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Metal Carbonyls A New Class of Pharmaceuticals.

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Metal Carbonyls in Medicine
Metal Carbonyl Pharmaceuticals
Metal Carbonyls: A New Class of Pharmaceuticals?**
Tony R. Johnson, Brian E. Mann,* James E. Clark, Roberta Foresti, Colin J. Green,
and Roberto Motterlini*
Keywords:
bioinorganic chemistry · carbon monoxide ·
cardiovascular agents · drug design ·
medicinal chemistry
I
t is now established that NO is a messenger molecule in mammals
despite its high toxicity. As NO+ and CO are isoelectronic, it should
not be unexpected that CO could also have a role as a messenger. CO is
produced naturally in humans at a rate of between 3 and 6 cm3 per day,
and this rate is increased markedly by certain inflammatory states and
pathological conditions associated with red blood cell hemolysis. Over
the last 10 years, the interest in the biological effects of CO has greatly
increased, and it is now established in the medical literature that CO
does have a major role as a signaling molecule in mammals. It is
particularly active within the cardiovascular system, for example, in
suppressing organ graft rejection and protecting tissues from ischemic
injury and apoptosis. Recently it has been shown that metal carbonyls
can also function as CO-releasing molecules and provide similar
biological activities. This opens the possibility to develop
pharmaceutically important metal carbonyls.
1. Introduction
Carbon monoxide (CO) is a colorless, odorless, tasteless,
noncorrosive gas of about the same density as air, and is the
most commonly encountered and pervasive poison in our
environment.[1] Paradoxically, more than half a century ago, it
was found that CO is constantly formed in humans in small
quantities,[2] and that under certain pathophysiological conditions this endogenous production of CO may be considerably increased.[3] The discovery that hemoglobin, a heme[*] Prof. B. E. Mann, T. R. Johnson
Department of Chemistry
The University of Sheffield
Sheffield, S3 7HF (UK)
Fax: (44) 114-2738673
E-mail: b.mann@sheffield.ac.uk
Dr. R. Motterlini, J. E. Clark, R. Foresti, Prof. C. J. Green
Department of Surgical Research
Northwick Park Institute for Medical Research
Harrow, Middlesex, HA1 3UJ (UK)
Fax: (+ 44) 208-8693270
E-mail: r.motterlini@ic.ac.uk
2. Sources of CO in the Human Body
[**] We wish to thank MRC, British Heart Foundation, Dunhill Medical
Trust, Northwick Park Institute for Medical Research, and the
University of Sheffield for financial support.
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dependent protein, is required as a
substrate for the production of CO
in vivo,[4] and the identification of the
enzyme heme oxygenase as the crucial
pathway for the generation of this
gaseous compound in mammals,[5] set
the basis for the early investigation of
an unexpected role of CO in the
vasculature.[6] The succeeding cloning,[7] and characterization
of constitutive (HO-2) and inducible (HO-1) isoforms of
heme oxygenase,[8] as well as studies on the kinetics and tissue
distribution of these enzymes,[9] started to reveal a major
importance of this pathway in the physiological degradation
of heme; that is, the end products of heme degradation (CO,
biliverdin and bilirubin) might possess, after all, crucial
biological activities.[10] This has led many research groups to
examine the role of CO. A book describing the role of carbon
monoxide in cardiovascular functions has been published,[11]
and the role of CO as a signaling molecule has been
reviewed.[12]
The role of CO in life may date from the prehistoric
environments that were rich in CO,[13] and may be linked to
biological pathways that developed during the origins of life.
It has been recently proposed that CO made a significant
contribution to the synthesis of the first amino and nucleic
acids.[14]
The major source of CO (86 %) in the human body arises
from the oxidation of heme, catalyzed by heme oxygenase,[15]
which was discovered in 1969.[16] The first step is the
DOI: 10.1002/anie.200301634
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B. E. Mann, R. Motterlini et al.
Scheme 1. Reaction intermediates in the heme oxygenase-catalyzed oxidation of heme to biliverdin.[17]
production
of
biliverdin
(Scheme 1).[17] Biliverdin (1) is normally reduced to bilirubin (2) by
biliverdin reductase and is excreted
after conjugation with glucuronic
acid.[18]
The action of heme oxygenase is
commonly observed in bruises. During the injury causing the bruise,
hemoglobin is liberated from lysed red blood cells leading
to a dark red/purple area under the skin, which is associated
with deoxygenated hemoglobin. Heme oxygenase in the
vascular tissue then oxidizes the heme released from hemoglobin to biliverdin with the liberation of CO and iron ions.
