Download full text pdf

Metallodrugs 2014; 1, 10–23
Research Article
Open Access
Seth S. Bradford, J. A. Cowan
From Traditional Drug Design to Catalytic
Metallodrugs: A Brief History of the Use of Metals
in Medicine
Abstract: Traditional drug design has been effective in the
development of therapies for a variety of disease states but
there is a need for new approaches that will tackle new
challenges and complement current paradigms. The use
of metals in medicine has resulted in several successes
and allows for the introduction of properties that cannot
be achieved by use of organic compounds alone, but
also introduces new challenges that can be addressed
by a careful understanding of the principles of inorganic
chemistry. Toward this end, the unique structural and
coordination chemistry, as well as the reactivity of metals,
has been used to design novel classes of therapeutic
and diagnostic agents. This review briefly summarizes
progress in the field of therapeutics, from the earliest
use of metals to more recent efforts to design catalytic
metallodrugs that promote the irreversible inactivation of
therapeutically relevant targets.
Keywords: drug design, enzyme inhibitors, metals in
medicine, catalytic, metallodrug
DOI 10.2478/medr-2014-0002
1 Introduction
History is filled with descriptions of disease states and
ailments, as well as attempts to combat them. The use of
chemical substances for the treatment of these conditions
*Corresponding author: J. A. Cowan: Evans Laboratory of Chemistry,
The Ohio State University, 100 West 18th Avenue, Columbus, Ohio
43210. Tel: 614 292 2703; Fax: 614 292 1685; e-mail: cowan@
chemistry.ohio-state.edu
Seth S. Bradford: Evans Laboratory of Chemistry, The Ohio State
University, 100 West 18th Avenue, Columbus, Ohio 43210
J. A. Cowan: MetalloPharm LLC, 1790 Riverstone Drive, Delaware, OH
43015
most likely stemmed from observations of cause and
effect, such as the discovery that a plant had healing
properties, or that it relieved pain. For example, the use of
salicylic acid-rich plants for pain and inflammation dates
back to before the Common Era, but it wasn’t until the mid
to late 1800’s that the active component was identified
as acetylsalicylic acid and marketed as aspirin [1]. More
recent advances in the sciences have allowed for the
determination of the exact chemical composition of drugs
as well as an appreciation of the importance of the drug
target. Essential techniques for studying the effects of a
drug on its target, both in the test tube and in vivo, required
key advances in basic science, such as the development of
the microscope and discovery of various microorganisms,
including bacteria by Antony Leeuwenhoek in the 1600’s
[2], the discovery of cells in 1665 by Robert Hooke [3], the
development of staining procedures, such as the Gram
stain, for cells and tissues developed in the 1700’s and
1800’s [4], and the identification of viruses by Dmitri
Ivanovsky and Martinus Beijerinck in the late 1800’s [5].
Treatment also required a deeper understanding of
the origins of the disease. Malaria has been known for over
4,000 years, but the malaria parasite wasn’t identified
until 1880 by Charles Louis Alphonse Laveran [6]. As
the molecular understanding of drugs and drug targets
has improved, so have the methodologies for optimizing
and testing them. Current approaches to the discovery
of natural products rely on the screening, separation,
characterization, and synthesis of the specific molecules
involved in achieving the desired response. The use of
drugs derived from nature remains an important aspect
of pharmaceutical development, but advances in the
sciences have also allowed for an improved understanding
of how drugs work and how best to administer them.
The rational design of drugs derives from a basic
understanding of the cause of a condition, as well as
the ability to alter the processes that ultimately led to
it. As advances in chemistry and the biological sciences
have continued, and a deeper understanding of drug
© 2014 Seth S. Bradford, J. A. Cowan, licensee De Gruyter Open.
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License.
Unauthenticated
Download Date | 6/15/17 8:02 PM
Past, Current and Future Use of Metals in Medicine interactions with a target has developed, the rational
design of drugs becomes more plausible. A compound can
be modified to alter its properties to generate higher activity,
lower toxicity, improved specificity, better stability, or an
improved half-life in vivo. Modifications can be made in a
systematic way to generate structure activity relationships
(SARs) that help to guide further optimization [7]. One of
the earliest examples of a medicinal chemistry approach
to drug design is illustrated by the work of Paul Ehrlich on
studies of arsenic compounds for the treatment of syphilis
[8]. Ehrlich’s concept of a “magic bullet” that selectively
targets a bacterium over other organisms is an important
concept even today, and achieving this selectivity is still
one of the most promising, yet challenging, aspects of
drug design.
2 Traditional Drug Design
Currently, the development of drugs usually involves a
combination of screening to identify lead compounds,
as well as rational design to further optimize these
compounds. Rational design acts as a guiding hand to
focus research, but the complexities ultimately make
prediction an uncertain process and there is still a
great deal of trial and error involved. A pharmaceutical
company will often have access to a very large number
of compounds that need to be narrowed down according
to other parameters such as computational results or
physical properties. Lipinski’s rule of five is commonly
used to determine the “druglikeness” of molecules [9]. It
11
does not matter how active a compound is in an assay if
it is insoluble or has other properties that would preclude
it from being used in vivo. Lipinski found that most of
the medications in use consisted of compounds with no
more than five hydrogen bond donors and 10 hydrogen
bond acceptors, had a molecular weight less than 500
grams per mole, and had an octanol-water partition
coefficient (log P) of less than five. These rules are used as
a guideline to focus the screening process and new drugs
tend to be small organic molecules with high affinity for
their target as well as good stability and solubility in vivo.
It is important to keep in mind, however, that these are
only guidelines. The recently approved protease inhibitor
for the treatment of hepatitis C, telaprevir, is a notable
example of a compound that breaks all of Lipinski’s rules.
The most common drug targets are enzymes. For
example, a common approach to blood pressure regulation
is inhibition of angiotensin converting enzyme (ACE). ACE
promotes an increase in blood pressure by converting
angiotensin I to angiotensin II, a vasoconstrictor, and
also by degrading the vasodilator bradykinin [10].
Proper regulation of this enzyme is key to good health. In
situations where blood pressure is high, inhibition of ACE
by small molecules is a common treatment. This is how
some commonly used blood pressure medications such as
captopril (Capoten) [11] and lisinopril (Zestril, Tensopril)
(Figure 1) [12] work. The general scheme for this type of
inhibition is shown in Figure 2 and is the most common
approach to drug design. The small molecule inhibitor (I)
binds to the active site of the enzyme (E) and blocks it so
that the substrate (S) cannot bind.
H 2N
HS
HO
O
O
O
H
H
N
N
N
H
OH
O
OH
O
Lisinopril
Captopril
Figure 1: Known small molecule inhibitors of angiotensin converting enzyme.
E+S
+
ES
+
I
I
E+P
K'i
Ki
EI
ESI
Figure 2: Reversible inhibition of an enzyme (E) that acts on a substrate (S) by an inhibitor (I).
