title: A contribution to the rational design of Ru(CO)3Cl2L complexes for in vivo delivery of CO.
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.
authors.affiliation: Instituto de Tecnologia Química e Biológica-António Xavier da Universidade Nova de Lisboa, Av. da República, EAN, 2780-157 Oeiras, Portugal. ccr@itqb.unl.pt.
authors.forename: João D
authors.initials: JD
authors.lastname: Seixas
authors.forename: Marino F A
authors.initials: MF
authors.lastname: Santos
authors.forename: Abhik
authors.initials: A
authors.lastname: Mukhopadhyay
authors.forename: Ana C
authors.initials: AC
authors.lastname: Coelho
authors.forename: Patrícia M
authors.initials: PM
authors.lastname: Reis
authors.forename: Luís F
authors.initials: LF
authors.lastname: Veiros
authors.forename: Ana R
authors.initials: AR
authors.lastname: Marques
authors.forename: Nuno
authors.initials: N
authors.lastname: Penacho
authors.forename: Ana M L
authors.initials: AM
authors.lastname: Gonçalves
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Romão
authors.forename: Gonçalo J L
authors.initials: GJ
authors.lastname: Bernardes
authors.forename: Teresa
authors.initials: T
authors.lastname: Santos-Silva
authors.forename: Carlos C
authors.initials: CC
authors.lastname: Romão
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002245:Carbon Dioxide / Q000737:chemistry; D002248:Carbon Monoxide / Q000737:chemistry*; D002460:Cell Line; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D015195:Drug Design; D065546:Drug Liberation; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D011789:Quantum Theory; D012995:Solubility; D014018:Tissue Distribution; D014867:Water / Q000737:chemistry
chemical_list: D000893:Anti-Inflammatory Agents; D004337:Drug Carriers; D009942:Organometallic Compounds; D011506:Proteins; C447082:tricarbonyldichlororuthenium (II) dimer; D014867:Water; D002245:Carbon Dioxide; D002248:Carbon Monoxide; D004121:Dimethyl Sulfoxide