The pharmaceutical potential of manganese-based superoxide dismutase mimics

Article abstract of DOI:10.1002/1521-3773(20001215)39:24<4469::AID-ANIE4469>3.0.CO;2-9

Oxidative stress and too many superoxide radical anions O₂^·- can cause considerable damage to organisms. Superoxide dismutase (SOD) enzymes with Mn- or Cu/Zn centers can repress the accumulation of radicals. SOD mimics such as 1 are

Full text of DOI:10.1002/1521-3773(20001215)39:24<4469::AID-ANIE4469>3.0.CO;2-9

HIGHLIGHT
The Pharmaceutical Potential of Manganese-Based Superoxide Dismutase
Mimics
Roland Krämer*
A considerable part of O2 metabolized by the human
organism is converted by one-electron reduction to the highly
withsecond-order catalytic rate constants of up to 2
Â
109 mÀ1 sÀ1 for the Cu/Zn-SOD system :diffusion controlled
reaction).
.
reactive superoxide radical anion, O2 À. Sources of superoxide
include ªleaksº in the cytochrome c oxidase mediated O2-to-
H2O transformation pathway in mitochondria, various au-
tooxidation reactions :e.g. of glutathione in red blood cells)
In the reduced state the metal :MnII or CuI) converts
superoxide into H2O2 by a one electron reduction [Eq. :1)],
.
followed by oxidation of a second equivalent O2 À to O2 by the
.
À
but also the controlled production of O2 by membrane-
bound NAD:P)H oxidase in phagocytes to support immune
defense against bacterial and fungal infections.
MnIII or CuII center, respectively [Eq. :2)]. The less aggressive
H2O2 is destroyed or metabolized by other enzymes such as
catalase.
.
À
Endogenous overproduction of O2 :and a number of
highly reactive oxidizing agents thus formed) combined with
reduced ability to eliminate radicals :ˆ oxidative stress)
clearly has the potential to inflict considerable damage on
biological systems.[1] In particular, the protonated form HO2
:pKa ˆ 4.8) is a very potent initiator for the selective
autooxidation of lipid membrane components at the allylic
position of unsaturated fatty acids and is also an active agent
for the abstraction of ribose hydrogen atoms in DNA leading
to extremely mutagenic DNA damage.
.
À
‡
O2 ‡ Mn‡ ‡ 2H À! H2O2 ‡ M:n‡1)‡
:1)
:2)
.
À
O2 ‡ M:n‡1)‡ À! O2 ‡ Mn‡
Net reaction:
.
À
‡
2O2 ‡ 2H À! H2O2 ‡ O2
:3)
Oxidations mediated by superoxide are currently believed
to participate in the pathogenesis of a number of important
degenerative diseases.
The presence of superoxide in bio-
logical systems was first revealed by the
discovery in 1969 of superoxide dismu-
tase :SOD) enzymes by McCord and
Fridovich.[2] In healthy organisms rad-
ical accumulation is suppressed by
these enzymes which contain, in the
active site, either a manganese ion :Mn-
SOD, Scheme 1, present in mitochon-
The typical course of myocardial or cerebral infarct
includes transient ischemia :stopping of the blood flow) of
tissue areas followed by reperfusion withoxygenated blood.
Since during the hypoxic events the cell is continuing to build
reducing equivalents, reperfusion results in high levels of
superoxide which are responsible to a great extent for cell
deathand tissue damage. In autoimmune conditions oxidants
produced by activated neutrophiles at sites of inflammation
can have serious consequences for the organism, for example,
joint damage in arthritis. Severe neurological disorders, such
as amyotrophic lateral sclerosis :ALS), Parkinsonꢁs and
Alzheimerꢁs disease may be related to nerve cell damage
caused by superoxide. Some types of cancer are thought to
arise from oncogene :tumor forming) mutations caused by
oxidative damage to DNA.
Application of SOD enzymes to animals has clearly shown
beneficial effects in some of the above mentioned diseases.
Cu/Zn-SOD preparations :trade names: palosein, orotein)
are available for the treatment of inflammatory diseases in
dogs and horses. In spite of encouraging results in animal
models, SOD is not yet used for the treatment of human
disease, a result of complications in clinical trials, in particular
immunogenic :allergic) responses.
Scheme 1. MnII coor-
dination sphere in
manganese superox-
ide dismutase from
dria) or a dinuclear Cu/Zn unit :Cu/Zn-
SOD, present in the cytosol and extra-
human
dria.[7]
mitochon-
cellular space). The second-order rate
constant for the spontaneous dispro-
.
portionation of O2 À to O2 and H2O2 is 5 Â 105 mÀ1 sÀ1 at 218C
and pH 7.4. This corresponds to a half-life of about 0.2 seconds
.
at an initial O2 À concentration of 10À5 m :t1/2 is proportional to
.
1/[O2 À]), sufficient to effect serious damage to cell compo-
.
À
nents. The SOD enzymes dramatically accelerate O2 decay
[*] R. Krämer
Anorganisch-Chemisches Institut
Im Neuenheimer Feld 270
69120 Heidelberg :Germany)
Fax : :‡49)6221-548599
E-mail: roland.kraemer@urz.uni-heidelberg.de
Angew. Chem. Int. Ed. 2000, 39, No. 24
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1433-7851/00/3924-4469 $ 17.50+.50/0
4469