Unauthenticated
Download Date | 6/15/17 8:02 PM
12 S.S. Bradford, J.A. Cowan
There are many advantages to traditional drug design
and the majority of the drugs currently on the market were
discovered and developed in this way. The scheme shown
in Figure 2 shows a series of equilibrating reactions and
the requirement for a sufficient amount of inhibitor (I)
to shift the equilibrium and achieve the desired effect.
This can lead to a need for higher concentrations of drug,
potentially more frequently, leading to toxicity and issues
with patient compliance. Also, because it is reversible,
the inhibitor will be released and be cleared by the body,
leaving the enzyme to start converting substrate to product
all over again.
The use of a small number of elements in current
drugs, primarily C, H, N, O, and S, limits the range of
available properties available to them. The shapes that
can be achieved, for example to fit into an enzyme active
site, will be limited to geometries available to those atoms
whereas higher coordination numbers, and hence more
diverse shapes, can be attained with compounds that take
advantage of a wider range of the periodic table. The use
of metals in medicine is a less traditional approach which
addresses some of these limitations while introducing
disadvantages of its own, such as considerations of the
stability and toxicity of the complex. Proper ligand design
and application of basic inorganic principles, however,
allows for the design of stable compounds with a wide
array of properties available to them. The focus of this
review, following a historical perspective, is on actual,
or potential, metal-based drugs that promote therapeutic
activity through direct metal-centered binding or
reactivity. Other approaches that employ outer sphere
contacts of coordination complexes or reactivity toward
ill-defined cellular targets are not included for reasons of
space limitations, although interested readers are directed
to other informative reviews and articles [13-20].
3 Metals in Medicine
The importance of metals in biology has become apparent
over time as an increasing number of enzymes and
O
HS
O
other biological molecules have been identified that
contain metals that are important, if not essential, for
structure and/or function. Metals can perform functions
that cannot otherwise be achieved, such as electrolyte
balance (important for processes that include the firing of
neurons), as well as oxygen transport, electron transfer,
and catalysis. The importance of metals to health is
made clear by the abundance of diseases caused by
an excess or deficiency of a metal. For example, iron is
essential for life, but in humans too much iron can lead
to haemochromatosis and too little iron can lead to iron
deficiency. Therefore, iron regulation is essential. Other
examples of diseases related to metal ion regulation
include Wilson’s disease [21], Friedrich’s ataxia [22], and
hypozincemia [23]. Metal overload can often be treated
by use of metal chelating compounds, and British antiLewisite (dimercaprol, Figure 3) was the first chelating
compound used medicinally [24]. Metal overload can
also be caused by intake of metals either involuntarily or
voluntarily, as was often the case in historical examples of
the use of metals to treat disease. Silver has found many
uses in medicine, most notably as an antibiotic, although
its mechanism of action remains unclear. Prior to the
development of more effective and targeted antibiotics
around the time of World War I, colloidal silver was used
as a disinfectant and it still finds use today in the form
of silver sulfadiazine (Figure 3) for the treatment of burn
wounds [25]. Organotin compounds find use as pesticides
but their use has been limited by toxicity concerns
[26]. The use of mercury is another common example
of a compound that was used in the past without a full
understanding of how it works [27]. Probably the most
commonly known use of mercury was in the processing
of felt hats which caused toxicity and led to the term “mad
as a hatter” [28]. Medicinally, it was administered in the
form of mercury (I) chloride as a disinfectant and diuretic
and later found use in the form of mercury (II) chloride
for the treatment of syphilis. These compounds showed
some activity but their major downfall was that they
were administered without a full understanding of their
N
S
N
OH
HS
Ag
H 2N
Dimercaprol
N
+
Silver Sulfadiazine
Figure 3: Metal related therapies used throughout history.
Unauthenticated
Download Date | 6/15/17 8:02 PM
toxicity. They also illustrate the potential for activity from
inorganic compounds, but also the possible pitfalls when
used without taking proper precautions and without a
clear understanding of their mechanism of action.
While there are some metal-based therapeutics
currently used, they often tend to be the exception
rather than the rule and tend to be discovered rather
than rationally designed. The potential for toxicity from
the metal center is a serious concern, but one that can
be addressed by proper ligand design and knowledge
of coordination chemistry. Nevertheless, it is important
that the use of a metal center is necessary for the chosen
application, such as for the introduction of properties that
cannot be achieved by a traditional organic compound.
Examples include the use of metals for imaging, such as a
positron emitting metal for positron emission tomography
(PET) [29], a gadolinium complex for MRI contrast [30], or
for the introduction of new reactivity such as in bleomycin
[31]. Another potential use of metals is to generate new
shapes that can more effectively explore structure activity
space [32], such as the use of an inert metal center to
introduce an octahedral geometry that better fits the
active site of protein kinases. In the current market, former
problems and perceptions associated with metal toxicity
are less likely to be a major issue, due to an increased
emphasis on proper testing and understanding of the
Past, Current and Future Use of Metals in Medicine 13
mechanism of potential therapeutics. There are several
examples of metal-based drugs that are still currently in
use and these compounds illustrate both the potential of
this class of compounds and the need for further work to
optimize their uses in a clinical setting.
3.1 Overview of Metal-Based Therapeutics in
Current Use
The number of metal-based therapeutics that have
received FDA-approval is limited and this is a reflection
both of the challenges involved and the lack of interest
of pharmaceutical companies in inorganic compounds.
There is precedent, however, for a willingness to approve
a compound quickly, especially if it fits an identified
need that is not being met. A good example of this is the
large number of imaging agents currently on the market,
such as the imaging agent Prohance (Figure 4) which was
approved in 1992 and is an MRI contrast agent used for
imaging of the central nervous system [33]. Gadolinium
contains seven unpaired electrons and interacts with
water to enhance its relaxivity. This enhancement occurs
only where the gadolinium is present and can be used
to image where the complex localizes in the body. The
history of FDA approved metal compounds used for
therapy is more limited. The use of lithium carbonate for
Figure 4: Clinically used inorganic based drugs.
Unauthenticated
Download Date | 6/15/17 8:02 PM
14 S.S. Bradford, J.A. Cowan
drugs shows the potential for generating compounds that
have unique activity, but also emphasizes the limitations
and potential challenges involved in controlling the
toxicity and establishing a detailed understanding of the
mechanism of action.
the treatment of depression, primarily bipolar disorder,
was approved in 1970 [34]. Its mechanism of action is
still not well understood. In 1985, the gold compound
auranofin (Ridaura, Figure 4) was approved for the
treatment of rheumatoid arthritis. Its primary mechanism
of action is thought to be inhibition of an esterase that
breaks down cartilage tissue but this mechanism of action
is still debated [35]. Bismuth salicylate (Figure 4), the
active ingredient in Pepto-Bismol, was approved in 1996
for use as an antacid and antidiarrheal [36]. Bismuth has
also found use as a treatment for leishmaniasis in the
form of meglumine antimoniate (Glucantim) [37]. Another
inorganic compound, sodium stibogluconate (Pentostam),
has also been used in the treatment of leishmaniasis and
is still used worldwide [38]. In 1997, Sclerosol Intrapleural
Aerosol, Mg3Si4O10(OH)2, was approved for treatment of
malignant pleural effusion in lung cancers [39]. Malignant
pleural effusion is a condition where an abnormal amount
of fluid collects in the lungs, and this compound is
thought to induce an inflammatory response and to act as
a sealant to prevent the further accumulation of liquids.
