A contribution to the rational design of Ru(CO)3Cl2L complexes for in vivo delivery of CO

João D. Seixas, Marino F. A. Santos, Abhik Mukhopadhyay, Ana C. Coelho, Patrícia M. Reis, Luís F. Veiros, Ana R. Marques, Nuno Penacho, Ana M. L. Gonçalves, Maria J. Romão, Gonçalo J. L. Bernardes, Teresa Sacadura Santos-Silva, Carlos José Romão

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44 Citations (Scopus)

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 (4UWV) shows the addition of RuII(CO)(H2O)4 at the His15 binding site. Soakings with 7 (4UWU) 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. This journal is

Original languageEnglish
Pages (from-to)5058-5075
Number of pages18
JournalDalton Transactions
Volume44
Issue number11
DOIs
Publication statusPublished - 21 Mar 2015

Keywords

  • GAS-SHIFT REACTION
  • MONOXIDE-RELEASING MOLECULES
  • CONTINUUM SOLVATION MODELS
  • GAUSSIAN-TYPE BASIS
  • CARBON-MONOXIDE
  • RUTHENIUM(II) COMPLEXES
  • EQUILIBRIUM GEOMETRIES
  • POLARIZATION FUNCTIONS
  • ORGANIC-MOLECULES
  • TRANSITION-STATES

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