Novel lead structures and activation mechanisms for CO‐releasing molecules (CORMs)

Abstract

Carbon monoxide (CO) is an endogenous small signalling molecule in the human body, produced by the action of haem oxygenase on haem. Since it is very difficult to apply safely as a gas, solid storage and delivery forms for CO are now explored. Most of these CO-releasing molecules (CORMs) are based on the inactivation of the CO by coordinating it to a transition metal centre in a prodrug approach. After a brief look at the potential cellular target structures of CO, an overview of the design principles and activation mechanisms for CO release from a metal coordination sphere is given. Endogenous and exogenous triggers discussed include ligand exchange reactions with medium, enzymatically-induced CO release and photoactivated liberation of CO. Furthermore, the attachment of CORMs to hard and soft nanomaterials to confer additional target specificity to such systems is critically assessed. A survey of analytical methods for the study of the stoichiometry and kinetics of CO release, as well as the tracking of CO in living systems by using fluorescent probes, concludes this review. CORMs are very valuable tools for studying CO bioactivity and might lead to new drug candidates; however, in the design of future generations of CORMs, particular attention has to be paid to their drug-likeness and the tuning of the peripheral 'drug sphere' for specific biomedical applications. Further progress in this field will thus critically depend on a close interaction between synthetic chemists and researchers exploring the physiological effects and therapeutic applications of CO. LINKED ARTICLESThis article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10. 1111/bph.2015.172.issue-6 Abbreviations BODIPY, boron dipyrromethene difluoride; CORM, CO-releasing molecule; EPR, electron paramagnetic resonance; ET-CORM, enzyme-triggered CORM; HO, haem oxygenase; Mb, myoglobin; MbCO, carboxymyoglobin; MO, molecular orbital; MOF, metal-organic framework; PhotoCORM, photoactivatable CORM; sGC, soluble guanylate cyclase; YFP, yellow fluorescent protein Carbon monoxide: a small signalling molecule with specific target structuresCarbon monoxide (CO) is now well established as the third small signalling molecule in higher organisms, including humans (Wu and Wang, 2005;Kim et al., 2006;Piantadosi, 2008). It is endogenously generated by the action of haem oxygenase (HO) on haem (see Alexander et al., 2013c), which also leads to the formation of iron(II) and biliverdin. The latter is further converted to bilirubin by biliverdin reductase. The enzymatic mechanism has been elucidated at the molecular level by a combination of spectroscopic and BJP British Journal of Pharmacology DOI:10.1111/bph.12688 www.brjpharmacol.org 1638 British Journal of Pharmacology (2015) 172 1638-1650© 2014 The British Pharmacological Society theoretical approaches (Chen et al., 2008;Lai et al., 2010;Matsui et al., 2010) as well as X-ray crystal structure analysis (Friedman et al.,...

Bactericidal Effect of a Photoresponsive Carbon Monoxide-Releasing Nonwoven against Staphylococcus aureus Biofilms

“…For the controlled delivery and release of the toxic gas in aqueous environments, carbon monoxide-releasing molecules (CORMs) have proven to be the most promising for therapeutic usage (27,28). Transition metal carbonyl complexes are the most prominent CORMs because they can be triggered via light, solvent exchange on the metal coordination sphere, and enzymes (29,30). Macromolecular systems have also been exploited as CORM carriers to adapt CO release kinetics and retain toxic metabolites after CO release (27 (10,(31)(32)(33)(34).…”

Manganese(I)-Based CORMs with 5-Substituted 3-(2-Pyridyl)Pyrazole Ligands

“…All manganese atoms are embedded in distorted octahedral environments. The molecular structure and numbering scheme of the mixed-valent centrosymmetric complex [(MeOH) 4 Mn 4 (Br) 2 (OMe) 6 (2-PyPz Naph ) 2 ] (3b) is depicted in Figure 4; again symmetry related atoms are marked with the letter A. Two methoxide ligands occupy µ 3 -and four methoxide ions µ 2 -bridging positions.…”

“…Metal carbonyls are usually considered for this purpose because numerous carbonyl ligands can be transported to a predetermined disease site and liberated via diverse triggers. Thus, CORMs are distinguished by the liberation initiators such as enzymes (ET-CORMs), illumination (photoCORMs), pH change, or substitution reactions (for recent reviews see [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]). Especially photoCORMs represent a prominent group because a clean delivery of CO seems to be possible without the necessity to add another chemical trigger [8,[13][14][15].…”

Gas Mediators in the Nervous System: Nitric Oxide, Hydrogen Sulfide and Carbon Monoxide

“…Bunu, sitokrom oksidaza bağ-lanıp bu enzimi inhibe ederek yapmakta ve böyle-likle hücresel solunumu aksatmaktadır. 156 CO, hedef hücrede sGC bağlanarak onu aktive etmekte ve cGMP'yi artırmaktadır. 157 Bu mekanizmayı kullanarak CO hem nörotransmisyon hem de vazodilatasyon etkisi gerçekleşmektedir.…”