TY - JOUR
T1 - New insights into the chemistry of fac-[Ru(CO)3]2 + fragments in biologically relevant conditions: The CO releasing activity of [Ru(CO)3Cl2(1,3-thiazole)], and the X-ray crystal structure of its adduct with lysozyme
AU - Santos, Marino F. A.
AU - Seixas, João D.
AU - Coelho, Ana C.
AU - Mukhopadhyay, Abhik
AU - Reis, P. M.
AU - Romão, M. J.
AU - Romão, C. C.
AU - Santos-Silva, T.
N1 - This work was financed by Alfama Lda, REQUIMTE (PEst-C/EQB/LA0006/2011), and Fundacao para a Ciencia e a Tecnologia (FCT) through project PTDC/QUI-BIQ/117799/2010. The authors thank FCT for the grants SFRH/BPD/30142/2006 (A.M.), SFRH/BPD/70163/2010 (A.C.C.), SFRH/BPD/20655/2004 (P.M.R.) and SFRH/BD/77894/2011 (M.F.A.S.). The LC-MS equipment was acquired in the scope of the national program for scientific re-equipment, financed by FCT through the scientific re-equipment project; the NMR spectrometers are part of the National NMR Network and were purchased in the framework of the National Program for Scientific Re-equipment, contract REDE/1517/RMN/2005, with funds from POCI 2010 (FEDER) and FCT.
PY - 2012/12
Y1 - 2012/12
N2 - Complexes of the general formula fac-[Ru(CO)3L3] 2 +, namely CORM-2 and CORM-3, have been successfully used as experimental CO releasing molecules (CO-RMs) but their mechanism of action and delivery of CO remain unclear. The well characterized complex [Ru(CO) 3Cl2(1,3-thiazole)] (1) is now studied as a potential model CO-RM of the same family of complexes using LC-MS, FTIR, and UV-vis spectroscopy, together with X-ray crystallography. The chemistry of [Ru(CO) 3Cl2(1,3-thiazole)] is very similar to that of CORM-3: it only releases residual amounts of CO to the headspace of a solution in PBS7.4 and produces marginal increase of COHb after long incubation in whole blood. 1 also reacts with lysozyme to form Ru adducts. The crystallographic model of the lysozyme-Ru adducts shows only mono-carbonyl Ru species. [Ru(H 2O)4(CO)] is found covalently bound to a histidine (His15) and to two aspartates (Asp18 and Asp119) at the protein surface. The CO release silence of both 1 and CORM-3 and their rapid formation of protein-Ru(CO) x(H2O)y (x = 1,2) adducts, support our hypothesis that fac-[Ru(CO)3L3] CO-RMs deliver CO in vivo through the decay of their adducts with plasma proteins.
AB - Complexes of the general formula fac-[Ru(CO)3L3] 2 +, namely CORM-2 and CORM-3, have been successfully used as experimental CO releasing molecules (CO-RMs) but their mechanism of action and delivery of CO remain unclear. The well characterized complex [Ru(CO) 3Cl2(1,3-thiazole)] (1) is now studied as a potential model CO-RM of the same family of complexes using LC-MS, FTIR, and UV-vis spectroscopy, together with X-ray crystallography. The chemistry of [Ru(CO) 3Cl2(1,3-thiazole)] is very similar to that of CORM-3: it only releases residual amounts of CO to the headspace of a solution in PBS7.4 and produces marginal increase of COHb after long incubation in whole blood. 1 also reacts with lysozyme to form Ru adducts. The crystallographic model of the lysozyme-Ru adducts shows only mono-carbonyl Ru species. [Ru(H 2O)4(CO)] is found covalently bound to a histidine (His15) and to two aspartates (Asp18 and Asp119) at the protein surface. The CO release silence of both 1 and CORM-3 and their rapid formation of protein-Ru(CO) x(H2O)y (x = 1,2) adducts, support our hypothesis that fac-[Ru(CO)3L3] CO-RMs deliver CO in vivo through the decay of their adducts with plasma proteins.
KW - CO therapy
KW - CORM
KW - Protein crystallography
KW - Ruthenium complexes
UR - http://www.scopus.com/inward/record.url?scp=84869090746&partnerID=8YFLogxK
U2 - 10.1016/j.jinorgbio.2012.06.018
DO - 10.1016/j.jinorgbio.2012.06.018
M3 - Article
C2 - 22883959
AN - SCOPUS:84869090746
SN - 0162-0134
VL - 117
SP - 285
EP - 291
JO - Journal of Inorganic Biochemistry
JF - Journal of Inorganic Biochemistry
ER -