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

doi:10.1039/c4dt02966f

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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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 Ru^II(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 language	English
Pages (from-to)	5058-5075
Number of pages	18
Journal	Dalton Transactions
Volume	44
Issue number	11
DOIs	https://doi.org/10.1039/c4dt02966f
Publication status	Published - 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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Seixas, J. D., Santos, M. F. A., Mukhopadhyay, A., Coelho, A. C., Reis, P. M., Veiros, L. F., Marques, A. R., Penacho, N., Gonçalves, A. M. L., Romão, M. J., Bernardes, G. J. L., Santos-Silva, T. S., & Romão, C. J. (2015). A contribution to the rational design of Ru(CO)₃Cl₂L complexes for in vivo delivery of CO. Dalton Transactions, 44(11), 5058-5075. https://doi.org/10.1039/c4dt02966f

@article{7d97aed2b6344d7d8b4299fa6a29d1da,

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 (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",

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",

author = "Seixas, {Jo{\~a}o D.} and Santos, {Marino F. A.} and Abhik Mukhopadhyay and Coelho, {Ana C.} and Reis, {Patr{\'i}cia M.} and Veiros, {Lu{\'i}s F.} and Marques, {Ana R.} and Nuno Penacho and Gon{\c c}alves, {Ana M. L.} and Rom{\~a}o, {Maria J.} and Bernardes, {Gon{\c c}alo J. L.} and Santos-Silva, {Teresa Sacadura} and Rom{\~a}o, {Carlos Jos{\'e}}",

note = "We thank Fundacao para a Ciencia e Tecnologia (FCT), Portugal (PTDC/QUI-BIQ/117799/2010, PEst-C/EQB/LA0006/2013 and PEst-OE/QUI/UI0100/2013) for funding. J.D.S. and M.F.A.S. thank FCT for the award of doctoral studentships. A.M., A.C.C. and P.M.R. thank FCT for the award of postdoctoral fellowships. The National NMR Network (REDE/1517/RMN/2005) was supported by POCI 2010 (FEDER) and FCT. We also thank the ESRF for provision of synchrotron radiation facilities (beamlines ID14-1 and ID14-2).",

year = "2015",

month = mar,

day = "21",

doi = "10.1039/c4dt02966f",

language = "English",

volume = "44",

pages = "5058--5075",

journal = "Dalton Transactions",

issn = "1477-9226",

publisher = "RSC - Royal Society of Chemistry",

number = "11",

}

TY - JOUR

T1 - A contribution to the rational design of Ru(CO)3Cl2L complexes for in vivo delivery of CO

AU - Seixas, João D.

AU - Santos, Marino F. A.

AU - Mukhopadhyay, Abhik

AU - Coelho, Ana C.

AU - Reis, Patrícia M.

AU - Veiros, Luís F.

AU - Marques, Ana R.

AU - Penacho, Nuno

AU - Gonçalves, Ana M. L.

AU - Romão, Maria J.

AU - Bernardes, Gonçalo J. L.

AU - Santos-Silva, Teresa Sacadura

AU - Romão, Carlos José

N1 - We thank Fundacao para a Ciencia e Tecnologia (FCT), Portugal (PTDC/QUI-BIQ/117799/2010, PEst-C/EQB/LA0006/2013 and PEst-OE/QUI/UI0100/2013) for funding. J.D.S. and M.F.A.S. thank FCT for the award of doctoral studentships. A.M., A.C.C. and P.M.R. thank FCT for the award of postdoctoral fellowships. The National NMR Network (REDE/1517/RMN/2005) was supported by POCI 2010 (FEDER) and FCT. We also thank the ESRF for provision of synchrotron radiation facilities (beamlines ID14-1 and ID14-2).

PY - 2015/3/21

Y1 - 2015/3/21

N2 - 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

AB - 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

KW - GAS-SHIFT REACTION

KW - MONOXIDE-RELEASING MOLECULES

KW - CONTINUUM SOLVATION MODELS

KW - GAUSSIAN-TYPE BASIS

KW - CARBON-MONOXIDE

KW - RUTHENIUM(II) COMPLEXES

KW - EQUILIBRIUM GEOMETRIES

KW - POLARIZATION FUNCTIONS

KW - ORGANIC-MOLECULES

KW - TRANSITION-STATES

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U2 - 10.1039/c4dt02966f

DO - 10.1039/c4dt02966f

M3 - Article

C2 - 25427784

AN - SCOPUS:84923384344

SN - 1477-9226

VL - 44

SP - 5058

EP - 5075

JO - Dalton Transactions

JF - Dalton Transactions

IS - 11

ER -

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

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Keywords

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