Chemistry:Carbon monoxide-releasing molecules

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Short description: Substances delivering CO within the body
Structure of RuCl(gly)(CO)3, known as CORM-3.

Carbon monoxide-releasing molecules (CORMs) are chemical compounds designed to release controlled amounts of carbon monoxide (CO). CORMs are being developed as potential therapeutic agents to locally deliver CO to cells and tissues, thus overcoming limitations of CO gas inhalation protocols.

CO is best known for its toxicity in carbon monoxide poisoning at high doses. However, CO is a gasotransmitter and supplemental low dosage of CO has been linked to therapeutic benefits. Pre-clinical research has focused on CO's anti-inflammatory activity with significant applications in cardiovascular disease, oncology, transplant surgery, and neuroprotection.[1]

History

The simplest source of CO is from a combustion reaction via burning sources such as fossil fuels or fire wood. Sources releasing CO upon thermal decomposition or combustion are generally not considered CORMs.

Therapeutic interest in CO dates back to the study of factitious airs (hydrocarbonate) in the 1790s by Thomas Beddoes, James Watt, James Lind, Humphry Davy, Tiberius Cavallo and many others.[2]

Nickel tetracarbonyl was the first carbonyl-complex used to achieve local delivery of CO and was the first CO delivery molecule suggested to have therapeutic potential in 1891.[2] The acronym CORM was coined in 2002 which marks the first modern biomedical and pharmaceutical initiative.[3] The enzymatic reaction of heme oxygenase inspired the development of synthetic CORMs.

The first synthetic CORMs were typically metal carbonyl complexes. A representative CORM that has been extensively characterized both from a biochemical and pharmacological view point is the ruthenium(II) complex Ru(glycinate)Cl(CO)3, commonly known as CORM-3. Therapeutic data pertaining to metallic CORMs are being reappraised to elucidate if observed effects are actually due to CO, or, if metal reactivity mediates physiological effects via thiol depletion, facilitating reduction, ion channel blockage, or redox catalysis.[4][5] Despite questions pertaining to transition metals, pure CO gas and alternative non-metallic CO prodrugs and drug delivery devices have confirmed CO's therapeutic potential.

CORM classifications

Transition metal CORMs

The majority of therapeutically relevant CORMs are transition metal complexes primarily based on iron, molybdenum, ruthenium, manganese, cobalt, rhenium and others.[6]

PhotoCORMs

The release of CO from carrier agents can be induced photochemically. These carriers are called photoCORMs and include both metal complexes and metal-free (organic) compounds of various structural motifs which could be regarded as a special type of photolabile protecting group.[7]

ET-CORMs

Enzyme-triggered CORMs (ET-CORMs) have been developed to improve selective local delivery of CO. Some ET-CORM prodrugs are activated by esterase enzymes for site specific liberation of CO.[8]

CO prodrugs

Organic CORMs are being developed to overcome reactivity and certain toxicity limitations of inorganic CORMs.

Methylene chloride was the first organic CORM orally administered based on previous reports of carboxyhemoglobin formation via metabolism. The second organic CORM, CORM-A1 (sodium boranocarbonate), was developed based on a 1960s report of CO release from potassium boranocarbonate.[2]

In 2003, cyclic oxocarbons were suggested as a source for therapeutic CO including deltic acid, squaric acid, croconic acid, and rhodizonic acid and their salts.[9]

Recent years have seen increasing interests in organic CO prodrugs because of the need to consider drug developability issues in developing CO-based therapeutics.[10] These CO prodrugs have tunable release rate, triggered release, and the ability to release more than one payload from a single prodrug.[11]

Enzyme hybrids

Based on the synergism of the heme oxygenase system and CO delivery, a new molecular hybrid-CORM (HYCO) class emerged consisting of a conjoined HO-1 inducer and CORM species. One such HYCO includes a dimethyl fumarate moiety which activates NRF2 to thereby induce HO-1, whilst the CORM moiety also liberates CO.[12]