HIGHLIGHT
Low molecular weight mimics could have significant
advantages over SOD enzymes suchas lack of immunogenic
response, longer half-life in the blood, improved access to
cells and intercellular space, potential for oral delivery, and
low costs. The effects of metal-based SOD analogues on
biological systems have been investigated for two decades,[3±5]
but the requirements for a mimic that could be used as a
human pharmaceutical agent are high: high chemical and
metabolic stability, SOD enzyme like activity and specificity
under physiological conditions, low toxicity, and favorable
biodistribution. In this respect, the manganese complexes 1
and, in particular, 2 :discovered by the research group of D.
Salvemini and P. Riley at MetaPhore Pharmaceuticals[6]) are
among the most promising candidates. Complex 2 was
designed on the basis of molecular modeling considerations.
These studies predicted that, of a class of complexes derived
from the 1,4,7,10,13-pentaazacyclopentadecane framework,
the properties for 2 were most favorable.
The anti-inflammatory effect of 2 was tested in rats in which
paw edema :swelling) was provoked by a local injection of
carrageenan.[6] The increase of paw volume, a consequence of
inflammatory response, as well as the infiltration by neutro-
phile blood cells was almost completely blocked by admin-
istering complex 2 :10 mgkgÀ1) 30 min before the carrageenan
injection.
In another rat experiment certain arteries were occluded to
generate prolonged ischemia of intestinal tissue. Subsequent
reperfusion results in neutrophile infiltration of the intestine,
increased plasma levels of lipid peroxidation products and
cytokines, severe hypotension , and finally in circulatory
shock. The consequence is a high mortality rate within the
first two hours. All these effects are significantly reduced
when 15 min before reperfusion infusions of 2 :1 mgkgÀ1 rat)
are given, with survivals rates of 90% after 4 hours. Thus
superoxide radical anions appear to be one of the mediators
for the above mentioned events.
In summary the potent SOD mimic 2 which is about 60
times smaller than the natural enzyme has strong anti-
inflammatory and cytoprotective effects in rats. It is a
powerful pharmacological tool to explore the selective role
of superoxide in physiological processes. The potential of
SOD mimics suchas 2 for the treatment of a broad range of
inflammatory and cardiovascular diseases and their efficiency
compared with other antioxidants has to be explored by
clinical studies.
Complex 2 is thermodynamically stable, the constant for its
formation from the macrocycle and MnII ions in water is >17
:lg K). After intravenous injection in rats it is taken up into
the heart, lungs, brain, liver, and kidneys and is excreted
intact. The second-order rate constant for catalytic break-
down of superoxide is 2 Â 108 mÀ1 sÀ1 at pH 6 and 218C and is
comparable to that of manganese SOD enzymes. This is a rare
example for a low molecular weight enzyme mimic that
displays structural similarities to the enzyme active site :MnII/
MnIII redox cycle, nitrogen donors) and at the same time
approaches the catalytic rate of the enzyme under physio-
logical conditions. Complex 2 is selective for superoxide and
[1] A. Petkau, Cancer Treat. Rev. 1986, 13, 17 ± 44.
[2] J. M. McCord, I. Fridovich, J. Biol. Chem. 1969, 244, 6049 ± 6055.
[3] D. P. Riley, Chem. Rev. 1999, 99, 2573 ± 2587.
[4] D. P. Riley, Adv. Supramol. Chem. 2000, 6, 217 ± 244.
[5] K. M. Faulkner, I. Fridovich, Antiox. Health Dis. 1997, 4, 375 ± 407.
[6] D. Dalvemini, Z.-Q. Wang, J. L. Zweier, A. Samouilov, H. Macarthur,
T. P. Misko, M. G. Currie, S. Cuzzocrea, J. A. Sikorski, D. P. Riley,
Science 1999, 286, 304 ± 306.
[7] G. E. Borgstahl, H. E. Parge, M. J. Hickey, W. F. Beyer, Jr., R. A.
Hallewell, J. A. Trainer, Cell 1992, 71, 107 ± 118.
does not react withNO and H O2.
2
4470
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1433-7851/00/3924-4470 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2000, 39, No. 24