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Carbon monoxide and its donors - Chemical and biological properties
Journal Pre-proof Carbon monoxide and its donors - Chemical and biological properties Weronika Adach, Mateusz Błaszczyk, Beata Olas PII:
S0009-2797(19)31520-0
DOI:
https://doi.org/10.1016/j.cbi.2020.108973
Reference:
CBI 108973
To appear in:
Chemico-Biological Interactions
Received Date: 6 September 2019 Revised Date:
17 January 2020
Accepted Date: 31 January 2020
Please cite this article as: W. Adach, M. Błaszczyk, B. Olas, Carbon monoxide and its donors Chemical and biological properties, Chemico-Biological Interactions (2020), doi: https://doi.org/10.1016/ j.cbi.2020.108973. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier B.V.
Carbon monoxide and its donors - chemical and biological properties
Weronika Adach, Mateusz Błaszczyk, Beata Olas* Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
*Corresponding author: Prof. Beata Olas, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland. Email: [email protected], Tel: +48 42 635 44 84
1
Abstract Carbon monoxide (CO) is an inorganic chemical compound that can bind with hemoglobin with highly toxic effects. In living organisms, it is produced endogenously during the degradation of heme by oxygenase, which occurs in three isoforms: HO-1, HO-2 and HO3. CO can play an important role in the regulation of many physiological functions. Carbon Oxide Releasing Molecules (CORMs) are a novel group of chemical compounds capable of controlled CO release directly in tissues or organs. This release depends on concentration, pH, solvent type and temperature. The biological role and the therapeutic potential of different CORMs is not always well demonstrated. However, this mini review summarizes the various function of these compounds.
Key words: carbon monoxide, CORM, chemical, biological properties
2
1. Chemical and biological properties Carbon monoxide (CO) is a colourless, odourless gas that is flammable and lighter than air. Although increasing amounts of CO are currently entering the atmosphere as a result of the development of civilization, it has always been present, mainly as a result of volcanic activity. Unfortunately, due to the wide diversity of natural sources of atmospheric CO, it is not possible to make an accurate estimation of its total emission rates. In urban areas, high concentrations of inhaled CO can have a negative impact on the health of residents. It is often formed as a result of incomplete combustion of carboncontaining compounds, primarily in internal combustion engines. It can also be stored and transported in a compressed form, and prolonged contact with fire or high temperature can lead to the explosion of containers [1]. CO is a highly toxic compound and inhalation of larger amounts commonly leads to pathologies of the central nervous system and the cardiovascular system. The intensity of symptoms is dependent on the dose of inhaled CO, and ranges from slight headaches to rapid death: concentrations above 1000 ppm are considered to be life threatening [2]. 2. Endogenous formation of carbon monoxide Despite the toxic effects on the nervous system and the cardiovascular system, carbon monoxide also plays an important role in the proper functioning of the human body, where it is also produced endogenously [3; 4]. The main source of endogenous CO in the human body is heme degradation, catalysed by by haemoxygenase (HO) (Figure 1). This enzyme breaks up porphyrin IX in the presence of NADP and molecular oxygen, resulting in the formation of various so-called primary degradation products (HDP): carbon monoxide, ferrous cations (Fe2+) and biliverdin IX [3; 4; 5].
3
(Fig. 1) Disintegration of heme [modified, 5].
The next stage in decay is catalysed by biliverdin reductase, which begins the reaction of biliverdin to the second-degree metabolite bilirubin in the presence of NADPH and H+. This bilirubin is then secreted into the bile and excreted in the urine. The colours of both biliverdin (green) and bilirubin (yellow) are well visible during the maturation of bruises, in which a change in skin colour can be seen with the degradation of heme. About 16 µmoles of carbon monoxide per hour are produced through the breakdown of heme in the human body [6]. HO exists in two major isoforms: HO-1 (induced) and HO-2 (constitutive). The gene for HO-1 is on chromosome 22, and HO-2 on chromosome 16. Although both HO isoforms act according to similar mechanisms, they differ in their methods of regulation. High expression of HO-1 occurs in the liver and spleen, where the enzyme participates in the
4
breakdown of erythrocytes and the removal of toxic heme from the body; however, oxidative stress may increase HO-1 production in other tissues, including the vascular endothelium and the brain. Therefore, HO-1 is included in the group of heat shock proteins (HSP). Under physiological conditions, HO-1 is not produced in the central nervous system; however, increased secretion has been observed in patients with chronic neurodegenerative diseases (Alzheimer's syndrome, Parkinson Dementia) [7]. In contrast, HO-2 is mainly produced in the brain, and its expression is commonly seen in neurons, glial cells and cerebral vessels. Pathophysiological disorders (hypoxia, epileptic seizures) do not increase the level of HO-2 production but increase its activity. While the gene responsible for HO-2 coding does not typically undergo transcriptional modulation, adrenal glucocorticosteroids have been found to induce HO-2 production. Finally, a third heme oxygenase isoform (HO-3) also exists in the human body. It has a primary structure similar to HO-2 in 90%, but does not show any enzymatic activity, and is believed to play a role in the function of heme binding in cells [7, 8].
