Developing drug molecules for therapy with carbon monoxide

Abstract

The use of Carbon Monoxide (CO) as a therapeutic agent has already been tested in human clinical trials. Pre-clinically, CO gas administration proved beneficial in animal models of various human diseases. However, the use of gaseous CO faces serious obstacles not the least being its well-known toxicity. To fully realise the promise of CO as a therapeutic agent, it is key to find novel avenues for CO delivery to diseased tissues in need of treatment, without concomitant formation of elevated, toxic blood levels of carboxyhemoglobin (COHb). CO-releasing molecules (CO-RMs) have the potential to constitute safe treatments if CO release in vivo can be controlled in a spatial and temporal manner. It has already been demonstrated in animals that CO-RMs can release CO and mimic the therapeutic effects of gaseous CO. While demonstrating the principle of treatment with CO-RMs, these first generation compounds are not suitable for human use. This tutorial review summarises the biological and chemical behaviour of CO, the current status of CO-RM development, and derives principles for the creation of the next generation of CO-RMs for clinical applications in humans.

PhotoCORMs: CO release moves into the visible

“…This donor ability is also implicated in other aspects of the dangers of CO: COHb formation alone cannot fully account for the acute toxicity seen. 1 This same ability to bind strongly to metal centres provides CO with an additional, beneficial role. Studies on the biological role of CO have established that it functions as a signalling molecule, [2][3][4][5] reminiscent of the discovery that NO plays a similar role in cell processes.…”

“…Non-organometallic systems are in the main limited by low rates and/or harsh conditions for CO release. 1 CORMs may release carbon monoxide in response to a range of stimuli. Dissolution of many CORM systems in aqueous media leads to release of CO at physiological temperatures: thermodynamic CORMs.…”

Vitamin B12–Metal Conjugates for Targeted Chemotherapy and Diagnosis: Current Status and Future Prospects

“…In this context, transition-metal complexes bearing carbonyl ligands have been widely explored as CORMs for the controlled delivery of small doses of CO inside cells. [26][27][28]31] In particular, {Re(CO) 2 }-based CORMs showed promise in the protection of cardiomyocytes against ischemia reperfusion injury. These monomeric dicarbonyl species have unique properties, because the rates of CO release can be appropriately tuned by variation of pH and use of additional ligands.…”

“…[25][26][27][28][29][30] Despite several advantages, the administration of gaseous CO in new therapies is associated with some drawbacks, such as safe handling and sitespecific delivery. Therefore, research moved toward the development of biocompatible CO-releasing molecules (CORMs) as an alternative approach.…”

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

“…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].…”