This has several obvious results: In the extravascular space,
oxygen is consumed to give blue oxygen-free hemoglobin, and
a green color, indicating the presence of biliverdin, appears in
the underlying tissues. The reduction of biliverdin to bilirubin
produces a yellow coloration, which then gradually fades
(Figure 1). Some of the CO that is produced binds to the iron
Brian E. Mann graduated from Oxford (BA
(1965), MA, DPhil (1968, all in Chemistry),
DSc (1989)) and was at the University of
Leeds (1968–1973) before moving to the
University of Sheffield. He is the author or
co-author of over 200 publications and three
books. He has been a visiting Professor at
eight universities. He ran the EPSRC HighField NMR Service in Sheffield, 1980–1986.
Angew. Chem. Int. Ed. 2003, 42, 3722 – 3729
Figure 1. The changes in the appearance of a bruise with time. The
pictures are of the thigh of an inline hockey player taken at various
times after being hit by the puck. a) 12 h, showing the red and purple
of heme; b) 2 days, showing green tinges because of the formation
of biliverdin; c) 5 days showing yellow coloration resulting from the
formation of bilirubin; d) 10 days, showing some residual bilirubin.
The bright red color in (d) results from carboxyhemoglobin. Taken
from LondonSkaters.com with permission.
center of hemoglobin to produce the bright-red carboxyhemoglobin that is very apparent in Figure 1 d.
The remaining 14 % of the generated CO comes from a
mixture of sources, including photo-oxidation, lipid peroxidation, xenobiotics, and bacteria.[15]
The basal production of CO in the human body is
approximately 20 mmol h1 under normal conditions; the
majority of this originates from the turnover of the heme
molecule and the degradation of heme-dependent proteins
such as hemoglobin and myoglobin.[10] However, under stress
conditions, the inducible isoform of heme oxygenase (HO-1),
which is ubiquitously distributed in mammalian tissues, can be
highly up-regulated leading to a significant increase in
endogenously generated CO.[19] It is, therefore, not surprising
that elevated CO levels can be detected in the breath of
humans and can now be used as an indication of medical
Roberto Motterlini is Head of the Vascular
Biology Unit at Northwick Park Institute for
Medical Research and an Honorary Senior
Lecturer at University College London. He
obtained his doctoral degree in Biological
Science from the University of Milan (1986)
and was a Visiting Research Fellow at the
University of California, San Diego (1991–
1995). He has published several scientific
papers on the biological role of heme oxygenase and its metabolites (carbon monoxide and bilirubin) in the control of
cardiovascular function. He is a Fellow of
the American Heart Association as well as a member of the American
Society for Biochemistry and Molecular Biology.
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Metal Carbonyls in Medicine
conditions. The levels of the gas correlate with the severity of
a number of disease states,[20] such as asthma,[21] bronchiectasis,[22] cystic fibrosis,[23] diabetes,[24] and rhinitis.[25] The
increased production of CO as a result of HO-1 induction
during pathophysiological states must be viewed as the
intrinsic capacity of the body to respond to stressful situations,
as HO-1 is now regarded as the most sensitive inducible
protein possessing cytoprotective and regulatory functions.[26]
3. Roles of Heme Oxygenase-1 (HO-1)
There have been extensive studies of the beneficial effects
of HO-1.[27] These range over a wide variety of diseases and
physiological functions including pulmonary, cardiovascular,
renal, and neurological diseases. Research is centering on the
breakdown products of heme, namely biliverdin, bilirubin,
iron ions, and CO. The iron ions liberated during heme
catabolism are promptly bound to ferritin. Except for the iron
ions, all the products of heme degradation have an antioxidant and/or signaling function.[26] There are two approaches
to exploit the beneficial role of heme oxygenase in medicine:
The first method has been to induce and up-regulate HO-1
protein levels in tissues. The second approach is to deliver
compounds which provide the breakdown products. In this
review, some of the beneficial applications of CO are
examined.