3. Carbon monoxide donors CO has important signalling, antiapoptotic and anti-inflammatory effects; hence, pharmacological agents that can imitate its action may yield therapeutic benefits [4]. Such practical applications have been extensively studied by pharmacists and biochemists for many years. However, the basic problem associated with administering CO is that it exists in gaseous form at room temperature. Although inhalation would commonly result in toxic effects, devices have been invented that strictly control the concentration of inhaled CO and automate the level of its release. Despite this, the need to avoid the toxic effects of CO administration is not the only complicating aspect of inhalation therapy.
5
In 2002, a prodrug incorporating a transport vector, known as a CO-releasing molecule (CORM) was developed that could be used in carbon monoxide therapy. Although many organic compounds were initially considered as vectors for CO, haloalkans, aldehydes, oxalates and organic acids, for example, these substances were rejected due to their unfavourable toxicological profile. Alternatively, inorganic complex compounds in which CO binds to a metal could also serve as potential carbon monoxide transporters; this bond is fixed by the bonds between the d-metal orbits and the sp orbits of the CO. In addition, carbonyl group can be used, which offer the advantage that their binding strength can be modified with the appropriate ligands. Hence, CO donors exist, and can form the basis of a precise method for therapeutic CO administration [9]. Structurally, CORMs can be divided into a CORM sphere and a drug sphere. The CORM sphere determines the stoichiometric and pharmacokinetic properties of CO secretion. Using an appropriate selection of metal oxidation state and colligands, it is possible to target the supply of carbon monoxide to specific tissues. In further studies on the development of therapeutic carbon monoxide donors, it will be necessary to choose an appropriate drug sphere that will determine the pharmacological properties; this sphere will be dependent on the specific disease the donor will work on [10]. The release of CO from CORM can be initiated by various specific triggers. Therefore, it is important to identify the specific stimulus that will induce CO release when the molecule reaches its destination. The first such mechanism involves the exchange of ligands in the target tissue; however, as the CORM molecule is exposed to many potential ligands following administration, it is necessary to consider the half-life of the drug when determining the correct therapeutic concentration. One way of achieving successful delivery is by introducing the donor into the body in a polymeric hydrophobic carrier [11].
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Another way to release CO from the donor molecule is through the action of esterases and cellular phosphatases. Some CORMs are designed in such a way that carbon monoxide is released under the influence of enzymatic phosphorylation or esterification [12]. The disconnection of CO from the donor is also achievable through the action of physical stimuli; currently, the most promising such approach involves photochemical external activation by various wavelengths of light. Such CORMs are often called PhotoCORM, with one example being CORM-1. By replacing the ligand and creating a new bond, e.g. with sulphur, CORM-2 can be made to release CO spontaneously. The temperature of CO release may be equally important, especially in physiological conditions. CORM-3 has the ability to release CO through a combination of triggering factors such as thermal degradation and ligand replacement. Other triggers are also pH change and oxidation. The precise control of photolytic CO release could lead to the creation of convenient forms of local skin medications, which would be able to penetrate into the body under the influence of infrared radiation [13; 14]. As mentioned above, the half-life for the release of CO from CORM is also an important consideration when determining potential therapeutic applications. Ligand reactions with water, most often used as a solvent, take place immediately after being dissolved in buffer; under these conditions, the half-lives of individual molecules are too short and could prevent CORM from reaching target sites in the body. Hence, processes other than ligand exchange, typically with water serving as a solvent, have been investigated with regard to their potential to elicit CO release from metal carbonyl complexes [15]. CORM molecules are frequently tested to determine their appropriate concentrations for physiological use. Almost all are synthetic metal carbonyl complexes. Although it is very important to know the detailed mechanism of CO release, this is not well understood for most molecules. CO release is most commonly determined by the myoglobin test: CORM is added 7
to an aqueous solution containing deoxymoglobin (Mb) and sodium dithionite (Na2S2O4), which is used to reduce Fe (III) in oxymyoglobin to deoxymyoglobin. Carboxymoglobin formation is observed spectrophotometrically during the release of CO from the CORM as the intensity of the myoglobin absorption band decreases (556 nm) and the two carboxymoglobin absorption bands (Mb-CO) increase (541 nm, 578 nm). The myoglobin test should be carried out under physiological conditions (pH 7.4 and 37 °C). It is a simple method that can help track the amount of released CO over time, as well as calculate the half-life for the breakdown of the CO complex [16, 17]. However, this approach has some drawbacks, and it should be used in conjunction with other methods. The myoglobin test provides information on the total amount of CO released, but does not provide detailed information on reaction mechanisms. Another disadvantage is the myoglobin test should be performed in an anaerobic environment, therefore under physiological conditions the release of CO can be changed compared to anaerobic [18]. In the case of CORM-2 and CORM-3 molecules, sodium dithionite may induce CO release [16]. Klein et al. [18] indicate that the release of CO from CORM-2 is strongly dependent on sodium dithionate, and that CORM-S1 loses all its CO molecules after irradiation with light [18]. Other methods used to measure CO release from CORMs include fluorescence probes, gas chromatography, electrochemical detection and infrared gas phase spectroscopy. The first method is used to detect CO in lower concentrations than the myoglobin test; however neither test is suitable for short-term kinetic measurements due to their long response time, i.e. about one hour [19]. Direct CO detection can also be performed using gas chromatography, i.e. the GC-RGD reducing gas detector and GC-TCD thermal conductivity detector; however, this method is not suitable for continuous, long-term measurements, as in the case of GC-TCD, the samples must be taken from the reaction mixture or from the space above the liquid. 8
Electrochemical sensors can also be used to determine the CO concentration directly in the solution, as they do not require anaerobic conditions. Unfortunately, this method is only based on indirect measurements of CO release, and there is a lack of additional studies on the influence of this reaction on the kinetics of CO release. Finally, gaseous phase infrared spectroscopy can also be used for determining CO release, in both the gaseous phase and in solution; this method offers the advantage that no additives such as buffer or sodium dithionate
reducer
are
required
[14,19].