Another important field of research in the application of
metals to medicine is photodynamic therapy, exemplified
by Photofrin, approved in 1995 as a photosensitizing agent
for the treatment of esophageal cancer and later for the
treatment of non-small cell lung cancer [40]. Trisenox
is a formulation of As4O6 that was approved in 2000 for
administration in combination with all-trans retinoic acid
(ATRA) for the treatment of some forms of leukemia [41].
The metal-based radiopharmaceutical Zevalin (Figure 4)
was approved in 2002 for the treatment of low-grade, B-cell,
non-Hodgkin’s lymphoma [42]. This compound consists of
the monoclonal mouse IgG1 antibody ibritumomab linked
to the metal binding domain tiuxetan, which coordinates
either indium-111 or yttrium-90. Zevalin binds to the CD20
antigen found on the surface of B cells and selectively kills
them. Other therapeutic radiopharmaceuticals include
Metastron, a 89Sr complex used for skeletal metastases,
Quadramet, a 153Sm complex also used for osteoblastic
bone metastases, and Xofigo, a 223Ra complex used for
castration-resistant prostate cancer [43-45]. This range of
H 3N
Cl
Probably the most successful metal-based drugs are
represented by cisplatin and its analogs. Like many of the
drugs mentioned, and many drugs in general, cisplatin
(structure shown in Figure 5) was not rationally designed
but serendipitously discovered by Barnett Rosenberg
in 1965 [46]. Cisplatin was approved by the FDA in 1978
for the treatment of testicular and ovarian cancers. It is
delivered as a neutral compound, but is susceptible to
hydrolysis as shown in Figure 5. In the blood, the chloride
concentration is sufficiently high that the equilibrium lies
to the neutral compound on the left. Upon entering the
cell, the [Cl-] drops and the cisplatin hydrolyzes to form
the charged complex on the right which then cannot
cross the cell membrane and therefore is trapped inside
the cell. This is the active form of cisplatin. The detailed
mechanisms of uptake and transport within the cell, as
well as export pathways that provide potential resistance
mechanisms, are only now becoming understood, with
evidence that Pt-based drugs, in addition to passive
diffusion mechanisms, can also be bound and mobilized
by copper trafficking and transport proteins [47], and so
the conversion to the aquated complex may involve sulfurbound protein forms as intermediates. Nevertheless, in
one of the major therapeutic pathways, the active hydrated
Pt salt reacts with DNA to generate inter- and intrastrand
crosslinks that inhibit transcription and DNA repair,
leading to apoptosis [48]. Understanding the factors that
contribute to efficient targeting of DNA is an important
problem with much activity [49]. There is also an
increasing body of evidence that suggests that alternative
cellular targets may be important for therapeutic activity
of platinum compounds [50,51]. Understanding the
chemistry of platinum drugs with cellular and serum
H 3N
+ 2 H 2O
Pt
H 3N
0
3.2 Cisplatin
Cl
OH
+ 2 Cl - +
Pt
H 3N
+
H+
OH 2
cisplatin
Figure 5: Hydrolysis of cisplatin to generate the active form.
Unauthenticated
Download Date | 6/15/17 8:02 PM
Past, Current and Future Use of Metals in Medicine proteins, and the impact on cellular toxicology and
pharmacology, is an area of developing interest in light of
the availability of modern analytical tools [50-52].
The selectivity of cisplatin derives from an enhanced
uptake in cancer cells relative to healthy cells as well
as the higher accessibility of the DNA in cells that are
undergoing division. This is why other cells that are
continuously dividing, such as hair cells or cells in the
gastrointestinal tract, are also damaged by cisplatin and
this is the basis for common side effects such as hair
loss and nausea. Therefore, while cisplatin does have a
preference for killing cancer cells, it does not have a high
level of specificity.
Many derivatives of cisplatin have been studied and
two have received approval by the FDA. Carboplatin
(Figure 6) was approved in 1989 for the treatment of
ovarian cancer and oxaliplatin [53] was approved in
2002 for the treatment of advanced colorectal cancer.
Both compounds replace the chloride leaving group of
cisplatin with a bidentate dicarboxylate ligand that is less
reactive. This results in fewer side reactions, and therefore
lower toxicity, particularly with proteins, and also better
retention in the body relative to cisplatin.
Cisplatin and its derivatives are a good example of
the promise of inorganic pharmaceuticals and they also
illustrate the concerns that need to be addressed by future
metal based drugs. Their effectiveness and contributions
to human health are undeniable but there is room for
improvement in specificity in order to achieve lower toxicity.
Resistance to cisplatin is also a major hurdle to overcome
and novel approaches to treating cisplatin-resistance are
needed, such as the use of gold(III) porphyrin complexes
[17], as well as iridium and ruthenium compounds [16,20].
Multiple side reactions for platinum complexes, and the
fact that the drug is irreversibly consumed by its mode of
action, lead to a requirement for high doses, and targeted
approaches are also being explored [14,19]. Achieving
selective targeting to the cells of interest is still one of the
biggest challenges in the use of metals in medicine as well
as in drug design in general.
15
3.3 Bleomycin
Bleomycin (Figure 7) was isolated from Streptomyces
verticillus in 1966 and is an example of a drug designed
by nature that takes advantage of the reactivity of metals
[54]. It received approval in the United States in 1973 and
is used for the treatment of squamous cell carcinomas,
testicular cancer, and Hodgkin’s lymphoma. Bleomycin
is not actually administered as a metal complex but
instead consists of several domains, including one
that is important for binding to DNA and another that
coordinates to metals. The mechanism of action of
bleomycin is the induction of DNA strand breaks due to
recruitment of a metal, probably iron, and subsequent
generation of reactive oxygen species which react with
the DNA [55]. Much like cisplatin, bleomycin shows a
preference for cancer cells but its mechanism of action
is not specific to them. It is a good example, though, of a
drug incorporating a metal ion to promote chemistry on
a target. It is also another example of a metal-based drug
that would benefit greatly from enhanced selectivity for
cancer cells.