4. Medical Investigations of Beneficial Applications
of CO Gas
The story of the investigations of the physiological
function of CO began in the early 1990's and has predominantly involved the use of CO gas, although CH2Cl2 is also
used as a precursor. In addition there is a substantial number
of papers where heme oxygenase-1 has been induced to
produce CO.
The recognition that CO possesses vasodilatory properties[28] is, perhaps, the most significant evidence in favor of a
pharmacological function of CO. Although the molecular
mechanisms and the chemical modifications that are required
to transduce the signals mediated by CO into a specific
biological effect need to be fully elucidated, convincing
scientific reports have recently highlighted the signaling
properties of endogenously generated CO.[29] There are now
a wide range of documented physiological effects of CO:
1. It is anti-inflammatory.
a) It attenuates endotoxic shock: Mice pre-exposed to
CO gas followed by administration with lipopolysaccharide (LPS) displayed significantly less tumor
necrosis factor-a levels in plasma and increased
production of IL-10, a protective or anti-inflammatory cytokine.[30]
b) It reduces allergic inflammation: CO gas administered to allergen-challenged mice blocks eosinophil
efflux and IL-5 production.[31]
2. Organ graft rejection is suppressed by CO: A model of
mouse-to-rat cardiac transplantation was performed.
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Rats were exposed to 400 ppm of CO gas for only 2 days
following transplant and the graft survived for 50 days. In
comparison, the control exposed to air survived only 5 to
7 days.[32]
3. It protects against hyperoxia: Pre-exposure of a rat to CO
gas protected its lung from oxidative injury.[33]
4. It protects against ischemia: CO gas has been used
recently to prevent ischemia/reperfusion injury in the
liver.[34]
5. CO gas has been used to protect pancreatic beta cells
from apoptosis.[35]
6. Leydig cells appear to use HO-1-derived CO to trigger
apoptosis of premeiotic germ cells and thereby modulate
spermatogenesis under conditions of stress.[36]
7. CO decreases perfusion pressure in isolated human
placenta.[37]
8. CO has been shown to protect against septic shock and
lung injury in animal models, and the mitogen-activated
protein kinase system appears to mediate this cytoprotective effect.[38]
9. It modulates vascular smooth muscle tone.[19, 39]
10. It regulates blood pressure under stress conditions.[19]
11. Carbon monoxide suppresses arteriosclerotic lesions
associated with chronic graft rejection and with balloon
injury.[40]
The scientific investigations of the role of CO in the body
are still at an early stage. There is research that suggests that it
may be significant in a number of other areas of medicine
including transplant surgery, neuroprotection in strokes and
Alzheimer's disease,[41] and ovulation.[42] Endogenous CO and
bilirubin may have important roles in the control of placental
vascular function.[43]
As a result of the beneficial role of CO in the body, three
patent applications have recently appeared. One describes
the application of CO gas in medicine.[44] A second covers
both CO gas and the use of CH2Cl2.[45] The CH2Cl2 is
metabolized to CO and thus provides a source of the gas. The
third patent uses metal carbonyls as the source of the CO
gas.[46]
5. Medical Investigations of the Beneficial
Applications of CO-Releasing Metal Carbonyls
The investigation of applications of metal carbonyls as
CO-releasing molecules (CO-RMs) is in its infancy. A paper
has appeared reporting the use of [Fe(CO)5], [Mn2(CO)10],
and [{RuCl2(CO)3}2] to act as CO-RMs.[47] In the cases of
[Fe(CO)5] and [Mn2(CO)10], photolysis was necessary to
release CO, but in the case of [{RuCl2(CO)3}2], which
dissolved in DMSO, CO was released directly to myoglobin
(Mb) to form CO-Mb. Further tests were performed and it
was shown that CO-RMs:
1. Caused vasodilation of pre-contracted rat aortic rings.
2. Attenuated coronary vasoconstriction in hearts ex vivo.
3. Significantly reduced acute hypertension in vivo.
Recently a patent has been published which gives further
developments in this work.[46] A wide range of {RuII(CO)3}
complexes were shown to readily liberate one equivalent of
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B. E. Mann, R. Motterlini et al.
CO in the presence of myoglobin and cause vasodilation in
precontracted rat aortic rings. A number of FeII carbonyls
were also shown to be active.