Tab 1. Chemical structures, properties and profile of CO release from different CORMs.
CO release PBS pH = 7.4 37° C
Solvent type
References
CORM-1 [Mn2(CO)10]
T½ < 1 min, Dependent on light 1mol CO/mol CORM
DMSO/ Ethanol
[20]
CORM-A1 [Na2H3BCO2]
T½ = 27.06 min pH 7.4 T½ = 2.02 min pH 5.5 Dependent on pH 1mol CO/mol CORM
H 2O
CORM-2 [Ru(CO)3Cl2]2
T½ < 2 min 0,75moles CO/mol CORM
DMSO/ Ethanol/ Methanol
CORM-3 [Ru(CO)3Clglicynian]
T½ ≈ 1 min 1mol CO/mol CORM
H 2O
CORMs
Chemical structures
9
[20; 21]
[18; 20]
[20; 21; 22]
CORM-S1 [Fe(CO)2(SCH2CH2 NH2)2]
T½ ≈ 25 min Dependent on light 2moles CO/mol CORM
H 2O
CORM-401 Mn(CO)4(S2CNMe CH2CO2H)
T½ ≈ 20 min 3moles CO/mol CORM
H 2O
[23; 24; 25]
CORM-F3 [C9H5BrFeO5]
T½ ≈ 55 min 0.25moles CO/mol CORM
DMSO/ Ethanol
[20; 26]
CORM-F7 [ƞ-4- (4-chloro-2pyrone) tricarbonyl iron (0)]
0.007moles CO/mol CORM
DMSO/ Ethanol
[27]
CORM-F8 [ƞ-4- (4-chloro-6methyl-2-pyrone) tricarbonyl iron (0)]
0.041moles CO/mol CORM
DMSO/ Ethanol
[27]
No release of CO
DMSO/ Ethanol
[27]
CORM-F11 [ƞ-4- (4-methyl-6methyl-2-pyrone) żelazo tricarbonyl iron (0)]
[18; 21]
4. Biological properties of CORM Carbon monoxide donors are best studied in vitro to determine their pro- and anticoagulation
activity.
Three CORMS
have been
studied:
CORM-2
(carbonyl
dichlorororutene (II) tricarbonyl dimer), CORM-3 (ruthenium (II) tricarbonyl dimer) and CORM-A1 (sodium borate). All three molecules demonstrated similar degrees of CO release: 0.75 mole CO per mole of CORM-2, and one mole CO per mole of CORM-3 and CORM-A1.