4 Catalytic Metallodrugs
Cisplatin and bleomycin are two examples of toxic
compounds that show some level of selectivity for
a disease state but would benefit greatly from more
specific targeting to the site of interest. As an extension
of early work on artificial proteases and nucleases [5667], catalytic metallodrugs were developed as a class of
metal-based drugs that helped to address some of these
concerns [68]. The basic design strategy is shown in
Figure 8 and consists of a metal binding domain linked
to a target recognition domain. The target recognition
domain binds to the therapeutic target of interest and
provides selectivity while the metal binding domain
performs chemistry on that target. This simple modular
design allows for the variation of the different domains
O
H 3N
H2
N
O
Pt
H 3N
O
O
Pt
N
H2
O
O
carboplatin
O
O
oxaliplatin
Figure 6: Clinically approved derivatives of cisplatin.
Unauthenticated
Download Date | 6/15/17 8:02 PM
16 S.S. Bradford, J.A. Cowan
Figure 7: Structure of bleomycin identifying domains primarily involved in association with DNA and metal coordination (the imidazole ring
has also been implicated in metal binding).
to modify the properties of the metallodrug and can
be quickly adapted to a variety of different therapeutic
targets. As shown in the reaction scheme at the bottom of
Figure 8, the metal-ligand complex (ML) binds to its target
(T) in a process that is under equilibrium and analogous
to the enzyme inhibition strategy described above. The
next step, however, involves irreversible reaction with the
target to generate the product (P). In this way it acts like
an enzyme. This irreversible step pulls the equilibrium to
the right, according to Le’Chatelier’s principle, and aids
the progress of the reaction even under situations where
binding might not be as tight as would be required for
a traditional drug. The final step involves release of the
metal-ligand complex from the target to regenerate the
metallodrug. Hence, another important design feature is
the ability to act catalytically.
One of the major advantages of this approach is its
ability to address some of the issues previously mentioned
in terms of specificity and toxicity. One feature that
emerges from the design as described is a double filter
mechanism for reactivity, as shown in Figure 9. Drugs
will often have side effects and toxicity due to nonspecific
interactions with macromolecules other than their
therapeutic target. For catalytic metallodrugs, however,
there is a requirement for both binding and proper
positioning of the metal binding site for reactivity. Even if
nonspecific binding occurs, as shown on the right, if the
metal binding domain isn’t properly oriented to react with
the target then it will not be active.
This extra level of selectivity addresses one of the
biggest issues with the currently used metal-based drugs
described above, which is their inherent toxicity. This
feature, combined with the fact that these metallodrugs are
designed to act catalytically, allows for higher selectivity
at a lower dose. Lower dosages should also contribute to
lower costs and, combined with reduced toxicity, better
patient compliance. The unique mechanism of action
also makes catalytic metallodrugs a perfect complement
to current therapies both in terms of combination therapy
and to combat resistance. The novel mechanism of action
makes it very difficult for resistance to develop against
both a catalytic metallodrug and another drug at the
same time. Often resistance can occur by mutation of the
therapeutic target to prevent or reduce binding. In the
case of catalytic metallodrugs, however, this reduction
in binding could potentially not affect, or even enhance,
catalyst activity depending on what the rate limiting step
is for a particular system.
4.1 The Metal Binding Domain
As mentioned, the role of the metal binding motif is to
perform chemistry on the therapeutic target. In order
to be useful as a metallodrug, it must also bind to the
Unauthenticated
Download Date | 6/15/17 8:02 PM
Past, Current and Future Use of Metals in Medicine 17
Figure 8: (Top) Basic catalytic metallodrug design. (Bottom) Reaction scheme for catalytic inactivation of target T by the catalytic metallodrug consisting of a metal binding domain (M) and a target recognition domain (L).
Figure 9: Double filter mechanism for catalytic metallodrugs [89].
metal very tightly and be stable both kinetically and
thermodynamically. This domain allows for further
customization and optimization of the metallodrug.
Selection criteria include factors such as intrinsic
reactivity, stability, and compatibility with the targeting
domain. Selection of the metal binding domain will
also determine the range of metals that can be used another factor that can be varied to optimize therapeutic
activity. Other common metal binding ligands include
ethylenediaminetetraacetic acid (EDTA), terpyridine,
cyclen and its derivatives, as well as porphyrins and
expanded porphyrins. Examples of the use of these metal
binding domains are discussed later in section 4.3.
Another metal binding domain that has been used
extensively in design efforts is the amino terminal copper
and nickel binding (ATCUN) motif derived from the
N-terminus of serum albumins (Figure 10) [69]. It has been
shown to bind to copper and nickel very tightly (KD for
copper of 1.18 x 10-16 M) [70], with precedence for reaction
with nucleic acids [71]. Copper and nickel coordination
is promoted by binding of the N-terminal amine, two
backbone amides, and the histidine side chain in the
third position (Figure 10). NMR, EPR, visible spectroscopy
and X-ray crystallography are consistent with a divalent
metal ion coordinated in a square planar configuration
[70,72-74], leaving two faces accessible for binding to a
Unauthenticated
Download Date | 6/15/17 8:02 PM
18 S.S. Bradford, J.A. Cowan
Figure 10: The amino terminal copper and nickel binding (ATCUN) motif.
target molecule. This design allows for variation of the
properties of this domain by changing the side chains (R
and R’, Figure 10) contributed by the first two residues.
Both copper and nickel undergo redox chemistry through
the M3+/2+ couple rather than M2+/+ [75] lending the complex
greater reactivity and thermodynamic stability.
Reaction pathways appear to vary from system to
system, but usually involve the generation of reactive
oxygen species through pathways such as those shown in
Figure 11, and can involve superoxide, peroxide, hydroxyl
radicals, or metal bound oxygen species. Coreagents can
also be important for cycling and regenerating the metal
complex in the starting state, such as by reduction of Cu3+
to Cu2+ by ascorbic acid, or can be important for other
related redox processes. These conditions are expected to
be present in some form under physiological conditions
since ascorbic acid (as vitamin C), hydrogen peroxide, and
many other reducing and oxidizing agents are available
in vivo.
4.2 The Target Recognition Domain and
Linker
The target recognition domain is anything that can bind
to and recognize a specific target of interest. While tight
binding is generally desirable, this could inhibit turnover
through product inhibition and lead to a less effective
catalyst if a high affinity resulted in a slow off-rate for
catalyst release. More important than tight binding,
however, is specificity, which can be retained even with
weaker binding through a property described as the double
filter effect (Figure 9). This recognizes the fact that in the
case of a catalytic drug that promotes chemical change
on the target molecule, specificity will reflect not only
Figure 11: Relevant reduction potentials (relative to NHE) for oxidative chemistry of catalytic metallodrugs.
Unauthenticated
Download Date | 6/15/17 8:02 PM
Past, Current and Future Use of Metals in Medicine binding propensity, but also an appropriate orientation
for efficient chemistry to occur. Such a combination is less
likely to arise for off-target binding, and so specificity is
maintained.