[Ru(CO)3Cl(glycinate)] was selected for further study. It
releases CO rapidly when placed in a solution containing
myoglobin and can be viewed as a rapid source of CO giving
up one equivalent of CO within 5 min of mixing. Several
medical applications of [Ru(CO)3Cl(glycinate)] were examined:
1. Ischemia was induced in an isolated rat heart by stopping
the fluid supply for 30 min. When the fluid supply was
restarted there was about 50 % damage to the heart in the
absence of [Ru(CO)3Cl(glycinate)] and no damage in its
presence.
2. Heart transplantation was performed on mice. In the
absence of [Ru(CO)3Cl(glycinate)] all the mice died
within 8 days. In its presence, 40 % of the mice were still
alive after 50 days.
3. Blood platelet aggregation is partially inhibited by
[Ru(CO)3Cl(glycinate)].
4. Macrophages pretreated with [Ru(CO)3Cl(glycinate)]
followed by a challenge with LPS displayed significantly
less NO production compared to LPS-treated macrophages.
[Fe(bpy)(SPh)2(CO)2] is remarkable among the compounds so far examined. It does not release CO to myoglobin,
but it does cause vasodilation. It would therefore appear that
the CO is liberated within the cell in this case and raises the
possibility of targeting tissues with metal carbonyls.
It is still early in the investigation of metal carbonyls as
pharmaceuticals, but work on CO gas has shown the
important role of CO in biology and these investigations of
metal carbonyls have shown that there is a future for their use
as a solid form of carbon monoxide. Their role may be
enhanced by the presence of the metal. In humans, most of the
CO is produced by the heme oxygenase enzymes that also
produce iron ions. The iron ions could also be required for
activity. Metal carbonyls are capable of providing both the
CO and the metal ions.
6. Target Sites of CO in Mammals
Although there is strong evidence for the mechanism of
action of NO, research into the mechanism of action of CO is
in a much earlier state. Several targets for CO gas have been
identified: guanylyl cyclase,[48] p38 mitogen-activated protein
kinase,[30] and p51. However, what then happens is a matter of
speculation.
6.1. Soluble Guanylyl Cyclase
The soluble guanylyl cyclase system (sGC) has been
extensively investigated as it is an active site for the action of
NO.[49] Guanylyl cyclase catalyses the conversion of guanosine
5’-triphosphate to cyclic guanosine 3’,5’-monophosphate
(Scheme 2).
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Scheme 2. The guanylyl cyclase-catalyzed conversion of guanosine 5’triphosphate to cyclic guanosine 3’,5’-monophosphate.
The target for NO is probably the heme, and it is generally
assumed that this is also the target for CO. This is the point at
which mechanistic problems start. The reactions of NO and
CO with heme are markedly different. The binding of NO to
sGC is extremely fast (kon > 1.4 E 108 m 1 s1 at 4 8C), to give a
six-coordinate intermediate.[50] The reverse reaction is very
slow (koff = 8.2 E 104 s1 at 25 8C[51] and koff = 1.7 E 102 s1 at
37 8C) resulting in a formation constant > 1012 m 1.[52] There is
then a subsequent reaction giving a five-coordinate complex
with the loss of the histidine from coordination to the metal
center. The rate of this reaction also depends on NO
concentration, with a rate of 2.4 E 105 m 1 s1 at 4 8C. The
X-ray structure of the five-coordinate NO adduct of
microbial cytochrome c’ shows that NO binds to the proximal
side of the cytochrome, which displaces the histidine
ligand.[53] This produces a substantial conformation change
in the protein, and could provide the mechanism for the
signaling.
