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FEATURE ARTICLE

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Targeting proteins with metal complexes

Eric Meggers

Published on 12 January 2009. Downloaded by University of Belgrade on 21/02/2016 19:43:54.

Received (in Cambridge, UK) 11th August 2008, Accepted 17th November 2008
First published as an Advance Article on the web 12th January 2009
DOI: 10.1039/b813568a
Unique properties of metal complexes, such as structural diversity, adjustable ligand exchange
kinetics, ne-tuned redox activities, and distinct spectroscopic signatures, make them exciting
scaolds not only for binding to nucleic acids but increasingly also to proteins as non-traditional
targets. This feature article discusses recent trends in this eld. These include the use of chemically
inert metal complexes as structural scaolds for the design of enzyme inhibitors, new strategies
for inducing selective coordination chemistry at the protein binding site, recent advances in the
development of catalytic enzyme inhibitors, and the design of metal complexes that can inject
electrons or holes into redox enzymes. A common theme in many of the discussed examples is
that binding selectivity is at least in part achieved through weak interactions between the ligand
sphere and the protein binding site. These examples hint to an exciting future in which organiclike molecular recognition principles are combined with properties that are unique to metals and
thus promise to yield compounds with novel and unprecedented properties.

Introduction
The design of synthetic molecules that are capable of
selectively perturbing the function of individual biomolecules
is at the heart of chemical biology and medicinal chemistry.
Strikingly, the stark majority of such compounds is of purely
organic origin.1 This may seem surprising since chemists have
the opportunity to recruit elements with ne-tuned characteristics from all over the periodic table of elements. For example,
unique properties of metal complexes may oer untapped
opportunities for the development of novel probes to unravel

Fachbereich Chemie, Philipps-Universitat Marburg,

Hans-Meerwein-Strasse, 35043 Marburg, Germany.
E-mail: meggers@chemie.uni-marburg.de; Fax: +49 6421 2822189;
Tel: +49 6421 2821534

Eric Meggers was born in

Bonn, Germany, and received
his Diploma in Chemistry
from the University of Bonn
in 1995 and a PhD from the
University of Basel in 1999,
working under the guidance
of Professor Bernd Giese on
the transport of charge in
DNA. After postdoctoral research on metal-mediated base
pairing in DNA with Professor
Peter G. Schultz at the
Scripps Research Institute in
La Jolla, USA, he became
Eric Meggers
in 2002 an Assistant Professor
in the Chemistry Department at the University of Pennsylvania.
Since 2007, Eric Meggers is Professor at the Philipps-University
Marburg. His main research interest is currently the design of
inert organometallic compounds with biological activity.
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the function of proteins, the design of sensors, as well as the

generation of drugs and diagnostics. The most notable
features of metal complexes are listed below:
 A variety of coordination numbers and geometries of
metal complexes result in a high structural diversity. This
might be exploited for the design of pharmacophores that
are not accessible with purely organic elements.
 Metal complexes are readily susceptible to combinatorial
synthesis since compounds are built from a common center
and ligand exchange reactions often proceed in a predictable
fashion. This allows one to discover complexes with desired
properties by combinatorial library synthesis followed by
high-throughput screening.
 Unique and tunable properties of metals, such as adjustable ligand exchange kinetics, catalytic properties, redox
activities, Lewis acidities, access to radical species, magnetic
properties, spectroscopic properties, and radioactivity, can be
exploited for the generation of tailored function.
This feature article will focus on recent advances in the
design of metal-containing compounds as protein binders.
Emphasis will be placed on the strategies for achieving target
binding along with the particular functions of the involved
metals.

Metal complexes as inert scaolds

From tetrahedral carbon to octahedral metal
Metal complexes can complement purely organic molecules by
serving as structural scaolds for the design of compounds
with bioactivity. Whereas carbon is limited in binding geometries to linear (sp-hybridization), trigonal planar (sp2-hybridization), and tetrahedral (sp3-hybridization) geometries,
transition metals oer the opportunity to go beyond the
coordination number four. For example, it is intriguing that
an octahedral center with six dierent substituents is capable
of forming 30 stereoisomers compared to just two for an
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Fig. 1 The number of possible stereoisomers as an indicator for

structural opportunities that a single center can provide.