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These donors are also known to influence the blood coagulation process through the secretion of CO, since the inactive forms of these compounds do not themselves show hemostatic effects. CORM-2 [Ru(CO)3Cl2]2 and CORM-3 [Ru(CO)3Cl(glycinate)] were found to increase the intensity of blood coagulation, giving a similar scale effect on the rate of blood clot formation and strength of the thrombus. In contrast, CORM-A1 [Na2H3BCO2] did not affect blood coagulation, but demonstrated similar inhibitory effects on fibrinolysis [28]. CORM-2 is known to influence the ion-mineral balance of living organisms. It lowers the plasma concentration of vitamin D3 by modifying the transcription of the Cyp27b1 gene in the kidneys, which is responsible for coding 1-alpha-hydroxylase [29]. CORM-2 at concentration 50 μM, has been found to reduce the level of oxidative stress created in cells by significantly reducing the activity of NADPH oxidase [30]. Following activation by lipopolysaccharide, macrophages were found to quickly become oxidized and produce large amounts of reactive oxygen species; however, cells previously exposed to CORM-2 at a concentration of 50 µM for one hour were found to display significantly lower accumulation of ROS. A study of Adach and Olas [31] on the effect of CORM-2 on haemostasis and oxidative stress (by examining the levels of TBARS, carbonyl groups and thiol groups) found that longer incubation time (30 and 60 min) to be associated with a significant reduction in lipid peroxidation caused by hydroxyl radicals, and that CORM-2 exerted a protective effect depending on the concentration [31]. In addition, CORM-2 also demonstrated inhibitory effects on the growth of drugresistant bacterial strains. It is thought to act by providing high amounts of intracellular CO, thus inhibiting the respiratory processes of bacteria, or possibly by damaging bacterial DNA through the generation of free oxygen radicals [32]. Studies by Motterlini et al. have shown that CORM-2 can modulate vessel contractility ex vivo. At the doses used (5, 10 and 20 μmol/kg) CORM-2 elicited a rapid and
11
significant vasodilatation, after adding to rat aortic rings precontracted with phenylephrine. This effect was prolonged [16]. CORM-3 exhibits similar activities to CORM-2 including vasodilation, antiinflammatory and antibacterial effects; it also acts as an inhibitor of platelet aggregation and prevents rejection of organ transplants after heart transplantation. Of the three donors, CORM-3 is most sensitive to the medium in which it is dissolved, with its kinetics of CO release being highly dependent on factors such as the pH of the environment or the presence of CORM-3-binding amino acid chains in proteins such as lysozyme. In addition, the use of ruthenium compounds as chemotherapeutic agents suggest that the CORM-3 fragments may exert biological properties following CO separation [9; 33; 34]. Motterlini et al. [3] describe the pharmacological and biochemical activities of watersoluble CORM-A1, which, contrary to the prototype molecule CORM-3, does not contain a transition metal in its structure. Under physiological conditions, CORM-A1 releases CO depending on the pH of the environment and temperature. Its half-life at 37°C and pH 7.4 is approximately 27 minutes. CORM-A1 (80 µM) has also been demonstrated to have vasodilative properties: following exposure to CORM-A1, shrunken aortic rings were observed to slowly, but significantly, relax. The maximal relaxation mediated by CORM-A1 was reached after 30 min. CORM-A1 is characterized by much slower release of CO to the environment, and it is believed that this distribution model may closer reflect the action of natural haemic oxygenase [3]. CORM-401 is a CO releasing molecule sensitive to oxidation. CORM-401 has been found to be more effective than other CORMs under conditions of oxidative stress induced by H2O2. CORM-401 released up to three moles of CO/mole of the compound depending on the concentration of the acceptor myoglobin; this level of release can be increased in the presence of oxidants such as H2O2, tert-butyl hydroperoxide or hypochlorous acid. CORM-401 also 12
relaxed pre-contracted aortic rings, and this process was intensified in the presence of H2O2 [25]. Like CORM-F3, CORM-1 (Manganese decacarbonyl, Mn2CO10) also contains manganese. It has the ability to release CO in a biological environment under appropriate conditions: an external light pulse is required. It is soluble only in organic solvents [20; 35]. CORM-S1 possesses two CO molecules associated with its iron core in the cis positions and two cysteamine bases in the trans positions. CORM-S1 is easy to prepare and dissolves well in water. This compound is broadly stable in the dark, with CO being released when exposed to visible light. Physiological tests show that CORM-S1 activates CO-sensitive ionic channels depending on light and time of decomposition, without any adverse effects at the cellular level [18; 21]. An important consideration associated with CO donor therapy concerns the biological properties of compounds related to the CO molecule. These reaction products, called inactivated CORM (iCORMs), are rarely subject to independent biological testing. Therefore, it is difficult to determine whether the characteristic biological effect of a given CORM is conditioned by the action of the released CO, or by the structure of the carrier itself [9]. Over the last few years, a wide range of CO-releasing compounds has been developed to optimise the therapeutic doses of CO donors. They exhibit various therapeutic activities in different concentrations (0.1 – 500 µM): they have been found to prevent vascular dysfunction, and to have anti-inflammatory, anticoagulant and anti-cancer effects. Their range of effects is strongly reliant on their kinetics of CO release, the combination of ligands with metals or their chemical structure. Some CORM molecules are poorly soluble in water and require organic solvents, which may prevent their biomedical application. It is evident that promising biological and pharmacological activities of various CORMs must be appropriately
13
confirmed not only in in vitro but also in in vivo. Further and more detailed biological studies on CO-releasing molecules are still awaited.
References:
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17
•
CO is an inorganic chemical compound that can bind with hemoglobin.
•
It is produced endogenously during the degradation of heme by oxygenase.
•
CO can play an important role in the regulation of many physiological functions.
