, S.; Alessio, E.; Sava, G.; Reedijk,
J. J. Inorg. Biochem. 2004, 98, 402-412.
[3] Brindell, M.; Stawoska, I.; Supel, J.; Skoczowski, A.; Stochel, G.; van_Eldik, R. J. Biol. Inorg. Chem. 2008,
DOI 10.1007/s00775-008-0378-3.
[4] Sava, G.; Bergamo, A.; Zorzet, S.; Gava, B.; Casarsa, C.; Cocchietto, M.; Furlani, A.; Scarcia, V.; Serli, B.;
Iengo, E.; Alessio, E.; Mestroni, G. Eur. J. Cancer 2002, 38, 427-435.
[5] Ravera, M.; Baracco, S.; Cassino, C.; Zanello, P.; Osella, D. Dalton Trans. 2004, 2347-2351.
[6] Brindell, M.; Piotrowska, D.; Shoukry, A. A.; Stochel, G.; van_Eldik, R. J. Biol. Inorg. Chem. 2007, 12, 809-
818.
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