asymmetric tetrahedral carbon. This number of stereoisomers

can be correlated with the ability of this center to build
structures (Fig. 1). This means, that by raising the number
of substituents from four (tetrahedral center) to six (octahedral center), the ability of this center to organize substituents in the three dimensional space increases substantially. In
addition, using a hexavalent center may provide new synthetic
opportunities for accessing globular shapes by building structures from a single center in six dierent directions. Interestingly, until our work on ruthenium complexes as kinase
inhibitors, only very few examples have been reported in which
structural properties of metal complexes are exploited as
pharmacophores with novel geometries.2
Metal complexes as kinase inhibitors
Starting at the University of Pennsylvania in 2002, my group
decided to systematically explore the ability of metal centers to
help creating unique and dened molecular structures for the
design of enzyme inhibitors.318 We envisioned that a substitutionally inert metal center could complement organic
elements, serving as a stable imaginary hypervalent carbon
with an improved ability to build structures.
We chose protein kinases as the principal target because
mutations and deregulation of protein kinases play causal
roles in many human diseases, making kinases an important
therapeutic target. In addition, kinases form one of the largest

family of enzymes with very conserved ATP binding sites for

which the design of selective organic inhibitors has proven to
be highly challenging.
The class of ATP-competitive indolocarbazole alkaloids
(e.g. staurosporine, Fig. 2(a)) was used as an inspiration and
initial lead structure. According to our design, the indolocarbazole alkaloid scaold is replaced by metal complexes in
which the main features of the indolocarbazole aglycon are
retained in the metal-chelating pyridocarbazole ligand,
whereas the carbohydrate is substituted by a globular metal
fragment (Fig. 2(a)). Following this strategy, nanomolar and
even picomolar ATP-competitive ruthenium-based inhibitors
for dierent protein kinases were discovered, some of them by
combinatorial chemistry, some by rational design, or a combination thereof.3 Such compounds are air-stable, stable in
water, and in buer solutions containing millimolar concentrations of thiols. This stability is due to the inert character of
typical coordinative bonds to ruthenium. This, together with
its modest price of the starting material RuCl3, its low toxicity,
and its predictable and established synthetic chemistry, makes
ruthenium maybe the most attractive metal for establishing
octahedral or pseudo-octahedral (e.g. half-sandwich) coordination geometries. We further demonstrated that such ruthenium compounds can exert their selective function within
mammalian cells, Xenopus embryos, and zebrash embryos.
Recent cocrystal structures conrm that these compounds
bind to the ATP-binding site of protein kinases. For example,
Fig. 2(b) displays the octahedral organoruthenium complex
L-FL172 (see also Fig. 2(c)) bound to the ATP-binding site of
the protein kinase PAK-1.18 PAK-1 has a particularly open
ATP-binding site, making it dicult to target with conventional organic scaolds, but especially suitable for lling it
with bulky and rigid octahedral complexes. In L-FL172, the
distance between the oxygen atom of the CO ligand and the
para-carbon of the pyridine in trans serves as a rigid yardstick

Fig. 2 Ruthenium complexes as protein and lipid kinase inhibitors. (a) Staurosporine as the lead structure for the design of metal complexes.
(b) Cocrystal structure of protein kinase PAK1 with the octahedral inhibitor L-FL172. Displayed are the most important H-bonding interactions
and a surface view demonstrating the shape match between active site and coordination sphere. (c) A selection of potent and selective rutheniumbased kinase inhibitors. IC50 values were measured at 100 mM ATP if not indicated otherwise.

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of about 8 A which is well accommodated by the active site of

PAK1, but not most other protein kinases. It is noteworthy
that the D-enantiomer is a signicantly weaker binder for
PAK1 (27-fold). Such a stereodierentiation is expected for
the molecular recognition of a chiral active site.
In summary, over the last ve years, our group reported
highly potent organometallic inhibitors for the kinases GSK-3,
Pim-1, MSK-1, PAK-1 and PI3K (Fig. 2(c)), thus demonstrating the generality of the design strategy. We deposited
seven cocrystal structures of metal complexes with kinases in
the PDB (Pim-1 with Ru:2BZH, 2BZI, 2OI4, 2 BZJ; Pim-2
with Ru:2IWI; PI3Kg with Ru:2CST; Pim-1 with Os:3BWF).
In all these crystal structures, the metal exerts a purely
structural role. Some of the published inhibitors belong to
the most potent and selective compounds known for their
respective kinases. We hypothesize that the high selectivities
are caused by the rigidities of these scaolds. The complex
EA1 (Fig. 2(c)) and derivatives thereof have also been demonstrated to display promising anticancer activities in several
cancer cell lines and in a melanoma spheroid model,12 and it
will now be important to investigate potential ecacy in an
animal model.

