4UWV

Lysozyme soaked with a ruthenium based CORM with a pyridine ligand (complex 8)

Summary for 4UWV

• Entry DOI: 10.2210/pdb4uwv/pdb
• Related: 4UWN 4UWU
• Descriptor: LYSOZYME C, CHLORIDE ION, SODIUM ION, ... (6 entities in total)
• Functional Keywords: hydrolase
• Biological source: GALLUS GALLUS (CHICKEN)
• Total number of polymer chains: 1
• Total formula weight: 14720.82

Authors

Santos, M.F.A.,Mukhopadhyay, A.,Romao, M.J.,Romao, C.C.,Santos-Silva, T. (deposition date: 2014-08-14, release date: 2014-12-10, Last modification date: 2024-11-06)

Primary citation

Seixas, J.D.,Santos, M.F.A.,Mukhopadhyay, A.,Coelho, A.C.,Reis, P.M.,Veiros, L.F.,Marques, A.R.,Penacho, N.,Goncalves, A.M.L.,Romao, M.J.,Bernardes, G.J.L.,Santos-Silva, T.,Romao, C.C.
A Contribution to the Rational Design of Ru(Co)3Cl2L Complexes for in Vivo Delivery of Co.
Dalton Trans, 44:5058-, 2015

PubMed Abstract: A few ruthenium based metal carbonyl complexes, e.g. CORM-2 and CORM-3, have therapeutic activity attributed to their ability to deliver CO to biological targets. In this work, a series of related complexes with the formula [Ru(CO)3Cl2L] (L = DMSO (3), L-H3CSO(CH2)2CH(NH2)CO2H) (6a); D,L-H3CSO(CH2)2CH(NH2)CO2H (6b); 3-NC5H4(CH2)2SO3Na (7); 4-NC5H4(CH2)2SO3Na (8); PTA (9); DAPTA (10); H3CS(CH2)2CH(OH)CO2H (11); CNCMe2CO2Me (12); CNCMeEtCO2Me (13); CN(c-C3H4)CO2Et) (14)) were designed, synthesized and studied. The effects of L on their stability, CO release profile, cytotoxicity and anti-inflammatory properties are described. The stability in aqueous solution depends on the nature of L as shown using HPLC and LC-MS studies. The isocyanide derivatives are the least stable complexes, and the S-bound methionine oxide derivative is the more stable one. The complexes do not release CO gas to the headspace, but release CO2 instead. X-ray diffraction of crystals of the model protein Hen Egg White Lysozyme soaked with 6b (4UWN) and 8 (4UWN) shows the addition of Ru(II)(CO)(H2O)4 at the His15 binding site. Soakings with 7(4UWN) produced the metallacarboxylate [Ru(COOH)(CO)(H2O)3](+) bound to the His15 site. The aqueous chemistry of these complexes is governed by the water-gas shift reaction initiated with the nucleophilic attack of HO(-) on coordinated CO. DFT calculations show this addition to be essentially barrierless. The complexes have low cytotoxicity and low hemolytic indices. Following i.v. administration of CORM-3, the in vivo bio-distribution of CO differs from that obtained with CO inhalation or with heme oxygenase stimulation. A mechanism for CO transport and delivery from these complexes is proposed.

PubMed: 25427784
DOI: 10.1039/C4DT02966F

Experimental method

X-RAY DIFFRACTION (1.77 Å)