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

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• 作者：Ana R. Marques ; Lukas Kromer ; David J. Gallo ; Nuno Penacho ; Sandra S. Rodrigues ; Jo茫o D. Seixas ; Gon莽alo J. L. Bernardes ; Patr铆cia M. Reis ; Sherrie L. Otterbein ; Rachel A. Ruggieri ; Ana S. G. Gon莽alves ; Ana M. L. Gon莽alves ; Marta N. De Matos ; Isabel Bento ; Leo E. Otterbein ; Walter A. Bl盲ttler ; Carlos C. Rom茫o
• 刊名：Organometallics
• 出版年：2012
• 出版时间：August 27, 2012
• 年：2012
• 卷：31
• 期：16
• 页码：5810-5822
• 全文大小：425K
• 年卷期：v.31,no.16(August 27, 2012)
• ISSN：1520-6041

文摘

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鈥睷鈥矯O₂R鈥?₃ (R鈥? R鈥?= H, Me, ⁱPr, CH₂Ph, CO₂Li, 鈭扖H₂CH₂鈥? 鈭扖H₂(CH₂)₃CH₂鈥? R鈥?= 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.