activities of chemically inert cationic polypyridyl complexes of

ruthenium(II).1923 Dwyer concluded that due to the marked
chemical and biological stability of such ruthenium cations,
their biological eects must be due to the cation as a whole and
not to its individual constituents. Such ruthenium complexes
also caused paralysis and respiratory failure after intraperitoneal injection into mice at high concentrations, apparently due
to their potent direct inhibition of acetylcholinesterase
(AChE). These cationic ruthenium complexes most likely bind
through a combination of electrostatic and hydrophobic interactions at the peripheral anionic site of AChE which is located
at the rim of the active-center gorge.24
Our group recently followed up on these discoveries and
screened a small library of trisheteroleptic ruthenium polypyridyl complexes, synthesized on solid phase, against AChE
and identied complex SPM1 to be a nanomolar inhibitor
(IC50 = 200 nM) for AChE from E. electricus (Fig. 3(a)).25
Compared to the parent [Ru(phen)3]Cl2 (IC50 = 10 mM) this is
an improvement by a factor of around 50-fold, just by
functionalizing the periphery of this ruthenium polypyridine
scaold. It is likely that further improvements in the anity of
this scaold would be possible in a straightforward fashion
through the synthesis and screening of larger libraries.

Ruthenium polypyridyl complexes as acetylcholinesterase

inhibitors

Iron Schi-base complexes as inhibitors of trypsin and thrombin

In pioneering work, Dwyer investigated the biological

activities of a variety of metal complexes and discovered,
among others, the bacteriostatic, bacteriocidal, and antitumor

Tanizawas group developed Cu(II) and Fe(III) Schi base

chelates as inhibitors for the serine proteases thrombin
and trypsin.26,27 The Schi bases were obtained from

Fig. 3 (a) IC50-curves of ruthenium polypyridine complexes SPM1 and [Ru(phen)3]Cl2 against AChE from E. electricus (both complexes
racemic). The activity of AChE as a function of the concentration of ruthenium inhibitors was measured by a standard colorimetric method using
acetylthiocholine as the substrate. (b) Bis(p-amidinosalicylidene-L-alanilato)iron(III) (1) as inhibitor for the protease trypsin. Right: Crystal
structure of the iron Schi base complex 1 bound to bovine b-trypsin (PDB code 1G3C). (c) Na7[Ru4(m3-O)4(C2O4)6] has been reported to be a very
potent inhibitor of HIV-1 reverse transcriptase (IC50 = 1.9 nM). (d) Metal complex of a pentaazacrown (2) suggested as nonpeptidyl amylase
inhibitor by mimicking the reverse turn sequence Trp18-Arg19-Tyr20 (highlighted in pink) of the natural inhibitor tendamistat.

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4-formyl-3-hydroxybenzamidines or 3-formyl-4-hydroxybenzamidines and amino acids. Most interestingly, a cocrystal