The design of metallodrugs is facilitated by
possession of functionality on the targeting molecule
that can be used to couple with a metal binding domain,
but without significantly perturbing recognition and
binding to the therapeutic target. This would most likely
be a small molecule that is already known to bind to a
particular target and would benefit from the reactivity
introduced by the metal binding domain, but other
larger biological molecules, such as proteins or peptides,
including antibodies, nucleic acids, or carbohydrates are
not excluded.
Targeting domains that are based on peptides can
readily incorporate the ATCUN motif described above,
but any compound that can be modified to allow for
conjugation to the metal binding domain can be elaborated.
The design can also include a linker moiety that separates
the metal binding and targeting domains and can be used
to further tailor reactivity. For example, the introduction of
flexibility could either enhance or reduce chemistry at the
target by influencing the placement and orientation of the
reactive metal center relative to potential scissile bonds.
This linker can also be varied to tailor other properties,
such as water solubility, partition coefficient, or in vivo
half-life. Depending on the mode of binding, other
Trp123
12 A
functional groups can be incorporated to further tailor
the properties of the catalytic metallodrug, including the
optimization of traditional in vivo and drug-like properties
such as the pharmacokinetic profile, cellular uptake, and
oral availability.
4.3 Development of Catalytic Metallodrugs
Among the first catalytic metallodrugs reported
were compounds acting as inhibitors of a class
of metalloproteases involved in regulation of the
cardiovascular system, such as angiotensin-converting
enzyme (ACE) and endothelin-converting enzyme 1
(ECE-1) [76]. These compounds, however, acted by this new
mechanism of catalytic inactivation rather than reversible
inhibition alone. Further studies with the model enzyme
carbonic anhydrase I (CA-I) demonstrated that copperATCUN complexes of the known inhibitor sulfanilamide
caused a time-dependent inactivation of CA-I that was
further shown by enzyme digestion and LC/MS/MS
analysis to be due to irreversible modification of active site
residues important for the enzyme mechanism (Figure 12,
left) [77]. More recent ACE targeted metallodrugs based on
the known inhibitor lisinopril (Figure 12, right) showed
both concentration- and time-dependent inactivation of
ACE [78]. These reactions occur by an oxidative mechanism
which, although the details vary from system to system,
involve the generation of reactive oxygen species that
His103
27 A
His243
19 A
His64
8 A
His67
6 A
His200
5.5 A
19
Trp97
15 A
Zn2+
His40
31 A
Figure 12: (left) Residues in carbonic anhydrase that are modified by Cu-GGH conjugates of sulfanilamide. His64, His67, and His200 have
been implicated in rate-limiting proton transfer within the active site [77]. Conjugates of lisinopril (right, where R = lisinopril) with a metal
binding domain have been shown to catalytically inactivate angiotensin converting enzyme [78].
Unauthenticated
Download Date | 6/15/17 8:02 PM
S.S. Bradford, J.A. Cowan
species.
Further work has demonstrated the targeted cleavage
of RNA critical to HIV-1 replication, the Rev Response
Element (RRE), and provided a series of compounds with
a unique mechanism of action that could find potential
use in the treatment of HIV [85,86]. Compounds based
on Cu-GGH-YrFK-amide were shown to target stem loop
IIb of the Hepatitis C Virus (HCV) internal ribosomal
entry site (IRES), which is important for viral translation,
and catalytically degrade it [87]. These compounds
demonstrated high activity both in vitro and in a cellular
replicon assay that, in the absence of a proven animal
model for HCV, is accepted by the USFDA as a measure
of drug efficacy (Figure 13, left). This compound showed
additive, possibly slightly synergic activity, when given in
combination with recombinant interferon α-2b (rIFNα-2b).
Site specific oxidative degradation of the target RNA
was demonstrated and the most likely mechanism
of action for these compounds is a mixed oxidative/
hydrolytic mechanism where generation of the copper
(III) center is necessary to enhance the Lewis acidity of
the metal ion. Real-time polymerase chain reaction (RTPCR) experiments showed that the mechanism in cells
is consistent with the proposed mechanism of HCV RNA
cleavage (Figure 13, right) [88].
5 Conclusions
Catalytic metallodrugs fill a current need in drug design by
introducing new properties and providing a new class of
drugs that act by a unique mechanism of action. They also
1.2
1.0
% of Virus Control (Efficacy)
Normalized Copies of HCV RNA
ultimately inactivate the target of interest. Research in the
Suh lab has taken a different approach to the ACE system,
designing Co(III) catalysts that target the angiotensin I
and I peptides rather than the enzyme itself [79], a reaction
that is likely to occur by a hydrolytic mechanism. Similarly,
another cobalt complex was identified that could cleave
both human islet amyloid polypeptide, important in type 2
diabetes mellitus, and soluble oligomers of amyloidogenic
peptides amyloid β-42, thought to be involved in the
pathogenesis of Alzheimer’s disease [80]. Work in the
Blum lab also demonstrated the use of copper and zinc
compounds for the irreversible inhibition of furin, an
enzyme that has been implicated in a variety of disease
states including HIV, anthrax infection, and cancer [81].
Catalytic metallodrugs targeting nucleic acids have
also been reported. Nucleic acids are more susceptible to
hydrolysis and much of the work in this area has focused
on artificial nucleases that cleave the phosphodiester
bond, as exemplified by work from Morrow and Richards
and coworkers [62]. There is still precedence, however
for the oxidative cleavage of nucleic acids and, in fact,
many of the catalytic metallodrugs that incorporate
the ATCUN motif react via oxidation of DNA [59]; this
nuclease activity has been implicated in the mechanism
of antimicrobial peptides [82]. The texaphyrins pioneered
in the Sessler lab also act through reactive oxygen species
(ROS) that react with DNA and lead to cell death [83].
Another unique approach to the site specific targeting of
DNA is demonstrated by the work of Komiyama et al. [84]
wherein the target recognition domain is a peptide nucleic
acid and cleavage is performed by a catalytic CeIV/EDTA
0.8
0.6
0.4
0.2
0.0
0
3
6
Day
9
0.2 ΙU/mL rIFNµ-2b
110
100 0.2 µM Complex
90
80
70
60
50
40
30
Both
20
10
0
I
II
III
% Virus Control
Drugs Evaluated
110
100
90
80
70
60
50
40
30
20
10
0
% of Cell Control (Toxicity)
20 % Cell Control
Figure 13: (left) RT-PCR results showing concentration and time-dependent degradation of HCV RNA in the replicon assays. 0 μM (black
square), 2.5 μM (white circle), 5 μM (black triangle), 10 μM (white diamond), 20 μM (black star). The graph is normalized to the RNA levels in
the absence of metallopeptide [87]. (right) HCV cellular replicon results showing additive to slightly synergic activity of the metallodrug CuGGHYrFK-amide when given in combination with pegylated interferon. (I, 0.2 μM 1, II, 0.2 IU/mL rIFNα-2b, III, 0.2 μM 1 + 0.2 IU/mL rIFNα-2b).