Carbon monoxide releasing materials

Carbon monoxide releasing materials (CORMAs) are essentially novel drug formulations and drug delivery platforms which have emerged to overcome the pharmaceutical limitations of most CORM species.[13] An exemplary CORMA developed by Hubbell consists of a formulation of micelles prepared from triblock copolymers with a CORM entity, which is triggered for release via addition of cysteine. Other CO-releasing scaffolds include polymers, peptides, silica nanoparticles, nanodiamond, magnetic nanoparticles, nanofiber gel, metallodendrimers, and CORM-protein (macromolecule) conjugates.[14][15]

Other advanced drug delivery devices, such as encapsulated CORMs and extracorporeal membrane-inspired technologies, have been developed.[5]

Carboxyhemoglobin infusion

Carboxyhemoglobin can be infused to deliver CO. The most common approaches are based on polyethylene glycol PEGylated bovine carboxyhemoglobin and maleimide PEG conjugated human carboxyhemoglobin.[16]

Porphyrins

Porphyrin structures such as heme, hemin, and metallic protoporphyrin IX (PPIX) analogs (such as cobalt PPIX) have been deployed to induce heme oxygenase and subsequently undergo biotransformation to liberate CO, the inorganic ion, and biliverdin/bilirubin.[17] Some PPIX analogs such as tin PPIX, tin mesoporphyrin, and zinc PPIX, are heme oxygenase inhibitors.

Endogenous CO

HMOX is regarded as the main source of endogenous CO production, though other minor contributors have been identified in recent years.[18] CO is formed at a rate of 16.4 μmol/hour in the human body, ~86% originating from heme via heme oxygenase and ~14% from non-heme sources including: photooxidation, lipid peroxidation, and xenobiotics.[19] The average carboxyhemoglobin (CO-Hb) level in a non-smoker is under 3% CO-Hb (whereas a smoker may reach levels near 10% CO-Hb),[20] though geographic location, occupation, health and behavior are contributing variables.

Heme oxygenase

Main page: Biology:Heme oxygenase

In the late 1960s Rudi Schmid characterized the enzyme that facilitates the reaction for heme catabolism, thereby identifying the heme oxygenase (HMOX) enzyme.

HMOX is a heme-containing member of the heat shock protein (HSP) family identified as HSP32. Three isoforms of HMOX have been identified to date including the stress-induced HMOX-1 and constitutive HMOX-2. HMOX-1 is considered a cell rescue protein which is induced in response to oxidative stress and numerous disease states. Furthermore, HMOX-1 is induced by countless molecules including statins, hemin, and natural products.[21][22]

HMOX catalyzes the degradation of heme to biliverdin/bilirubin, ferrous ion, and CO. Though present throughout the body, HO has significant activity in the spleen in the degradation of hemoglobin during erythrocyte recycling (0.8% of the erythrocyte pool per day), which accounts for ~80% of heme derived endogenous CO production. The majority of the remaining 20% of heme derived CO production is attributed to hepatic catabolism of hemoproteins (myoglobin, cytochromes, catalase, peroxidases, soluble guanylate cyclase, nitric oxide synthase) and ineffective erythropoiesis in bone marrow.[23]

The enzymatic velocity and catalytic activity of HMOX can be enhanced by a plethora of dietary substances and xenobiotics to increase CO production.

Minor CO sources

The formation of CO from lipid peroxidation was first reported in the late 1960s and is regarded as a minor contributor to endogenous CO production.[24][25] Other contributing sources include: the microbiome, cytochrome P450 reductase, human acireductone dioxygenase, tyrosinase, lipid peroxidation, alpha-keto acids, and other oxidative and redox mechanisms.[18]

CO pharmacology

Carbon monoxide is one of three gaseous signaling molecules alongside nitric oxide and hydrogen sulfide. These gases are collectively referred to as gasotransmitters. CO is a classical example of hormesis such that low-dose is essential and beneficial, whereas an absence or excessive exposure to CO can be toxic.