structure of bis(p-amidinosalicylidene-L-alanilato)iron(III)
(Fig. 3(b), 1, Ki = 1.6 mM) with bovine b-trypsin revealed
that the octahedrally coordinated iron is not involved in any
direct interactions with the active site and has a purely
structural role.26 One of the phenylamidinium residues forms
a bidentate salt bridge with the side chain of Asp189 at the
bottom of the hydrophobic selectivity (S1) pocket, in analogy
to many related organic inhibitors that are based on the
phenylamidinium scaold. Notably, the catalytic triad is not
involved in any interactions with the iron chelate. Due to the
facile access of these Schi base chelate complexes, a variation
of the aldehyde moiety, amino acid residues, and metal ions,
should allow for quick structureactivity-relationships for
improving the binding anities. In fact the authors recently
reported copper and iron complexes as nanomolar inhibitors
for thrombin.27 However, in the case of the octahedral
chelates, the use of labile metal ions prevents the synthesis of
mixed ligand complexes. Thus, the utilization of kinetically
more inert complexes of ruthenium, rhodium or iridium
instead of iron should enable a more sophisticated design
of the ligand sphere with the prospect of achieving higher
anities and selectivities.
Ruthenium-oxo-oxalato cluster as inhibitor of HIV-1 reverse
transcriptase
Many polyoxometallates (POMs) show promising antiviral
activities in vitro and in vivo.28 POMs active against HIV-1
exhibit at least three modes of actions: Interference with the
HIV gp120/CD4 interaction, inhibition of HIV reverse transcriptase (RT), and/or inhibition of HIV protease. Favorable
electrostatic interactions between the polyanionic POMs and
cationic binding sites at the protein component appear to
be very important. Unfortunately, most POMs are not
stable under physiological conditions, making it dicult to
determine the active species. This is however not the case for
the ruthenium-oxo-oxalato cluster Na7[Ru4(m3-O)4(C2O4)6]
(Fig. 3(c)), which is a particularly potent inhibitor of HIV
RT with an IC50 value of 1.9 nM.29 This cluster has been
demonstrated to be stable under physiological conditions and
shows promising anti-HIV-1 activity without being cytotoxic.
Metal coordinated pentaazacrowns as b-turn mimics
Metal coordination can control the conformation of a macrocycle. For example, Marshall and coworkers propose the
utilization of metal complexes of chiral azacrowns (MACs),
derived from the reduction of cyclic peptides, as a strategy for
controlling the conformation and xing chiral side chains in
orientations comparable with those of peptide b-turns.30,31 In
this design, the metal is buried in the middle only acting as a
glue to keep all the pharmacophore groups oriented together
in the right directions. Crystal structures of MACs and
calculated solution structures demonstrate that MACs provide
preferred templates closely resembling the overall direction of
reverse-turn motifs as well as the spatial locations of side
chains. For example, it was suggested that the MAC complex
2 (Fig. 3d) should serve as a nonpeptidic inhibitor of amylase
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by mimicking the active reversed b-turn sequence Trp18-Arg19Tyr20 of the proteinaceous amylase inhibitor tendamistat.32,33
However, it is noteworthy that Riley and coworkers are
developing related MACs for clinical use based on their
high catalytic dismutase activity, thus demonstrating that the
metal center in such MACs can exert functions beyond their
structural roles.34

Metal coordination to amino acid side chains

Whereas in the previous section metal complexes were
designed with the metal center exerting a purely structural
role, here examples will be discussed in which the metal forms
one or even multiple coordinative bonds to residues at the
protein surface or within the active site.
Spurred by the discovery of the guanine crosslinking properties of the anticancer drug cisplatin, metal complexes
have traditionally been targeted to the nucleophilic guanine
bases of DNA and proteins or enzymes were more or less
neglected. However, the available data of the sequenced
human genome together with eorts to understand the structure and function of every single human protein results in
fastly growing amounts of data available for targeted therapy.
In this respect, in particular the amino acids cysteine, histidine,
and tyrosine, constitute exquisite protein binding sites for
metal complexes with vacant coordination sites. In order
to create coordinating metal complexes with controlled biological properties, the ligand exchange kinetics can be adjusted
by the metal, its oxidation state, the (semi)labile ligand, and
the remaining coordination sphere. However, in order to
achieve a high degree of target selectivity it is necessary to
combine a ne-tuned reactivity of the metal center with
molecular recognition of the target site by the ligand sphere
of the metal complex. The here presented examples indicate
the interplay between coordination chemistry and molecular
recognition through weak interactions mediated by the
ligand sphere.
Oxorhenium(V) complex as selective cathepsin B inhibitor
Fricker et al. discovered a simple oxorhenium(V) complex 3
(Fig. 4(a)) with an impressive low nanomolar binding anity
for cathepsin B (IC50 = 9 nM).35,36 Cathepsin B is a cysteine
protease in which a cysteine is activated within a catalytic
triad, resulting in an increased reactivity of the cysteine
nucleophile. Mechanistic studies reveal that the rhenium
complex is an active site directed time-dependent slowly
reversible inhibitor in the presence of an excess of exogenous
cysteine, thus indicating a coordination to the active site
cysteine by substituting the labile chloride ligand. This
mode of action is analogous to the majority of organic cysteine
protease inhibitors which form a reversible or irreversible
covalent bond with the reactive cysteine in the active site.
However, it is intriguing that this compound showed a 44-fold
selectivity for cathepsin B over the related cathepsin K.
A structure-activity relationship around the tridentate
2,2 0 -thiodiethanethiolate ligand demonstrated the importance
of a particular coordination sphere which is most
likely dictated by the size and shape of the active site of
cathepsin B.
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Fig. 4 Examples of metal complexes undergoing coordination chemistry at the target site. (a) Selected complexes 37. (b) Crystal structure of
bovine low molecular weight phosphotyrosyl phosphatase coordinated to trigonal bipyramidal vanadate through the active site Cys12 (PDB code
1Z12). The vanadate oxygen atoms are involved in extensive H-bonds. (c) Crystal structure of a human glutathione reductase after the reaction
with the phosphole gold complex 8 (PDB code 2AAQ). Two gold binding sites are observed: Complex 8 binds to the surface-exposed Cys284 under
substitution of the chloride. In addition, one gold atom is linear coordinated between Cys58 and Cys63 in the active site. The gold atoms are shown
as orange spheres. (d) Histidine recognition with cupric imino diacetate chelates of 9 and BR30. Right: Crystal structure of human carbonic
anhydrase II with BR30 bound in the active site and coordination of the copper complex to His64 (PDB code 2FOV). (e) Metallated AMD3100
and the binding mode of one NiII-cyclam unit of NiII2-xylylbicyclam to hen egg white lysozyme (PDB code 2H9J). A second binding site which is
ca. 5 A away is not shown. The linker and second cyclam are not observed in the electron density map and are likely to be disordered. A water
molecule which occupies the second axial position at the NiII center is omitted.