•
CORMs are group of chemical compounds capable of controlled CO.
Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
Beata Olas Weronika Adach Mateusz Blaszczyk
S0009-2797(19)31520-0
DOI:
https://doi.org/10.1016/j.cbi.2020.108973
Reference:
CBI 108973
To appear in:
Chemico-Biological Interactions
Received Date: 6 September 2019 Revised Date:
17 January 2020
Accepted Date: 31 January 2020
Please cite this article as: W. Adach, M. Błaszczyk, B. Olas, Carbon monoxide and its donors Chemical and biological properties, Chemico-Biological Interactions (2020), doi: https://doi.org/10.1016/ j.cbi.2020.108973. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier B.V.
Carbon monoxide and its donors - chemical and biological properties
Weronika Adach, Mateusz Błaszczyk, Beata Olas* Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
*Corresponding author: Prof. Beata Olas, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland. Email: [email protected], Tel: +48 42 635 44 84
1
Abstract Carbon monoxide (CO) is an inorganic chemical compound that can bind with hemoglobin with highly toxic effects. In living organisms, it is produced endogenously during the degradation of heme by oxygenase, which occurs in three isoforms: HO-1, HO-2 and HO3. CO can play an important role in the regulation of many physiological functions. Carbon Oxide Releasing Molecules (CORMs) are a novel group of chemical compounds capable of controlled CO release directly in tissues or organs. This release depends on concentration, pH, solvent type and temperature. The biological role and the therapeutic potential of different CORMs is not always well demonstrated. However, this mini review summarizes the various function of these compounds.
Key words: carbon monoxide, CORM, chemical, biological properties
2
1. Chemical and biological properties Carbon monoxide (CO) is a colourless, odourless gas that is flammable and lighter than air. Although increasing amounts of CO are currently entering the atmosphere as a result of the development of civilization, it has always been present, mainly as a result of volcanic activity. Unfortunately, due to the wide diversity of natural sources of atmospheric CO, it is not possible to make an accurate estimation of its total emission rates. In urban areas, high concentrations of inhaled CO can have a negative impact on the health of residents. It is often formed as a result of incomplete combustion of carboncontaining compounds, primarily in internal combustion engines. It can also be stored and transported in a compressed form, and prolonged contact with fire or high temperature can lead to the explosion of containers [1]. CO is a highly toxic compound and inhalation of larger amounts commonly leads to pathologies of the central nervous system and the cardiovascular system. The intensity of symptoms is dependent on the dose of inhaled CO, and ranges from slight headaches to rapid death: concentrations above 1000 ppm are considered to be life threatening [2]. 2. Endogenous formation of carbon monoxide Despite the toxic effects on the nervous system and the cardiovascular system, carbon monoxide also plays an important role in the proper functioning of the human body, where it is also produced endogenously [3; 4]. The main source of endogenous CO in the human body is heme degradation, catalysed by by haemoxygenase (HO) (Figure 1). This enzyme breaks up porphyrin IX in the presence of NADP and molecular oxygen, resulting in the formation of various so-called primary degradation products (HDP): carbon monoxide, ferrous cations (Fe2+) and biliverdin IX [3; 4; 5].
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(Fig. 1) Disintegration of heme [modified, 5].
The next stage in decay is catalysed by biliverdin reductase, which begins the reaction of biliverdin to the second-degree metabolite bilirubin in the presence of NADPH and H+. This bilirubin is then secreted into the bile and excreted in the urine. The colours of both biliverdin (green) and bilirubin (yellow) are well visible during the maturation of bruises, in which a change in skin colour can be seen with the degradation of heme. About 16 µmoles of carbon monoxide per hour are produced through the breakdown of heme in the human body [6]. HO exists in two major isoforms: HO-1 (induced) and HO-2 (constitutive). The gene for HO-1 is on chromosome 22, and HO-2 on chromosome 16. Although both HO isoforms act according to similar mechanisms, they differ in their methods of regulation. High expression of HO-1 occurs in the liver and spleen, where the enzyme participates in the
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breakdown of erythrocytes and the removal of toxic heme from the body; however, oxidative stress may increase HO-1 production in other tissues, including the vascular endothelium and the brain. Therefore, HO-1 is included in the group of heat shock proteins (HSP). Under physiological conditions, HO-1 is not produced in the central nervous system; however, increased secretion has been observed in patients with chronic neurodegenerative diseases (Alzheimer's syndrome, Parkinson Dementia) [7]. In contrast, HO-2 is mainly produced in the brain, and its expression is commonly seen in neurons, glial cells and cerebral vessels. Pathophysiological disorders (hypoxia, epileptic seizures) do not increase the level of HO-2 production but increase its activity. While the gene responsible for HO-2 coding does not typically undergo transcriptional modulation, adrenal glucocorticosteroids have been found to induce HO-2 production. Finally, a third heme oxygenase isoform (HO-3) also exists in the human body. It has a primary structure similar to HO-2 in 90%, but does not show any enzymatic activity, and is believed to play a role in the function of heme binding in cells [7, 8].