Unauthenticated
Download Date | 6/15/17 8:02 PM
address some of the current drawbacks with metal-based
drugs, such as a requirement for high doses and poor
selectivity leading to high toxicity. The modular design
also allows for the variation of metal binding and targeting
components to optimize the properties of the drug. The
targeting domain represents a way to achieve enhanced
selectivity and also makes it generally applicable to any
system of interest.
Acknowledgements: This work was supported by
grants from the National Institutes of Health [HL093446
and AA016712]. Seth Bradford was supported by an NIH
Chemistry/Biology Interface training grant (T32 GM08512).
References
[1] Ibsim. 110 years history of aspirin: effectiveness and activity
mechanism. Hwahak Sekye 2009, 49, 48-52.
[2] Corliss J., O. A salute to Antony van Leeuwenhoek of Delft, most
versatile 17th century founding father of protistology. Protist
2002, 153, 177-190.
[3] Rao, K. K. Life and work of Robert Hooke (1635-1703). J. Inst.
Eng. (India), Part GE 1967, 48, 42-50.
[4] Popescu, A.; Doyle, R. J. The Gram stain after more than a
century. Biotech. Histochem. 1996, 71, 145-151.
[5] Artenstein A., W. The discovery of viruses: advancing science
and medicine by challenging dogma. Int. J. Infect. Dis. 2012, 16,
e470-473.
[6] Bruce-Chwatt, L. J. Alphonse Laveran’s discovery 100 years ago
and today’s global fight against malaria. J. R. Soc. Med. 1981,
74, 531-536.
[7] Guo, Z. Structure-activity relationships in medicinal chemistry:
development of drug candidates from lead compounds.
Pharmacochem. Libr. 1995, 23, 299-320.
[8] Thorburn, A. L. Paul Ehrlich: pioneer of chemotherapy and cure
by arsenic (1854-1915). Br. J. Vener. Dis. 1983, 59, 404-405.
[9] Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J.
Experimental and computational approaches to estimate
solubility and permeability in drug discovery and development
settings. Adv. Drug Delivery Rev. 2001, 46, 3-26.
[10] Izzo, J. L., Jr.; Weir, M. R. Angiotensin-converting enzyme
inhibitors. J. Clin. Hypertens. 2011, 13, 667-675.
[11] Opie, L. H.; Kowolik, H. The discovery of captopril: from large
animals to small molecules. Cardiovasc. Res. 1995, 30, 18-25.
[12] Noble, T. A.; Murray, K. M. Lisinopril: a nonsulfhydryl
angiotensin-converting enzyme inhibitor. Clin. Pharm. 1988, 7,
659-669.
[13] Butler, J. S.; Sadler, P. J. Targeted delivery of platinum-based
anticancer complexes Curr. Opin. Chem. Biol. 2013, 17, 175-188.
[14] Dhara, S.; Kolishettib, N.; J., L. S.; Farokhzadb, O. C. Targeted
delivery of a cisplatin prodrug for safer and more effective
prostate cancer therapy in vivo. Proc. Natl Acad. Sci. USA 2011,
108, 1850–1855.
[15] Dorr, M.; Meggers, E. Metal complexes as structural templates
for targeting proteins. Curr. Opin. Chem. Biol. 2014, 19, 76-81.
Past, Current and Future Use of Metals in Medicine 21
[16] Hearn, J. M.; Romero-Canelón, I.; Qamar, B.; Liu, Z.; HandsPortman, I.; Sadler, P. J. Organometallic iridium(III) anticancer
complexes with new mechanisms of action: NCI-60 screening,
mitochondrial targeting, and apoptosis. Chem. Biol. 2013, 8,
1335−1343.
[17] Lum, C. T.; Sun, R. W.-Y.; Zou, T.; Che, C.-M. Gold(III) complexes
inhibit growth of cisplatin resistant ovarian cancer in
association with upregulation of proapoptotic PMS2 gene.
Chem. Sci. 2014, 5, 1579-1584.
[18] Mjos, K. D.; Orvig, C. Metallodrugs in medicinal inorganic
chemistry. Chem. Rev. 2014, 114, 4540−4545.
[19] Valencia, P. M.; Pridgen, E. M.; Perea, B.; Gadde, S.; Sweeney,
C.; Kantoff, P. W.; Bander, N. H.; Lippard, S. J.; Langer, R.;
Karnik, R. Synergistic cytotoxicity of irinotecan and cisplatin
in dual-drug targeted polymeric nanoparticles. Nanomedicine
2013, 8, 687-698.
[20] Wu, K.; Liu, S.; Luo, Q.; Hu, W.; Li, X.; Wang, F.; Zheng, R.; Cui,
J.; Sadler, P. J.; Xiang, J. Thymines in single-stranded pligonucleotides and G-quadruplex DNA are competitive with guanines
for binding to an organoruthenium anticancer complex. Inorg.
Chem. 2013, 52, 11332−11342.
[21] Lorincz, M. T. Neurologic Wilson’s disease. Ann. N. Y. Acad. Sci.
2010, 1184, 173-187.
[22] Anderson, G. J. Ironing out disease: inherited disorders of iron
homeostasis. IUBMB Life 2001, 51, 11-17.
[23] Tubek, S.; Grzanka, P.; Tubek, I. Role of zinc in hemostasis: A
review. Biol. Trace Elem. Res. 2008, 121, 1-8.
[24] Nash Robert, A. Metals in medicine. Altern. Ther. Health Med.
2005, 11, 18-25.
[25] Nangia, A. K.; Hung, C. T.; Lim, J. K. C. Silver sulfadiazine in the
management of burns - an update. Med. Actual. 1987, 21-30.
[26] de Carvalho Oliveira; Santelli, R. E. Occurrence and
chemical speciation analysis of organotin compounds in the
environment: A review. Talanta 2010, 82, 9–24.
[27] Abromowitz, E. W. Historical points of interest on the mode of
action and ill effects of mercury. Bull. N. Y. Acad. Med. 1934, 10,
695-705.
[28] Waldron, H. A. Did the mad hatter have mercury poisoning? Br.
Med. J. (Clin. Res. Ed.) 1983, 287, 1961.
[29] Li, Z.; Conti, P. S. Radiopharmaceutical chemistry for positron
emission tomography. Adv. Drug Deliv. Rev. 2010, 62,
1031-1051.
[30] Waters, E. A.; Wickline, S. A. Contrast agents for MRI. Basic Res.
Cardiol. 2008, 103, 114-121.
[31] Galm, U.; Hager, M. H.; Van Lanen, S. G.; Ju, J.; Thorson, J. S.;
Shen, B. Antitumor antibiotics: bleomycin, enediynes, and
mitomycin. Chem. Rev. 2005, 105, 739-758.
