Download Exploring biologically relevant chemical space with metal complexes

Exploring biologically relevant chemical space with metal
complexes
Eric Meggers
Altering biological processes with small synthetic molecules is
a general approach for the design of drugs and molecular
probes. Medicinal chemistry and chemical biology are focused
predominately on the design of organic molecules, whereas
inorganic compounds find applications mainly for their
reactivity (e.g. cisplatin as a DNA-reactive therapeutic) or
imaging properties (e.g. gadolinium complexes as MRI
diagnostics). In such inorganic pharmaceuticals or probes,
coordination chemistry in the biological environment or at the
target site lies at the heart of their modes of action. However,
past and very recent results suggest that it is also worth
exploring a different aspect of metal complexes: their ability to
form structures with unique and defined shapes for the design
of ‘organic-like’ small-molecule probes and drugs. In such
metal–organic compounds, the metal has the main purpose to
organize the organic ligands in three-dimensional space. It is
likely that such an approach will complement the molecular
diversity of organic chemistry in the quest for the discovery of
compounds with superior biological activities.
Addresses
Department of Chemistry, University of Pennsylvania,
231 South 34th Street, Philadelphia, PA 19104, USA
Corresponding author: Meggers, Eric ([email protected])
Current Opinion in Chemical Biology 2007, 11:287–292
This review comes from a themed issue on
Combinatorial chemistry and molecular diversity
Edited by Gregory A Weiss and Richard Roberts
Available online 4th June 2007
1367-5931/$ – see front matter
# 2007 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.cbpa.2007.05.013
Introduction
The identification of compounds with novel and defined
biological functions is of high importance for research in
medicinal chemistry and chemical biology. The total number of theoretically accessible compounds with biological
activity span the ‘biologically relevant chemical space’ [1].
Charting this subset of the chemical space is focused
primarily on small organic molecules. In this respect one
might wonder whether organic-based scaffolds are capable
of covering all areas of the biologically relevant chemical
space in an efficient fashion. To address this question, it is
interesting to explore the opportunities of inorganic
elements to help build small compounds with defined
three-dimensional structures. Transition metals appear
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especially appealing for this purpose because they can
support a multitude of coordination numbers and geometries that go far beyond the linear (sp-hybridization),
trigonal planar (sp2-hybridization) and tetrahedral (sp3hybridization) binding geometries of carbon (Figure 1).
For example, it is intriguing that an octahedral center with
six different substituents is capable of forming 30 stereoisomers compared with just two for an asymmetric tetrahedral carbon [2]. Thus, by increasing the number of
substituents from four (tetrahedral center) to six (octahedral center), the ability of the center to organize substituents in the three-dimensional space increases
substantially. In addition, using a hexavalent center could
provide new synthetic opportunities for accessing globular
shapes by building structures from a single center in six
different directions.
Inorganic pharmaceuticals play an important role in
clinical therapy (e.g. cisplatin) and diagnostics (e.g.
MRI contrast agents) [3]. For these classes of inorganic
compounds the coordination chemistry itself is at the
heart of the mode of action. This short review is limited
to past and current research activities that aim to design
metal complexes with biological activities in which the
metal center mainly serves as a structural center for
organizing the presentation of organic ligands at the
binding site of protein targets.
Pioneering work by Dwyer
More than half a century ago, the Australian chemist
Francis Dwyer started to investigate the biological activities of simple coordination complexes such as ruthenium
complexes with 2,20 -bipyridine and 1,10-phenanthroline
(phen) ligands [4–8]. He discovered that some very
hydrophobic complexes (e.g. Figure 2a) displayed bacteriostatic and bacteriocidal activities and were capable of
inhibiting tumor growth in a mouse xenograph model
[5,6]. Interestingly, fluorescence microscopy studies
demonstrated that these dicationic ruthenium complexes
were able to pass the cellular membrane and were found
to localize in the mitochondria [6]. The ruthenium complexes also caused paralysis and respiratory failure after
intraperitoneal (IP) injection into mice at high concentrations, apparently owing to their potent direct inhibition
of acetylcholinesterase [7]. Investigations into the biological stability of [Ru(phen)3](ClO4)2] confirmed that the
ruthenium complex after IP injection into mice was not
metabolized and excreted mainly unchanged in the urine
[8]. Because of the coordinative saturation of the coordination sphere, their chemical and biological stabilities,
Dwyer drew the following important conclusion: ‘Such
Current Opinion in Chemical Biology 2007, 11:287–292
288 Combinatorial chemistry and molecular diversity
Figure 1
Transition metals provide an expanded set of coordination geometries for the generation of molecular diversity.
doubly charged pre-formed Ru(II) chelates are stable in
boiling concentrated acids or alkali and in animal tissues.