Co(III) Schi-base conjugated to thrombin active site-directed

peptides
Meade and Gray et al. demonstrated the inhibition of the human
serine protease a-thrombin with a Co(III) Schi base complex
conjugated to an active site-directed peptide (4a, Fig. 4(a)).37
Selectivity is conferred by the reversible binding of the peptide
component, while an irreversible inhibition is believed to occur
through cobalt(III) coordination to histidines in the active site
or near the active site.
Cu(II) complexes as HIV-protease inhibitors
In another example of metal complexes as protease inhibitors,
copper(II) complexes were designed as HIV-1 protease inhibitors.3840 Complex 5 (Fig. 4(a)) displays a Ki value of 1 mM for
HIV-1 protease. Molecular modeling suggests that the pyridyl
group occupies the S2/S2 0 pockets whereas the trimethoxybenzyl group occupies the larger S1/S1 0 subsite.40 The copper
ion is positioned to coordinate the structural catalytic water
molecule in the active site and a second water ligand interacts
with the ap residue of Ile50. However, such Cu(II) complexes
are kinetically very labile and CuCl2 itself displays the same
IC50 value of 1 mM and is known to inhibit HIV-1 protease by
targeting the thiol group of cysteines.
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Targeting zinc ngers with platinum complexes

The Farrell group designed platinum complexes to selectively
target zinc nger proteins.41,42 The reaction of the platinum
complex trans-[PtCl(9-EtG)(py)2]+ (6, Fig. 4(a)) with the
C-terminal zinc nger of the HIV NCp7 protein results in a
coordination of the platinum complex to the zinc nger under
zinc ejection and loss of tertiary structure. The proposed
mechanism involves an initial noncovalent recognition in
which the platinated purine nucleobase mimics the natural
nucleic acid-tryptophan recognition interaction of zinc nger
peptides by stacking the coordinated 9-ethylguanine ligand
against a tryptophan of NCp7. In a related fashion, Louie and
Meade used oligonucleotide-tethered cobalt salen complexes
4b (Fig. 4) to selectively target zinc ngers.43
Vanadium complexes as phosphatase inhibitors
The isostructural nature of the simple vanadate (VO43) and
phosphate together with the ability of vanadium(V) to easily
change its coordination number and geometry results in its
strong eect on the function of a large variety of phosphoryl
transfer enzymes.44 For example, in the course of the catalytic
cycle of phosphatases leading to the hydrolysis of a phosphate,
the phosphorus passes through a pentacoordinated transition
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state that can be trapped by a stable pentacoordinated vanadate which serves as a transition state analog.45 Fig. 4(b)
shows the example of a tyrosine phosphatase complexed with
the inhibitor vanadate through an active site cysteine.46 In a
modied mode of action, pervanadates can serve as strong
oxidants, for example causing an irreversible inhibition by
oxidizing the catalytic cysteine of protein tyrosine phosphatases.47 This eectiveness of vanadate to inhibit tyrosine
phosphatases appears to be responsible for the insulin-mimetic
eect of many vanadate complexes.
A strategy to render vanadium compounds more selective
towards a particular target is the introduction of ligands into
the coordination sphere.48 For example, a recent publication
by Rosivatz and Woscholski et al. described the design of a
selective vanadyl inhibitor for the phosphinositide 3-phosphatase
PTEN (phosphatase and tensin homologue deleted on
chromosome 10).49 PTEN is characterized by a wide and
deep catalytic pocket which distinguishes it from other
cysteine-based phosphatases.50 The bulky vanadyl complex 7
(Fig. 4(a)),51 containing two 3-hydroxypicolinate ligands, one
water molecule, and an oxo ligand, appears to t well into this
pocket (IC50 = 35 nM), but not into those of other cysteinebased phosphatases such as PTPb, SAC, MTM and SopB.
Binding of gold complexes to proteins
Anthiarthritic gold(I)-phosphine compounds are prodrugs
which undergo facile ligand displacement reactions.52 Due to