[32] Feng, L.; Geisselbrecht, Y.; Blanck, S.; Wilbuer, A.; AtillaGokcumen, G. E.; Filippakopoulos, P.; Kraling, K.; Celik, M.
A.; Harms, K.; Maksimoska, J. Structurally sophisticated
octahedral metal complexes as highly selective protein kinase
inhibitors. J. Am. Chem. Soc. 2011, 133, 5976-5986.
[33] Kumar, K.; Tweedle, M.; Brittain, H. G. Gadoteridol. Anal.
Profiles Drug Subst. Excipients 1996, 24, 209-241.
[34] Pachet, A. K.; Wisniewski, A. M. The effects of lithium on
cognition: an updated review. Psychopharmacology 2003, 170,
225-234.
[35] Fricker, S. P. Medical uses of gold compounds: Past, present
and future. Gold Bull. 1996, 29, 53-60.
Unauthenticated
Download Date | 6/15/17 8:02 PM
22 S.S. Bradford, J.A. Cowan
[36] Bierer, D. W. Bismuth subsalicylate: history, chemistry, and
safety. Rev. Infect. Dis. 1990, 12, S3-S8.
[37] Sundar, S.; Chakravarty, J. Leishmaniasis: an update of current
pharmacotherapy. Expert Opin. Pharmacother. 2013, 14, 53-63.
[38] Murray, H. W. Leishmaniasis in the United States: treatment in
2012. Am. J. Trop. Med. Hyg. 2012, 86, 434–440.
[39] Kennedy, L.; Sahn, S. A. Talc pleurodesis for the treatment
of pneumothorax and pleural effusion. Chest 1994, 106,
1215-1222.
[40] Moghissia, K.; Dixon, K.; Honsa, B. A.; Stringer, M.; Thorpe, J.
A. C. Photofrin PDT for early stage oesophageal cancer: long
term results in 40 patients and literature review. Photodiag.
Photodynam. Therap. 2009, 6, 159-166.
[41] Douer, D.; Hu, W.; Giralt, S.; Lill, M.; DiPersio, J. Arsenic trioxide
(Trisenox) therapy for acute promyelocytic leukemia in the
setting of hematopoietic stem cell transplantation. Oncologist
2003, 8, 132-140.
[42] Emmanouilides, C. Radioimmunotherapy for non-Hodgkin’s
lymphoma. Semin. Oncol. 2003, 30, 531-544.
[43] Anderson, P.; Nunez, R. Samarium lexidronam (Sm-153EDTMP): Skeletal radiation for osteoblastic bone metasteses
and osteosarcoma. Expert Rev. Anticancer Therap. 2007, 7,
1517-1527.
[44] Shirley, M.; McCormack, P. L. Radium-223 Dichloride: A review
of its use in patients with castration-resistant prostate cancer
with symptomatic bone metastases. Drugs 2014, 74, 579-586.
[45] Windsor, P. M. Predictors of response to strontium-89
(Metastron1) in skeletal metastases from prostate cancer:
report of a single centre’s 10-year experience. Clin. Oncol.
2001, 13, 219–222.
[46] Rosenberg, B.; Vancamp, L.; Krigas, T. Inhibition of cell division
in Escherichia coli by electrolysis products from a platinum
electrode. Nature 1965, 205, 698-699.
[47] Howell, S. B.; Safaei, R.; Larson, C. A.; Sailor, M. J. Copper
transporters and the cellular pharmacology of the platinumcontaining cancer drugs. Mol. Pharmacol. 2010, 77, 887-894.
[48] Fuertes, M. A.; Castilla, J.; Alonso, C.; Perez, J. M. Cisplatin
biochemical mechanism of action: from cytotoxicity to
induction of cell death through interconnections between
apoptotic and necrotic pathways. Curr. Med. Chem. 2003, 10,
257-266.
[49] Reedijk, J. Fast and slow versus strong and weak metal–DNA
binding: consequences for anti-cancer activity. Metallomics
2012, 4, 628-632.
[50] Casini, A.; Reedijk, J. Interactions of anticancer Pt compounds
with proteins: an overlooked topic in medicinal inorganic
chemistry? Chem. Sci. 2012, 3, 3135-3144.
[51] Li, H.; Snelling, J. R.; Barrow, M. P.; Scrivens, J. H.; Sadler, P.
J.; O’Connor, P. B. Mass spectrometric strategies to improve
the identification of Pt(II)-modification sites on peptides and
proteins. J. Am. Soc. Mass Spectrom. 2014, 25, 1217-1227.
[52] Stordal, B.; Pavlakis, N.; Davey, R. Oxaliplatin for the treatment
of cisplatin-resistant cancer: A systematic review. Cancer Treat.
Rev. 2007, 33, 347-357.
[53] Di Pasqua, A. J.; Goodisman, J.; Dabrowiak, J. C. Understanding
how the platinum anticancer drug carboplatin works: From the
bottle to the cell. Inorg. Chim. Acta 2012, 389, 29-35.
[54] Umezawa, H.; Maeda, K.; Takeuchi, T.; Okami, Y. New
antibiotics, bleomycin A and B. J. Antibiot., Ser. A 1966, 19,
200-209.
[55] Burger, R. M.; Projan, S. J.; Horwitz, S. B.; Peisach, J. The DNA
cleavage mechanism of iron-bleomycin. Kinetic resolution
of strand scission from base propenal release. J. Biol. Chem.
1986, 261, 15955-15959.
[56] Chin, J. Developing artificial hydrolytic metalloenzymes by
a unified mechanistic approach. Acc. Chem. Res. 1991, 24,
145-152.
[57] Cowan, J. A. Chemical nucleases. Curr. Opin. Chem. Biol. 2001,
5, 634-642.
[58] Haner, R. Artificial ribonucleases. Chimia 2001, 55, 1035-1037.
[59] Jin, Y.; Lewis, M. A.; Gokhale, N. H.; Long, E. C.; Cowan, J. A.
Influence of stereochemistry and redox potentials on the
single- and double-strand DNA cleavage efficiency of Cu(II)· and
Ni(II)·Lys-Gly-His-derived ATCUN metallopeptides. J Am Chem
Soc 2007, 129, 8353-8361.
[60] Kikuta, E.; Aoki, S.; Kimura, E. A New Type of Potent Inhibitors
of HIV-1 TAR RNA-Tat peptide binding by zinc(II)-macrocyclic
tetraamine complexes. J. Am. Chem. Soc. 2001, 123, 7911-7912.
[61] Livieri, M.; Mancin, F.; Tonellatoa, U.; Chin, J. Multiple
functional group cooperation in phosphate diester cleavage
promoted by Zn(II) complexes. Chem. Commun. 2004, 2862-63.