Hence their biological effects depend solely on the physico-chemical properties of the Ru(II) complex cation as a
whole since no ruthenium ion or ligand is liberated’ [6].
Ruthenium complexes as protein kinase
inhibitors
Following Dwyer’s spirit, Meggers and coworkers
developed organoruthenium compounds as protein kinase
inhibitors [9,10,11,12,13,14]. For this, the class of ATPcompetitive indolocarbazole alkaloids (e.g. staurosporine,
Figure 3a) was used as a lead structure. The indolocarbazole alkaloid scaffold was replaced with simple metal
complexes in which the main features of the indolocarbazole aglycon are retained in the metal-chelating pyridocarbazole ligand, whereas the carbohydrate is replaced by a
ruthenium fragment. Following this design strategy, nanomolar and even subnanomolar ATP-competitive ruthenium-based inhibitors for different protein kinases were
discovered (e.g. Figures 2b and 3b), some of them by
combinatorial chemistry [12,14]. These compounds are
air-stable, stable in water, and can even withstand millimolar concentrations of thiols. This stability is due to the
inert character of typical coordinative bonds to ruthenium.
This, together with the modest price of its starting material
RuCl3, its low toxicity, and its predictable and established
synthetic chemistry, makes ruthenium possibly the most
attractive metal for establishing octahedral or pseudo-octahedral coordination geometries. It was furthermore demonstrated that such ruthenium compounds can function
within mammalian cells [10,13], Xenopus embryos [10]
and zebrafish embryos [13]. Recent cocrystal structures
confirm that these compounds bind to the ATP-binding
site of protein kinases [11]. For example, Figure 3b shows
an organoruthenium half-sandwich complex bound to the
ATP-binding site of Pim-1. Importantly, the ruthenium
center is not involved in any direct interactions and has
solely a structural role. Furthermore, superposition of the
binding positions of cocrystalized ruthenium complex and
staurosporine (PDB code 1YHS) with Pim-1 demonstrates
Current Opinion in Chemical Biology 2007, 11:287–292
how closely the ruthenium complex mimics the binding
mode of staurosporine (Figure 3c). The pyridocarbazole
ligand perfectly mimics the position of the indolocarbazole
moiety of staurosporine, whereas the cyclopentadienyl ring
and the CO group occupy the binding position of the
carbohydrate moiety of staurosporine.
Mimicking the structure of natural products
with metal complexes
Whereas the work on metal-based kinase inhibitors used
the class of indolocarbazole alkaloids primarily as an
inspiration, it is also desirable to mimic the structure
and function of natural products more closely to gain
more efficient access to a complex three-dimensional
structure and to add desired physicochemical properties.
The latter is what Katzenellenbogen and coworkers had
in mind when they designed rhenium complexes as
mimics of the structure of steroid hormones [15–17].
Steroid receptors are often overexpressed in cancer cells
and are therefore a target in the design of radiolabeled
small-molecule diagnostics (e.g. Tc-99m) and therapeutics (e.g. Re-186 and Re-188) for cancer detection
and treatment, respectively [16]. Katzenellenbogen’s
group reported the bis-bidentate oxorhenium(V) complex
shown in Figure 2d, which is a remarkable structural and
stereochemical mimic of the androgen 5a-dihydrotestosterone (DHT) as can also be seen from the comparison of
the two space-filling models in Figure 2d [17]. An exciting
aspect of this study is that the metal center fulfils a dual
purpose. Unfortunately, the instability of such rhenium
compounds with bidentate ligands precludes in vivo
applications.