Signaling

The first evidence of CO as a signaling molecule occurred upon observation of CO stimulating soluble guanylate cyclase and subsequent cyclic guanosine monophosphate (cGMP) production to serve as a vasodilator in vascular smooth muscle cells. The anti-inflammatory effects of CO are attributed to activation of the p38 mitogen-activated protein kinase (MAPK) pathway. While CO commonly interacts with the ferrous iron atom of heme in a hemoprotein,[26] it has been demonstrated that CO activates calcium-dependent potassium channels by engaging in hydrogen-bonding with surface histidine residues.[18][27]

CO may have an inhibitory effect on numerous proteins including cytochrome P450 and cytochrome c oxidase.[28]

Pharmacokinetics

Main page: Chemistry:Carboxyhemoglobin

CO has approximately 210x greater affinity for hemoglobin than oxygen. The equilibrium dissociation constant for the reaction Hb-CO ⇌ Hb + CO strongly favours the CO complex, thus the release of CO for pulmonary excretion generally takes some time.

Based on this binding affinity, blood is essentially an irreversible sink for CO and presents a therapeutic challenge for the delivery of O2 to cells and tissues.

CO is considered non-reactive in the body and primarily undergoes pulmonary excretion.[29]

References

  1. ↑ "The therapeutic potential of carbon monoxide". Nature Reviews. Drug Discovery 9 (9): 728–743. September 2010. doi:10.1038/nrd3228. PMID 20811383. 
  2. ↑ 2.0 2.1 2.2 "A brief history of carbon monoxide and its therapeutic origins". Nitric Oxide 111-112: 45–63. June 2021. doi:10.1016/j.niox.2021.04.001. PMID 33838343. 
  3. ↑ "Carbon monoxide-releasing molecules: characterization of biochemical and vascular activities". Circulation Research 90 (2): E17–E24. February 2002. doi:10.1161/hh0202.104530. PMID 11834719. 
  4. ↑ "A thiol-reactive Ru(II) ion, not CO release, underlies the potent antimicrobial and cytotoxic properties of CO-releasing molecule-3". Redox Biology 18: 114–123. September 2018. doi:10.1016/j.redox.2018.06.008. PMID 30007887. 
  5. ↑ 5.0 5.1 ""CO in a pill": Towards oral delivery of carbon monoxide for therapeutic applications". Journal of Controlled Release 338: 593–609. October 2021. doi:10.1016/j.jconrel.2021.08.059. PMID 34481027. 
  6. ↑ "Novel lead structures and activation mechanisms for CO-releasing molecules (CORMs)". British Journal of Pharmacology 172 (6): 1638–1650. March 2015. doi:10.1111/bph.12688. PMID 24628281. 
  7. ↑ "Visible-to-NIR-Light Activated Release: From Small Molecules to Nanomaterials". Chemical Reviews 120 (24): 13135–13272. December 2020. doi:10.1021/acs.chemrev.0c00663. PMID 33125209. 
  8. ↑ "Different design of enzyme-triggered CO-releasing molecules (ET-CORMs) reveals quantitative differences in biological activities in terms of toxicity and inflammation". Redox Biology 2: 739–748. 2014. doi:10.1016/j.redox.2014.06.002. PMID 25009775. 
  9. ↑ "Chemistry and biological activities of CO-releasing molecules (CORMs) and transition metal complexes". Dalton Transactions (17): 1651–1660. May 2007. doi:10.1039/b701992k. PMID 17443255. 
  10. ↑ "Toward Carbon Monoxide-Based Therapeutics: Critical Drug Delivery and Developability Issues". Journal of Pharmaceutical Sciences 105 (2): 406–416. February 2016. doi:10.1016/j.xphs.2015.10.018. PMID 26869408. 
  11. ↑ "Strategies toward Organic Carbon Monoxide Prodrugs". Accounts of Chemical Research 51 (6): 1377–1385. June 2018. doi:10.1021/acs.accounts.8b00019. PMID 29762011. 