the softness of Au(I), the critical target sites are thought to be
cysteine residues in proteins and enzymes. However, Sadler
et al. investigated the reactions between the enzyme cyclophilin and the antiarthritic complex [Au(PEt3)Cl] and reported
a crystal structure of Au(I) phosphane adduct, in which,
unexpectedly, Au(I) binds to a histidine residue despite the
presence of four cysteine thiol groups.53
Becker et al. reported the eects of highly potent phospholecontaining gold and platinum complexes on human disulde
reductases.54 An X-ray crystal structure of human glutathione
reductase, after reaction with the gold phosphole complex 8,
revealed an almost linear SAu(I)S coordination in the active
site (Fig. 4(c)), conrming that the phosphine-gold chloride
complexes act as prodrugs with a stepwise ligand replacement.
Furthermore, one surface-exposed cysteine (Cys284) is
complexed to 8 by replacement of the chloride, showing how
the phosphole ligand forms hydrophobic contacts with neighboring surface residues (Fig. 4(c)).
Recognition of the surface histidine pattern
Mallik et al. designed cupric iminodiacetate chelate complexes
which recognize the unique pattern of histidine residues on
protein surfaces.5558 For example, carbonic anhydrase contains ve histidines exposed on its surface and molecular
modeling led to the design of the tris-chelate 9 (Fig. 4(d)),
which binds carbonic anhydrase with a binding constant
of 3  106 M1 and is selective over chicken-egg albumin
(six histidines on the surface, K o 1  103 M1).55,56
In a variation of this concept, two-prong inhibitors were
designed for carbonic anhydrase in which an organic benzenesulfonamide active site inhibitor was tethered to cupric
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iminodiacetate through designed linkers. For example, the

high-resolution crystal structure in Fig. 4(d) demonstrates that
the organic sulfonamide inhibitor BR30 binds within the
conical active site cleft and coordinates with the deprotonated
sulfonamide nitrogen to the catalytic zinc ion at the bottom of
the cleft.57 This brings the copper chelate in position to
coordinate to His64 which is located halfway out of the active
site cleft and serves as a proton shuttle during catalysis. This
rendered the otherwise weak benzenesulfonamide inhibitor
into a nanomolar and more selective inhibitor for human
carbonic anhydrase II (IC50 = 28 nM). This concept has
recently been expanded to a multi-prong design in which an
active site directed ligand is connected to multiple histidinerecognizing cupric iminodiacetate chelates.58
Metal-dependent binding of AMD3100 to CXCR4
p-Xylylbicyclam (AMD3100) is in phase II clinical trials for
stem cell transplantation and also a highly potent anti-HIV
agent by binding to the CXCR4 co-receptor which assists in
the entry of HIV into cells and anchors stem cells in the bone
marrow.59 Cyclam has a high anity for Zn(II) and should
therefore form a Zn(II) complex in the blood plasma.60 Interestingly, the anity of AMD3100 for the CXCR4 receptor is
enhanced after Zn(II) coordination by a factor of 36.61 The
Zn(II) inuences the conformation of the cyclam which probably aects the binding anity.62 Modeling studies suggest
that in addition to a variety of hydrophobic and H-bonding
interactions, one of the Zn(II) centers coordinates axially to an
aspartate carboxylate oxygen.63
The Sadler group investigated the binding of copper and
nickel cyclams to lysozyme as a model to study the recognition
of proteins by metallomacrocycles.64,65 For example, the
X-ray crystal structure of hen-egg white lysozyme soaked with
NiII2-xylylbicyclam 10 (Fig. 4(e), M = NiII) reveals two major
binding sites, with one being characterized by a coordination
of the Ni(II)-ion to an aspartate carboxylate group (Asp101) in
addition to hydrophobic interactions of the cyclam ring with
two tryptophan residues (Trp62 and Trp63).65 This example
demonstrates the capability of metallomacrocycles to combine
molecular recognition mediated by the macrocycle with the
ability to coordinate to the central metal ion through vacant
axial coordination sites.