3. Carbon monoxide donors CO has important signalling, antiapoptotic and anti-inflammatory effects; hence, pharmacological agents that can imitate its action may yield therapeutic benefits [4]. Such practical applications have been extensively studied by pharmacists and biochemists for many years. However, the basic problem associated with administering CO is that it exists in gaseous form at room temperature. Although inhalation would commonly result in toxic effects, devices have been invented that strictly control the concentration of inhaled CO and automate the level of its release. Despite this, the need to avoid the toxic effects of CO administration is not the only complicating aspect of inhalation therapy.
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In 2002, a prodrug incorporating a transport vector, known as a CO-releasing molecule (CORM) was developed that could be used in carbon monoxide therapy. Although many organic compounds were initially considered as vectors for CO, haloalkans, aldehydes, oxalates and organic acids, for example, these substances were rejected due to their unfavourable toxicological profile. Alternatively, inorganic complex compounds in which CO binds to a metal could also serve as potential carbon monoxide transporters; this bond is fixed by the bonds between the d-metal orbits and the sp orbits of the CO. In addition, carbonyl group can be used, which offer the advantage that their binding strength can be modified with the appropriate ligands. Hence, CO donors exist, and can form the basis of a precise method for therapeutic CO administration [9]. Structurally, CORMs can be divided into a CORM sphere and a drug sphere. The CORM sphere determines the stoichiometric and pharmacokinetic properties of CO secretion. Using an appropriate selection of metal oxidation state and colligands, it is possible to target the supply of carbon monoxide to specific tissues. In further studies on the development of therapeutic carbon monoxide donors, it will be necessary to choose an appropriate drug sphere that will determine the pharmacological properties; this sphere will be dependent on the specific disease the donor will work on [10]. The release of CO from CORM can be initiated by various specific triggers. Therefore, it is important to identify the specific stimulus that will induce CO release when the molecule reaches its destination. The first such mechanism involves the exchange of ligands in the target tissue; however, as the CORM molecule is exposed to many potential ligands following administration, it is necessary to consider the half-life of the drug when determining the correct therapeutic concentration. One way of achieving successful delivery is by introducing the donor into the body in a polymeric hydrophobic carrier [11].
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Another way to release CO from the donor molecule is through the action of esterases and cellular phosphatases. Some CORMs are designed in such a way that carbon monoxide is released under the influence of enzymatic phosphorylation or esterification [12]. The disconnection of CO from the donor is also achievable through the action of physical stimuli; currently, the most promising such approach involves photochemical external activation by various wavelengths of light. Such CORMs are often called PhotoCORM, with one example being CORM-1. By replacing the ligand and creating a new bond, e.g. with sulphur, CORM-2 can be made to release CO spontaneously. The temperature of CO release may be equally important, especially in physiological conditions. CORM-3 has the ability to release CO through a combination of triggering factors such as thermal degradation and ligand replacement. Other triggers are also pH change and oxidation. The precise control of photolytic CO release could lead to the creation of convenient forms of local skin medications, which would be able to penetrate into the body under the influence of infrared radiation [13; 14]. As mentioned above, the half-life for the release of CO from CORM is also an important consideration when determining potential therapeutic applications. Ligand reactions with water, most often used as a solvent, take place immediately after being dissolved in buffer; under these conditions, the half-lives of individual molecules are too short and could prevent CORM from reaching target sites in the body. Hence, processes other than ligand exchange, typically with water serving as a solvent, have been investigated with regard to their potential to elicit CO release from metal carbonyl complexes [15]. CORM molecules are frequently tested to determine their appropriate concentrations for physiological use. Almost all are synthetic metal carbonyl complexes. Although it is very important to know the detailed mechanism of CO release, this is not well understood for most molecules. CO release is most commonly determined by the myoglobin test: CORM is added 7
to an aqueous solution containing deoxymoglobin (Mb) and sodium dithionite (Na2S2O4), which is used to reduce Fe (III) in oxymyoglobin to deoxymyoglobin. Carboxymoglobin formation is observed spectrophotometrically during the release of CO from the CORM as the intensity of the myoglobin absorption band decreases (556 nm) and the two carboxymoglobin absorption bands (Mb-CO) increase (541 nm, 578 nm). The myoglobin test should be carried out under physiological conditions (pH 7.4 and 37 °C). It is a simple method that can help track the amount of released CO over time, as well as calculate the half-life for the breakdown of the CO complex [16, 17]. However, this approach has some drawbacks, and it should be used in conjunction with other methods. The myoglobin test provides information on the total amount of CO released, but does not provide detailed information on reaction mechanisms. Another disadvantage is the myoglobin test should be performed in an anaerobic environment, therefore under physiological conditions the release of CO can be changed compared to anaerobic [18]. In the case of CORM-2 and CORM-3 molecules, sodium dithionite may induce CO release [16]. Klein et al. [18] indicate that the release of CO from CORM-2 is strongly dependent on sodium dithionate, and that CORM-S1 loses all its CO molecules after irradiation with light [18]. Other methods used to measure CO release from CORMs include fluorescence probes, gas chromatography, electrochemical detection and infrared gas phase spectroscopy. The first method is used to detect CO in lower concentrations than the myoglobin test; however neither test is suitable for short-term kinetic measurements due to their long response time, i.e. about one hour [19]. Direct CO detection can also be performed using gas chromatography, i.e. the GC-RGD reducing gas detector and GC-TCD thermal conductivity detector; however, this method is not suitable for continuous, long-term measurements, as in the case of GC-TCD, the samples must be taken from the reaction mixture or from the space above the liquid. 8
Electrochemical sensors can also be used to determine the CO concentration directly in the solution, as they do not require anaerobic conditions. Unfortunately, this method is only based on indirect measurements of CO release, and there is a lack of additional studies on the influence of this reaction on the kinetics of CO release. Finally, gaseous phase infrared spectroscopy can also be used for determining CO release, in both the gaseous phase and in solution; this method offers the advantage that no additives such as buffer or sodium dithionate
reducer
are
required
[14,19].