[62] Morrow, J. R.; Amyes, T. L.; Richard, J. P. Phosphate binding
energy and catalysis by small and large molecules. Acc. Chem.
Res. 2008, 41, 539-548.
[63] Sreedhara, A.; Cowan, J. A. Catalytic hydrolysis of DNA by metal
ions and complexes. J. Biol. Inorg. Chem. 2001, 6, 337-347.
[64] Suh, J. Synthetic artificial peptidases and nucleases using
macromolecular catalytic systems. Acc. Chem. Res. 2003, 36,
562-570.
[65] Suh, J.; Chei, W. S. Metal complexes as artificial proteases:
toward catalytic drugs. Curr. Op. Chem. Biol. 2008, 12, 207-213.
[66] Yashiro, M.; Ishikubo, A.; Komiyama, M. Dinuclear
lanthanum(III) complex for Efficient hydrolysis of DNA. J.
Biochem. 1996, 120, 1067-1069.
[67] Yoo, S. H.; Lee, B. J.; Kim, H.; Suh, J. Artificial metalloprotease
with active site comprising aldehyde group and Cu(II) cyclen
complex. J. Am. Chem. Soc. 2005, 127, 9593-9602.
[68] Hocharoen, L.; Cowan, J. A. Metallotherapeutics: Novel
strategies in drug design. Chem. Eur. J. 2009, 15, 8670-8676.
[69] Sarkar, B.; Wigfield, Y. Evidence for albumin-Cu(II)-amino acid
ternary complex. Can. J. Biochem. 1968, 46, 601-607.
[70] Lau, S.-J.; Kruck, T. P. A.; Sarkar, B. Peptide molecule mimicking
the copper(II) transport site of human serum albumin.
Comparative study between the synthetic site and albumin. J.
Biol. Chem. 1974, 249, 5878-5884.
[71] Brittain, I. J.; Huang, X.; Long, E. C. Selective recognition and
cleavage of RNA loop structures by Ni (II)-Xaa-Gly-His metallopeptides. Biochemistry 1998, 37, 12113-12120.
[72] Camerman, N.; Camerman, A.; Sarkar, B. Molecular design
to mimic the copper(II) transport site of human albumin. The
crystal and molecular structure of copper(II)-glycylglycyl-Lhistidine-N-methyl amide monoaquo complex. Can. J. Chem.
1976, 54, 1309-1316.
[73] Conato, C.; Kozlowski, H.; Mlynarz, P.; Pulidori, F.; Remelli,
M. Copper and nickel complex-formation equilibria with
Lys-Gly-His-Lys, a fragment of the matricellular protein SPARC.
Polyhedron 2002, 21, 1469-1474.
[74] Harford, C.; Sarkar, B. Amino terminal Cu(II)- and Ni(II)-binding
(ATCUN) motif of proteins and peptides: metal binding, DNA
Unauthenticated
Download Date | 6/15/17 8:02 PM
cleavage, and other properties. Acc. Chem. Res. 1997, 30,
123-130.
[75] McDonald, M. R.; Fredericks, F. C.; Margerum, D. W. Characterization of copper(III)-tetrapeptide complexes with histidine as
the third residue. Inorg. Chem. 1997, 36, 3119-3124.
[76] Gokhale, N. H.; Cowan, J. A. Metallopeptide-promoted
inactivation of angiotensin-converting enzyme and endothelinconverting enzyme 1: toward dual-action therapeutics. J. Biol.
Inorg. Chem. 2006, 11, 937-947.
[77] Gokhale, N. H.; Bradford, S.; Cowan, J. A. Catalytic inactivation
of human carbonic anhydrase I by a metallopeptidesulfonamide conjugate is mediated by oxidation of active site
residues. J. Am. Chem. Soc. 2008, 130, 2388-2389.
[78] Joyner, J. C.; Hocharoen, L.; Cowan, J. A. Targeted catalytic
inactivation of angiotensin converting enzyme by lisinoprilcoupled transition metal chelates. J. Am. Chem. Soc. 2012, 134,
3396-3410.
[79] Kim, M.-s.; Jeon, J. W.; Suh, J. Angiotensin-cleaving catalysts:
conversion of N-terminal aspartate to pyruvate through
oxidative decarboxylation catalyzed by Co(III)cyclen. J. Biol.
Inorg. Chem. 2005, 10, 364-372.
[80] Chei, W. S.; Ju, H.; Suh, J. New chelating ligands for Co(III)based peptide-cleaving catalysts selective for pathogenic
proteins of amyloidoses. J. Biol. Inorg. Chem. 2011, 16, 511-519.
[81] Podsiadlo, P.; Komiyama, T.; S., F. R.; Blum, O. Furin inhibition
by compounds of copper and zinc. J. Biol. Chem. 2004, 279,
36219–36227.
Past, Current and Future Use of Metals in Medicine 23
[82] Joyner, J. C.; Hodnick, W. F.; Cowan, A. S.; Tamuly, D.; Boyd,
R.; Cowan, J. A. Antimicrobial metallopeptides with broad
nuclease and ribonuclease activity. Chem. Commun. 2013, 49,
2118-2120.
[83] Preihs, C.; Arambula, J. F.; Magda, D.; Jeong, H.; Yoo, D.;
Cheon, J.; Siddik, Z. H.; Sessler, J. L. Recent developments in
texaphyrin chemistry and drug discovery. Inorg. Chem. 2013,
52, 12184−12112.
[84] Kameshima, W.; Ishizuka, T.; Minoshima, M.; Yamamoto, M.;
Sugiyama, H.; Xu, Y.; Komiyama, M. Conjugation of peptide
nucleic acid with a pyrrole/imidazole polyamide to specifically
recognize and cleave DNA. Ang. Chem. Int. Ed. 2013, 52, 13681
–13684.
[85] Joyner, J. C.; Keuper, K. D.; Cowan, J. A. Kinetics and
mechanisms of oxidative cleavage of HIV RRE RNA by
Rev-coupled transition metal–chelates. Chem. Sci. 2013.
[86] Joyner, J. C.; Cowan, J. A. Targeted cleavage of HIV RRE RNA by
Rev-coupled transition metal chelates. J. Am. Chem. Soc. 2011,
133, 9912-9922.
[87] Bradford, S.; Cowan, J. A. Catalytic metalloDrugs targeting HCV
IRES RNA. Chem. Commun. 2012, 48, 3118-3120.
[88] Bradford, S. S.; Ross, M. J.; Fidai, I.; Cowan, J. A. Insight
into the recognition, binding, and reactivity of catalytic
metallodrugs targeting stem loop IIb of hepatitis C IRES RNA.
ChemMedChem 2014, 9, 1275–1285.
[89] Cowan, J. A. Catalytic metallodrugs. Pure & App. Chem. 2008,
80, 1799-1810.
Unauthenticated
Download Date | 6/15/17 8:02 PM