In contrast, the binding of CO to sGC is much slower
(kon ~ 105 m 1 s1 at 23 8C) to give a six-coordinate complex,
with the precise rate depending on the buffer used.[51, 54] The
off-rate is faster than for NO (koff ~ 10 s1 at 23 8C) resulting in
a formation constant ~ 104 m 1. Although a reliable formation
constant for the six-coordinate NO complex was not determined, it is clear that the formation constant for NO is much
larger than for CO. CO binds to the distal side of the microbial
cytochrome c’ without displacing the histidine.[53] This is
supported by measurements on the sGC system, which show
that while in the NO-bound form the Fe–histidinyl bond is
broken, it is intact in the CO adduct.[55] The difference
between NO and CO in displacing the histidine is probably
because of the trans influence. CO has a much smaller trans
influence than NO and hence is unlikely to labilize the
histidinyl group as effectively as does NO. The two ligands can
be compared directly in the crystal structures of [Fe(tpp)(NO)(1-Me-imidazole)]+ and [Fe(tpp)(CO)(1-Me-imidazole)] (tpp = anion of 5,10,15,20-tetraphenylporphyrin). In
[Fe(tpp)(NO)(1-Me-imidazole)]+, the FeN(imidazole) bond
length is 2.180(4) H,[56] while its counterpart in [Fe(tpp)(CO)(1-Me-imidazole)] is only 2.071(2) H.[57]
As a result of this, there are marked differences between
NO and CO in their ability to activate sGC; NO is about
80 times more effective than CO in activating sGC.[58]
However, when combined with 1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole
(YC-1; 3), the vasodilatory activity of CO
increases to that of NO.[59] The mechanism is not understood, however, it is
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Metal Carbonyls in Medicine
interesting to speculate whether there may be an endogenous
physiological counterpart of YC-1.
When NO binds to microbial cytochrome c’, the removal
of the histidinyl group from the coordination sphere produces
a substantial change in conformation, which could act as the
biological signal. In contrast, the binding of CO might be
expected to produce little conformational change. However,
when CO binds to cytochrome c’, there is considerable
reorganization of the surrounding peptide; Leu 16 moves
close to the CO moiety and the porphyrin ring flattens.[53] This
could provide a mechanism for CO acting as a signaling
molecule for sGC. As the bonding of CO to sGC produces a
different conformational change to NO, the two signaling
molecules could have different outcomes for their signal. This
is an area that requires further investigation.
6.2. p38 Mitogen-Activated Protein Kinase and p51
p38 Mitogen-activated protein kinase and p51 are proteins that do not contain a heme residue. It is then difficult to
see a mechanism of interaction of CO with these proteins.
Most CO is generated by the heme oxygenase enzyme system,
which liberates iron ions at the same time. This, therefore,
gives a possible mechanism of CO interaction with the
proteins. The bleomycin group of antibiotics (4) is closely
related to peptides and is known to bind to iron ions.[60] The
FeII–bleomycin complex coordinates CO.[61] In the light of this
observation, it is possible that FeII binds to the protein and
then binds CO.
6.3. Carbon Monoxide as a Reductant
cytochrome c oxidase shows that there are two heme units
and two copper centers. CO binds first to the CuI center and is
then transferred to the Fe center in cytochrome cbb3-CO.[66]
The reaction of the oxidized forms of hemoglobin and
myoglobin with peroxides generates intermediates containing
ferryl (FeIV¼O) groups.[67] Their oxygen atom is transferred to
CO to produce CO2.[68] Once reduced, the FeII cytochrome
can coordinate CO, which would also help to block the action
of cytochrome c oxidase.
One of the clearest examples of the water–gas shift
reaction in nature is with carbon monoxide dehydrogenases
(CODH). The key mechanism derives from the oxidation of
CO to CO2 by CODH, with the production of two electrons
[Eq. (1)].[69] The importance of this group can be judged from
the estimate that 108 tons of environmental CO is oxidized to
CO2 every year by aerobic and anaerobic bacteria containing
CODH enzymes.[70] The subject has been reviewed some
years ago.[71]
The X-ray structures of the NiFe-S carbon monoxide dehydrogenases of Carboxydothermus hydrogenoformans[72] and Rhodospirillium
rubrum[73] have been determined;
they contain a metal–sulfur cluster
(Figure 2). The crystal structure Figure 2. The metal core
shows the presence of a {Fe3NiS4} in Ni-Fe-S carbon moncore with an exo-cube Fe center. The oxide dehydrogenases.
suggested mechanism is a variation
on the water–gas shift reaction.[62, 74] It is proposed that CO
coordinates to the vacant site on the Ni center. An hydroxide
ion attacks CO to give NiCO2H, which then decomposes to
give CO2, with the transfer of two electrons to the {Fe3NiS4}
core.
A different CO dehydrogenase has been identified from
Oligotropha carboxidovorans[75, 76] and Hydrogenophaga
pseudoflava.[77] This enzyme contains a [CuSMo(¼O)OH]
cluster. The mechanism proposed for this enzyme involves
activation of CO by copper, with the intermediate being
trapped by using nBuNC in place of CO (Scheme 3).
