Carbon monoxide-releasing molecules
Carbon monoxide-releasing molecules (CO-RMs) are chemical compounds that release controlled amounts of carbon monoxide (CO) to cells and tissues and are being developed as potential therapeutic agents. Although long recognized as a poison, CO also exhibits beneficial effects in small doses. These effects include anti-inflammatory activity, vasodilatation, and cardioprotection. CO is produced in mammals during the degradation of heme by heme oxygenase-1, a redox-sensitive enzyme induced by oxidative stress. It is this enzymatic reaction that inspired the development of synthetic CO-RMs. Therapeutic drugs have historically been developed based on the similar activity of small molecules in biological signaling, examples exist in the case of both H2S and NO-releasing drugs.
Synthetic CO-RMs are typically metal carbonyl complexes. A representative CO-RM that has been extensively characterized both from a biochemical and pharmacological view point is the ruthenium(II) complex Ru(glycinate)Cl(CO)3, also known as CORM-3.
Testing of Ru(glycinate)Cl(CO)3
Studies have yielded evidence suggesting that high concentrations of CO in cellular medium can both inhibit or stimulate cellular respiration. In testing where high concentrations of CORM-3 were used (125-250 μM) E. coli respiration was considerably inhibited. But when the CORM-3 was tested in with cells placed in an O2 incubation chamber, so as to provide conditions mirroring normal cellular CO:O2 ratios, a 100 μM addition of CORM-3 stimulated respiration. Although CORM-3 doesn't show consistent results as successful inhibitor of cellular respiration it gives an understanding of fundamental reactivity of CO-RMs in biological systems.
The release of CO from carrier agents can be induced photochemically. These associated carriers are called photoCORMs.
- Vicki L Mahan "Neuroprotective, neurotherapeutic, and neurometabolic effects of carbon monoxide" Medical Gas Research 2012, 2:32. doi:10.1186/2045-9912-2-32.
- Motterlini R and Otterbein LE. "The therapeutic potential of carbon monoxide" Nat. Rev. Drug Discov. 9:728-743, 2010.
- Tenhunen R, Marver HS and Schmid R. "Microsomal heme oxygenase. Characterization of the enzyme" J Biol Chem. 244:6388-94, 1969.
- Maines MD, Trakshel GM, Kutty RK. "Characterization of two constitutive forms of rat liver microsomal heme oxygenase. Only one molecular species of the enzyme is inducible" J. Biol. Chem. 261:411-9, 1986.
- Motterlini, R.; Sawle, P.; Hammad, J.: Bains, S. K.; Alberto, R.; Foresti, R.;; Green, C. J. "CORM-A1: a new pharmacologically active carbon monoxide-releasing molecule" FASEB J. 19:284-286, 2005.
- Wallace JL. Hydrogen sulfide-releasing anti-inflammatory drugs. Trends Pharmacol Sci 28: 501–505, 2007.
- Clark JE, Naughton P, Shurey S, Green CJ, Johnson TR, Mann BE, Foresti R and Motterlini R. "Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule" Cir. Res. 93:e2-e8, 2003.
- Wilson JL, Jesse HE, Hughes B, et al. Ru(CO)3Cl(Glycinate) (CORM-3): A Carbon Monoxide–Releasing Molecule with Broad-Spectrum Antimicrobial and Photosensitive Activities Against Respiration and Cation Transport in Escherichia coli. Antioxidants & Redox Signaling. 2013;19(5):497-509. doi:10.1089/ars.2012.4784.
- Davidge KS, Sanguinetti G, Yee CH, Cox AG, McLeod CW, Monk CE, Mann BE, Motterlini R, Poole RK; J Biol Chem. 2009 Feb 13; 284(7):4516-24.
- Wright, Mark A.; Wright, Joseph A. (2016). "PhotoCORMs: CO release moves into the visible". Dalton Transactions. 45: 6801–6811. doi:10.1039/c5dt04849d.