Tab 1. Chemical structures, properties and profile of CO release from different CORMs.
CO release PBS pH = 7.4 37° C
Solvent type
References
CORM-1 [Mn2(CO)10]
T½ < 1 min, Dependent on light 1mol CO/mol CORM
DMSO/ Ethanol
[20]
CORM-A1 [Na2H3BCO2]
T½ = 27.06 min pH 7.4 T½ = 2.02 min pH 5.5 Dependent on pH 1mol CO/mol CORM
H 2O
CORM-2 [Ru(CO)3Cl2]2
T½ < 2 min 0,75moles CO/mol CORM
DMSO/ Ethanol/ Methanol
CORM-3 [Ru(CO)3Clglicynian]
T½ ≈ 1 min 1mol CO/mol CORM
H 2O
CORMs
Chemical structures
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[20; 21]
[18; 20]
[20; 21; 22]
CORM-S1 [Fe(CO)2(SCH2CH2 NH2)2]
T½ ≈ 25 min Dependent on light 2moles CO/mol CORM
H 2O
CORM-401 Mn(CO)4(S2CNMe CH2CO2H)
T½ ≈ 20 min 3moles CO/mol CORM
H 2O
[23; 24; 25]
CORM-F3 [C9H5BrFeO5]
T½ ≈ 55 min 0.25moles CO/mol CORM
DMSO/ Ethanol
[20; 26]
CORM-F7 [ƞ-4- (4-chloro-2pyrone) tricarbonyl iron (0)]
0.007moles CO/mol CORM
DMSO/ Ethanol
[27]
CORM-F8 [ƞ-4- (4-chloro-6methyl-2-pyrone) tricarbonyl iron (0)]
0.041moles CO/mol CORM
DMSO/ Ethanol
[27]
No release of CO
DMSO/ Ethanol
[27]
CORM-F11 [ƞ-4- (4-methyl-6methyl-2-pyrone) żelazo tricarbonyl iron (0)]
[18; 21]
4. Biological properties of CORM Carbon monoxide donors are best studied in vitro to determine their pro- and anticoagulation
activity.
Three CORMS
have been
studied:
CORM-2
(carbonyl
dichlorororutene (II) tricarbonyl dimer), CORM-3 (ruthenium (II) tricarbonyl dimer) and CORM-A1 (sodium borate). All three molecules demonstrated similar degrees of CO release: 0.75 mole CO per mole of CORM-2, and one mole CO per mole of CORM-3 and CORM-A1.