Vitamin B12 has also been shown to be involved in the
conversion of CO to CO2 by CO dehydrogenase/CoA
synthase.[78] Although its role appears to be that of a methyl
transfer agent, earlier work has shown that several corrinoids
are reduced by CO, presumably by a mechanism related to the
Heme oxygenase produces CO when there is oxidative
stress. The oxidation of heme removes oxygen and the CO
produced is also a reductant, being oxidized to CO2, and thus
removing more oxygen. Carbon monoxide can act as a
reducing agent in two ways: It can accept an oxygen atom and
be oxidized directly to CO2, as it does with cytochrome c
oxidase. Alternatively, it can react with water and undergo the
water–gas shift reaction, liberating H2 or two electrons
[Eq. (1)].[62]
Carbon monoxide is oxidized by cytochrome c oxidase to
CO2.[63] The X-ray structure of bovine[64] and bacterial[65]
Scheme 3. The proposed mechanism for CO dehydrogenase from the
eubacterium Oligotropha carboxidovoran.[75]
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water–gas shift reaction.[79] Hydroxycobalamin can also act as
a source of CO.[80]
7. Other Possible Roles for Metal Carbonyls in
Medicine
There have been reports of the investigation of metal
carbonyls for roles in medicine other than the cardiovascular
system. The CO vibration in the IR spectrum provides a
method to detect metal carbonyls and this led to the
development of the carbonylmetalloimmunoassay procedure.[81] Metal carbonyl moieties, such as {M(CO)3} (M = Cr,
Mn, Re, Fe), are attached to molecules that are capable of
molecular recognition, in order to label and assay specific
biological receptors. When M = Tc or Re, the same idea is
used to introduce radioactive 99mTc, 186Re, or 188Re at a
receptor for radiopharmaceutical applications.[81b, 82] There
has been considerable interest in testing metal carbonyls for
anticancer activity. For example, [Co2(CO)6(HC2CCH2O2CC6H4-2-OH)] has been shown to be more active than
cisplatin on the human mammary tumor cell lines MCF-7
and MDA-MB-231.[83] Also [{h5-(4-Me2N{CH2}4OC6H4)(4-HOC6H4)CHCHEtC5H4}Re(CO)3] has been shown to
behave in a similar manner to tamoxifen, and it appears that
the observed antiproliferative effect is dependent on the
oestradiol receptor a.[84]
8. Summary and Outlook
It appears that CO is of equal importance as NO as a
signaling molecule in mammals; the mechanism of action is
far from clear. One major target for CO is the iron center of
heme in soluble guanylyl cyclase, but there are other targets
with precedence for other coordination sites, including nonporphyrin iron, cobalt, nickel, and copper centers. There is
much work needed from biochemists and bioinorganic
modelers to understand how CO can have such an important
biological role; there are many questions to answer: Although
hemes and cytochromes are obvious binding sites for CO, p38
does not possess such a binding site; so, how does CO signal to
CO-sensitive receptors such as p38? Once the CO group has
bound to the receptor, is it the resulting conformational
change that acts as the trigger, or does CO become involved
chemically? Does the water–gas shift reaction play any
significant role in mammal biochemistry and signal transduction mechanisms? Does the ability of CO to remove
oxygen from a Fe¼O bond in a cytochrome play a defensive
role in mammals, or is this limited to being a mechanism for
the destruction of CO? Does CO binding to cytochromes in
mitochondria always play an inhibitory role? And finally, how
is the specificity in CO-mediated regulation of cellular
function achieved?
In view of the well-known toxicity of CO, it seems very
unlikely that this gaseous compound could have beneficial
medical applications. However, the toxicity of CO and NO
are very similar,[85] and NO is now very important in the
pharmaceutical industry, with a range of NO-releasing drugs
Angew. Chem. Int. Ed. 2003, 42, 3722 – 3729
currently available and under development with more than 70
US and World Patents on the applications of NO donors.[86]
It is probable that in the near future a range of new drugs
will be developed based on CO-releasing molecules for the
treatment of cardiovascular dysfunction, as well as neurodegenerative- and inflammatory-related diseases. This should
open up a new floodgate of interest into the whole field of
metal carbonyls and move the new field of bioorganometallic
chemistry into a mature subject that needs to be taken
seriously by the pharmaceutical industry.
Received: February 10, 2003 [M1634]
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