Catalytic metal complexes

Metal complexes serve as highly ecient everyday catalysts for
organic transformations. It is therefore an appealing strategy
to make use of metal catalysts for deactivating or functionalizing desired proteins. This concept may lead to the design of
reagents for the modication of proteins with imaging tags,
and even to the design of catalytic drugs that are able to
recognize and degrade multiple copies of a biomolecular
target.66
Articial proteases
Su and coworkers have designed articial proteases by tethering the peptide cleaving CuII and CoIII complexes of 1,4,7,10tetraazacyclododecane (cyclen) to peptide nucleic acids,
peptides, and small molecule binder.67 For example, the
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in a designed reporter system.76 For this, a mutant haloalkane

dehalogenase, the so called HaloTag protein (HTP), was
genetically fused to luciferase which served as the reporter.
The conjugate made out of [Ru(bpy)3]2+ and a halogenoalkane (13, Fig. 5) reacts irreversibly with the HaloTagluciferase fusion protein by forming a carboxylic ester through
an active site carboxylate of HaloTag (see Fig. 5, bottom
right). This brings the chromophore [Ru(bpy)3]2+ in close
proximity to luciferase and the subsequent UV-irradiation
produces reactive singlet oxygen, resulting in its deactivation
which can be conveniently monitored by luminescence measurements. The success of this strategy was veried in cell extract
and even within living cells.

Miscellaneous
Fig. 5 Examples of catalytically active metal complexes. Bottom
right: CALI model system with complex 13. HTP = HaloTag protein,
Luc = luciferase (adapted from ref. 76).

conjugate 11 (Fig. 5) was found to catalytically cleave the

enzyme peptide deformylase between Gln152 and Arg153
within the C-terminal a-helix.68 In a similar fashion, articial
proteases against myoglobin,69 amyloid b peptides,70 and
angiotensin II71 were designed.
Enzyme inactivation by catalytic oxidation of active site residues
Cowan reported the design of metallopeptide conjugates as
catalytic inactivators of enzymes by using the amino terminal
copper/nickel (ATCUN) binding motif.7274 For example, in
the sulfonamide-metallopeptide conjugate 12 (Fig. 5), the
sulfanilamide pharmacophore targets the Cu2+-bound GlyGly-His (GGH) peptide motif to the active site of carbonic
anhydrase.74 GGH has a high anity for the redox active
Cu2+ with the most likely active species being a Cu2+associated hydroxyl radical or Cu3+QO species. Under
oxidative conditions (no reducing agent present) and subsaturating conditions a time-dependent inactivation is observed.
A residual 20% activity of carbonic anhydrase was observed
and explained with the intrinsic reactivity of the Cu complex
towards its own substrate. No protein cleavage was observed
but several histidine residues and two tryptophans in proximity
to the active site were oxidatively modied. Apparently, the
oxidation of amino acid residues was restricted to the proximity
of the active site where the inhibitor tail with the Cu-GGH
motif would be oriented.
Ru(II) tris-bipyridyl as light-activated singlet oxygen generator
In the technique CALI (chromophore-assisted light inactivation),75 a chromophore capable of generating reactive singlet
oxygen when irradiated is delivered to a target protein. Due to
the short lifetime of the singlet oxygen, only proteins in
proximity to the singlet oxygen generator will become deactivated by oxidation, thus providing spatial and temporal
control over protein inactivation. [Ru(bpy)3]2+ is an ecient
photocatalyst for singlet oxygen generation and can be used as
a warhead to deactivate the function of target proteins or
enzymes.76,77 In a proof-of-principle experiment, Kodadek
demonstrated this by deactivating the function of luciferase
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Molecular wires to probe active site of redox enzymes