  12. ↑ "The role of carbon monoxide, heme oxygenase 1, and the Nrf2 transcription factor in the modulation of chronic pain and their interactions with opioids and cannabinoids". Medicinal Research Reviews 41 (1): 136–155. January 2021. doi:10.1002/med.21726. PMID 32820550. 
  13. ↑ "Carbon monoxide--physiology, detection and controlled release". Chemical Communications 50 (28): 3644–3660. April 2014. doi:10.1039/c3cc49196j. PMID 24556640. 
  14. ↑ "Macromolecular and Inorganic Nanomaterials Scaffolds for Carbon Monoxide Delivery: Recent Developments and Future Trends". ACS Biomaterials Science & Engineering 1 (10): 895–913. October 2015. doi:10.1021/acsbiomaterials.5b00230. PMID 33429521. 
  15. ↑ "CO-releasing molecule (CORM) conjugate systems". Dalton Transactions 45 (45): 18045–18063. November 2016. doi:10.1039/c6dt03515a. PMID 27808304. 
  16. ↑ "Where is the Clinical Breakthrough of Heme Oxygenase-1 / Carbon Monoxide Therapeutics?". Current Pharmaceutical Design 24 (20): 2264–2282. July 2018. doi:10.2174/1381612824666180723161811. PMID 30039755. 
  17. ↑ "Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications". FASEB Journal 2 (10): 2557–2568. July 1988. doi:10.1096/fasebj.2.10.3290025. PMID 3290025. 
  18. ↑ 18.0 18.1 18.2 "Role of Carbon Monoxide in Host-Gut Microbiome Communication". Chemical Reviews 120 (24): 13273–13311. December 2020. doi:10.1021/acs.chemrev.0c00586. PMID 33089988. 
  19. ↑ Carbon monoxide and cardiovascular functions (first ed.). CRC Press. 2001. p. 5. ISBN 978-1-4200-4101-9. 
  20. ↑ "Chapter 15: Carbon monoxide pathophysiology and treatment". Physiology and medicine of hyperbaric oxygen therapy. 2008. pp. 321–347. doi:10.1016/B978-1-4160-3406-3.50020-2. ISBN 978-1-4160-3406-3. 
  21. ↑ "Eat to Heal: Natural Inducers of the Heme Oxygenase-1 System.". Pharma-Nutrition. AAPS Advances in the Pharmaceutical Sciences Series. 12. Springer, Cham.. 2014. pp. 243–256. doi:10.1007/978-3-319-06151-1_12. ISBN 978-3-319-06150-4. 
  22. ↑ "Inducers of heme oxygenase-1". Current Pharmaceutical Design 14 (5): 473–486. 2008. doi:10.2174/138161208783597399. PMID 18289074. 
  23. ↑ "Chapter 15: Sources, Sinks, and Measurement of Carbon Monoxide". Carbon Monoxide and Cardiovascular Functions (2nd ed.). CRC Press. 30 October 2001. ISBN 978-0-8493-1041-6. 
  24. ↑ "The formation of carbon monoxide during peroxidation of microsomal lipids". Biochemical and Biophysical Research Communications 73 (4): 850–857. December 1976. doi:10.1016/0006-291X(76)90199-6. PMID 15625852. 
  25. ↑ Structure and Function of Cytochromes. University Park Press. 1968. pp. 658–665. 
  26. ↑ "Biological signaling by carbon monoxide and carbon monoxide-releasing molecules". American Journal of Physiology. Cell Physiology 312 (3): C302–C313. March 2017. doi:10.1152/ajpcell.00360.2016. PMID 28077358. 
  27. ↑ "Carbon monoxide: an emerging regulator of ion channels". The Journal of Physiology 589 (Pt 13): 3055–3062. July 2011. doi:10.1113/jphysiol.2011.206706. PMID 21521759. 
  28. ↑ "Inhibition of cytochrome P450 enzymes". Cytochrome P450. Boston, MA: Springer. 2005. pp. 247–322. doi:10.1007/0-387-27447-2_7. ISBN 978-0-306-48324-0. 
  29. ↑ "Health Effects". Toxicological Profile for Carbon Monoxide. U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry. 2012. https://www.ncbi.nlm.nih.gov/books/NBK153687/. 

Further reading



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