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These donors are also known to influence the blood coagulation process through the secretion of CO, since the inactive forms of these compounds do not themselves show hemostatic effects. CORM-2 [Ru(CO)3Cl2]2 and CORM-3 [Ru(CO)3Cl(glycinate)] were found to increase the intensity of blood coagulation, giving a similar scale effect on the rate of blood clot formation and strength of the thrombus. In contrast, CORM-A1 [Na2H3BCO2] did not affect blood coagulation, but demonstrated similar inhibitory effects on fibrinolysis [28]. CORM-2 is known to influence the ion-mineral balance of living organisms. It lowers the plasma concentration of vitamin D3 by modifying the transcription of the Cyp27b1 gene in the kidneys, which is responsible for coding 1-alpha-hydroxylase [29]. CORM-2 at concentration 50 μM, has been found to reduce the level of oxidative stress created in cells by significantly reducing the activity of NADPH oxidase [30]. Following activation by lipopolysaccharide, macrophages were found to quickly become oxidized and produce large amounts of reactive oxygen species; however, cells previously exposed to CORM-2 at a concentration of 50 µM for one hour were found to display significantly lower accumulation of ROS. A study of Adach and Olas [31] on the effect of CORM-2 on haemostasis and oxidative stress (by examining the levels of TBARS, carbonyl groups and thiol groups) found that longer incubation time (30 and 60 min) to be associated with a significant reduction in lipid peroxidation caused by hydroxyl radicals, and that CORM-2 exerted a protective effect depending on the concentration [31]. In addition, CORM-2 also demonstrated inhibitory effects on the growth of drugresistant bacterial strains. It is thought to act by providing high amounts of intracellular CO, thus inhibiting the respiratory processes of bacteria, or possibly by damaging bacterial DNA through the generation of free oxygen radicals [32]. Studies by Motterlini et al. have shown that CORM-2 can modulate vessel contractility ex vivo. At the doses used (5, 10 and 20 μmol/kg) CORM-2 elicited a rapid and
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significant vasodilatation, after adding to rat aortic rings precontracted with phenylephrine. This effect was prolonged [16]. CORM-3 exhibits similar activities to CORM-2 including vasodilation, antiinflammatory and antibacterial effects; it also acts as an inhibitor of platelet aggregation and prevents rejection of organ transplants after heart transplantation. Of the three donors, CORM-3 is most sensitive to the medium in which it is dissolved, with its kinetics of CO release being highly dependent on factors such as the pH of the environment or the presence of CORM-3-binding amino acid chains in proteins such as lysozyme. In addition, the use of ruthenium compounds as chemotherapeutic agents suggest that the CORM-3 fragments may exert biological properties following CO separation [9; 33; 34]. Motterlini et al. [3] describe the pharmacological and biochemical activities of watersoluble CORM-A1, which, contrary to the prototype molecule CORM-3, does not contain a transition metal in its structure. Under physiological conditions, CORM-A1 releases CO depending on the pH of the environment and temperature. Its half-life at 37°C and pH 7.4 is approximately 27 minutes. CORM-A1 (80 µM) has also been demonstrated to have vasodilative properties: following exposure to CORM-A1, shrunken aortic rings were observed to slowly, but significantly, relax. The maximal relaxation mediated by CORM-A1 was reached after 30 min. CORM-A1 is characterized by much slower release of CO to the environment, and it is believed that this distribution model may closer reflect the action of natural haemic oxygenase [3]. CORM-401 is a CO releasing molecule sensitive to oxidation. CORM-401 has been found to be more effective than other CORMs under conditions of oxidative stress induced by H2O2. CORM-401 released up to three moles of CO/mole of the compound depending on the concentration of the acceptor myoglobin; this level of release can be increased in the presence of oxidants such as H2O2, tert-butyl hydroperoxide or hypochlorous acid. CORM-401 also 12
relaxed pre-contracted aortic rings, and this process was intensified in the presence of H2O2 [25]. Like CORM-F3, CORM-1 (Manganese decacarbonyl, Mn2CO10) also contains manganese. It has the ability to release CO in a biological environment under appropriate conditions: an external light pulse is required. It is soluble only in organic solvents [20; 35]. CORM-S1 possesses two CO molecules associated with its iron core in the cis positions and two cysteamine bases in the trans positions. CORM-S1 is easy to prepare and dissolves well in water. This compound is broadly stable in the dark, with CO being released when exposed to visible light. Physiological tests show that CORM-S1 activates CO-sensitive ionic channels depending on light and time of decomposition, without any adverse effects at the cellular level [18; 21]. An important consideration associated with CO donor therapy concerns the biological properties of compounds related to the CO molecule. These reaction products, called inactivated CORM (iCORMs), are rarely subject to independent biological testing. Therefore, it is difficult to determine whether the characteristic biological effect of a given CORM is conditioned by the action of the released CO, or by the structure of the carrier itself [9]. Over the last few years, a wide range of CO-releasing compounds has been developed to optimise the therapeutic doses of CO donors. They exhibit various therapeutic activities in different concentrations (0.1 – 500 µM): they have been found to prevent vascular dysfunction, and to have anti-inflammatory, anticoagulant and anti-cancer effects. Their range of effects is strongly reliant on their kinetics of CO release, the combination of ligands with metals or their chemical structure. Some CORM molecules are poorly soluble in water and require organic solvents, which may prevent their biomedical application. It is evident that promising biological and pharmacological activities of various CORMs must be appropriately
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confirmed not only in in vitro but also in in vivo. Further and more detailed biological studies on CO-releasing molecules are still awaited.
References:
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•
CO is an inorganic chemical compound that can bind with hemoglobin.
•
It is produced endogenously during the degradation of heme by oxygenase.
•
CO can play an important role in the regulation of many physiological functions.
•
CORMs are group of chemical compounds capable of controlled CO.
Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
Beata Olas Weronika Adach Mateusz Blaszczyk