The Gray laboratory developed a powerful photochemical
method for injecting electrons and holes into buried active
sites of redox proteins by using so-called molecular
wires.7887 Such molecular wires consist of a tail group that
makes contact to the active site and a redox active metal
complex as a head group that is tethered to the tail group
through a linker which spans the distance between the bottom
of the active site and the protein surface. This design allows
one to investigate mechanistic questions associated with redox
enzymes and may be developed into a highly sensitive and
selective detection method. Over the last 10 years, the strategy
has been applied to probe a variety of proteins, such as
cytochrome P450,7882 myoglobin,83 inducible nitric oxide
synthase,84,85 and copper amine oxidase.86,87
Multiple crystal structures of molecular wires that access the
metal sites of redox enzymes have been reported over the last
few years.7980,86,87 For example, Fig. 6(b) shows the binding
of the ruthenium(II) molecular wire 14 (Fig. 6(a)) to the amine
oxidase of Arthrobacter globiformis (AGAO).87 Complex
14 is a potent inhibitor of AGAO with nanomolar anity
(Ki = 32 nM) and this anity is independent of the chirality of
the [Ru(phen)(bpy)2]2+ head group. The wire binds in the
AGAO active-site channel with the dimethylaniline tail group
being in contact with the trihydroxyphenylalanine quinone
cofactor of the enzyme (Fig. 6(b)). The interactions of this tail
with the active site cavity are mainly through hydrophobic
interactions. The C4-linker stretches through the channel,
enabling the ruthenium head group to t into the end of the
active site channel and contributing to the high anity by
hydrophobic contacts with protein surface residues. It can be
envisioned that this scaold might be rendered even more
potent by modifying the ruthenium head group through
functionalizing the polypyridyl ligands in a structure-based
and/or combinatorial fashion in order to improve the contacts
to the entrance of the active site channel.
Ferrocifen, an organometallic prodrug
Ferrocifen 15 (Fig. 6(a)) is a derivative of the anticancer drug
tamoxifen in which a phenyl group is replaced by a ferrocene
moiety.8891 Tamoxifen is the front-line chemotherapeutic
agent for patients with hormone-dependent breast cancer.
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unique to the target site, or a combination thereof. Many

current approaches use modes of molecular recognition that
are analogous to typical organic protein binders and enzyme
inhibitors. Target selectivity together with aspects of metal
complex stabilities in biological systems will be the two most
critical aspect for the next generation of metal-containing
compounds used in chemical biology and medicinal chemistry.
In such compounds, dened molecular recognition will be
combined with properties that are unique to metal complexes,
such as photophysical signatures or catalysis, in order to create
compounds with novel and unprecedented properties.

Acknowledgements
I would like to thank all my past and present coworkers along
with many collaborators for their contributions. Financial
support from the US NIH (GM071695) and DFG (ME
1805/2-1) is gratefully acknowledged.

Fig. 6 (a) Metal complex 14 binds to amine oxidase, 15 to the estrogen

receptor, and 16 to cyclooxygenase. (b) Cutaway and surface view of the
L-enantiomer 14 bound to amine oxidase from Arthrobacter globiformis
(PDB code 2CFD).

The antiproliferative action of tamoxifen results from the competitive binding to the estrogen receptor ERa, thus repressing the
estradiol-mediated DNA transcription in the tumor tissue. The
activity of ferrocifen was believed to follow the same principle.89
However, recently it was shown that ferrocifen also acts against
tumor cells that lack this estrogen receptor, thus indicating a
yet unknown mode of action. Interestingly, the isostructural
ruthenocene derivative of 15 also acts as an antiestrogen in
hormone-dependent breast cancer cells but lacks the antiproliferative eect of ferrocifen against hormone-independent cells.90
This indicates that the function of ferrocifen in hormoneindependent cells is at least in part due to the redox activity of
the ferrocene unit. A recent electrochemical study by Jaouen,
Amatore and co-workers revealed that it may be a quinone
methide oxidative product that is involved in the mode of
action.91
Cobaltalkyne complexes of aspirin as COX inhibitors
The cobaltalkyne derivative 16 (Fig. 6(a)) of the drug aspirin
(acetylsalicylic acid) exhibits high cytotoxicity in breast cancer
cell lines.92 This cytotoxicity correlates with cyclooxygenase
(COX) inhibition and it can be speculated that 16 binds to
cyclooxygenase in a fashion similar to aspirin followed by an
acetylation of a surface residues or even a reaction of the
cobaltalkyne complex.

Conclusions
This collection of recent literature illustrates the latest emerging
strategies for targeting metal complexes to proteins, particularly
the use of the unique shapes of metal complexes as structural
scaolds, the linkage of metal complexes to known organic
protein binders, the application of coordination modes that are
1008 | Chem. Commun., 2009, 10011010

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