TY - JOUR
T1 - Generation of carbon monoxide releasing molecules (CO-RMs) as drug candidates for the treatment of acute liver injury: Targeting of CO-RMs to the liver
AU - Marques, Ana R.
AU - Kromer, Lukas
AU - Gallo, David J.
AU - Penacho, Nuno
AU - Rodrigues, Sandra S.
AU - Seixas, João D.
AU - Bernardes, Gonçalo J. L.
AU - Reis, Patrícia M.
AU - Otterbein, Sherrie L.
AU - Ruggieri, Rachel A.
AU - Gonçalves, Ana S. G.
AU - Gonçalves, , Ana M. L.
AU - de Matos, Marta N.
AU - Bento, Isabel
AU - Otterbein, Leo E.
AU - Blättler, Walter A.
AU - Romão, Carlos C.
N1 - L.K. acknowledges the Swiss National Science Foundation for Grant No. PBZHP2-125507. P.M.R. thanks the Fundacao para a Ciencia e Tecnologia for Grant No. SFRH/BPD/20655/2004. The NMR spectrometers are part of the National NMR Network and were purchased in the framework of the National Program for Scientific Re-equipment, Vontract REDE/1517/RMN/2005, with funds from POCI 2010 (FEDER) and the Fundacao para a Ciencia e a Tecnologia (FCT).
PY - 2012/8/27
Y1 - 2012/8/27
N2 - The discovery of the biological effects of carbon monoxide (CO) in recent years strongly suggests that CO could find applications as a therapeutic agent. CO is a highly toxic gas when used at industrial doses, due in part to its binding affinity to hemoglobin. Since hemoglobin binds CO with the highest affinity in vivo, it also constitutes a major barrier to the delivery of CO to tissues in need of therapy. A method of delivering CO that can bypass hemoglobin is the use of pro-drugs or CO carriers, called CO-releasing molecules (CO-RMs) that become activated and release CO in tissues in need of treatment. Organometallic carbonyl complexes are best suited to play the role of CO carriers, and indeed the natural CO carrier molecules hemoglobin and myoglobin belong to this class of chemical compounds. Here we describe the preparation of novel molybdenum CO-RMs of general formula Mo(CO)3(CNCR′ RCO2R)3 (R′, R = H, Me, iPr, CH 2Ph, CO2Li, -CH2CH2-, -CH 2(CH2)3CH2-; R = H, Li), which present favorable druglike characteristics, have low toxicity, and demonstrate specific CO delivery to the liver in the treatment of acetaminophen (APAP)-induced acute liver failure in mice.
AB - The discovery of the biological effects of carbon monoxide (CO) in recent years strongly suggests that CO could find applications as a therapeutic agent. CO is a highly toxic gas when used at industrial doses, due in part to its binding affinity to hemoglobin. Since hemoglobin binds CO with the highest affinity in vivo, it also constitutes a major barrier to the delivery of CO to tissues in need of therapy. A method of delivering CO that can bypass hemoglobin is the use of pro-drugs or CO carriers, called CO-releasing molecules (CO-RMs) that become activated and release CO in tissues in need of treatment. Organometallic carbonyl complexes are best suited to play the role of CO carriers, and indeed the natural CO carrier molecules hemoglobin and myoglobin belong to this class of chemical compounds. Here we describe the preparation of novel molybdenum CO-RMs of general formula Mo(CO)3(CNCR′ RCO2R)3 (R′, R = H, Me, iPr, CH 2Ph, CO2Li, -CH2CH2-, -CH 2(CH2)3CH2-; R = H, Li), which present favorable druglike characteristics, have low toxicity, and demonstrate specific CO delivery to the liver in the treatment of acetaminophen (APAP)-induced acute liver failure in mice.
UR - http://www.scopus.com/inward/record.url?scp=84865520405&partnerID=8YFLogxK
U2 - 10.1021/om300360c
DO - 10.1021/om300360c
M3 - Article
AN - SCOPUS:84865520405
SN - 0276-7333
VL - 31
SP - 5810
EP - 5822
JO - Organometallics
JF - Organometallics
IS - 16
ER -