Bioorganometallic chemistry with ferrocene
The organometallic sandwich compound ferrocene is an
interesting building block for the design of biologically
active molecules because of its unique structure, its
robustness in aqueous solutions, and its favorable redox
properties [18]. For example, Metzler-Nolte and coworkers incorporated the organometallic amino acid 10 aminoferrocene-1-carboxylic acid into peptides to induce
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Biologically relevant metal complexes Meggers 289
Figure 2
Towards chemical biology with metal complexes. (a) Ruthenium complex with antibacterial and antitumor activity. (b) Nanomolar inhibitors
for the protein kinases GSK-3a (left) and MSK1 (right). (c) 10 -Aminoferrocene-1-carboxylic acid induces turns in peptides. (d) A bis(bidentate)
rhenium(V) complex mimics the structure of dihydrotestosterone. (e) Organometallic estrogen receptor modulator ferrocifen derived from
the drug tamoxifen. (f) [Fe(EDTA)(H2O)] binds to the periplasmic nickel transporter NikA. (g) Copper complex as HIV-1 protease inhibitor.
(h) AMD3100 binds with high affinity to the CXCR4 coreceptor and this binding is enhanced in the presence of zinc ions.
turns (Figure 2c) [19]. In this system, the peptides are
arranged in an antiparallel b-sheet-like arrangement
stabilized by intramolecular hydrogen bonds. Because
turn structures and b-sheets are important recognition
motifs in protein–protein interactions, it can by expected
that ferrocene serves as an interesting building block for
turn-containing peptidomimetics.
In another application of ferrocene in bio-organometallic
chemistry, Jaouen and coworkers developed simple
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organometallic analogs of tamoxifen [20]. Tamoxifen
(Figure 2e) is an antagonist of the estrogen receptor
(ER) and widely used in the clinic for the treatment of
hormone-dependent breast cancer. The organometallic
analog ferrocifen (Figure 2e), which bears an additional
hydroxyl group and has one phenyl group replaced by a
bulky and hydrophobic ferrocene moiety, exhibits strong
antiproliferative effects [21]. It is thought that ferrocifen,
in analogy to tamoxifen, suppresses estradiol-mediated
DNA transcription by binding to ERa. However, it was
Current Opinion in Chemical Biology 2007, 11:287–292
290 Combinatorial chemistry and molecular diversity
Figure 3
Ruthenium complexes as ATP-competitive protein kinase inhibitors. (a) Shape mimicry: staurosporine as a lead structure. (b) Cocrystal structure
of a pseudo-octahedral ruthenium half-sandwich compound with protein kinase Pim-1 (PDB code 2BZI). (c) The superimposed cocrystal
structure of Pim-1 with staurosporine (gray color, PDB code 1YHS) demonstrates the close match in binding mode between the natural product
and the organometallic complex.
recently discovered that ferrocifen displays strong antiproliferative activities both in hormone-dependent (contain ER) and hormone-independent (lack ER) breast
cancer cells, indicating a distinguished mode of action
[20]. Because the ruthenium derivative does not show the
same cytotoxicity profile, it is assumed that the prominent
redox properties of ferrocene play an important role. A
sequence of oxidation, deprotonation, and further oxidation could generate an electrophile that is capable of
damaging DNA or reacting with proteins [22]. Thus, in
ferrocifene, the organometallic unit fulfils both a structural and reactive role.
Related uses of metal complexes
It is apparent that for in vitro and in vivo applications, metal
complexes with kinetically inert bonds are highly desirable. However, multidentate ligands such as the hexadentate ligand ethylenediaminetetraacetate (EDTA) can
form highly stable complexes even with kinetically very
Current Opinion in Chemical Biology 2007, 11:287–292
labile metals. Fontecilla-Camps and coworkers found serendipitously that the heptacoordinated pentagonal bipyramidal iron complex [Fe(EDTA)(H2O)] (Figure 2f)
binds tightly to the periplasmic nickel transport protein
NikA [23]. A 1.8 Å cocrystal structure is shown in Figure 4
and demonstrates that the complex is bound through a
combination of hydrogen bonds, electrostatic, and hydrophobic contacts. Accordingly, carboxylate groups of EDTA
hydrogen bond with Arg97 and Arg137 and form three
additional water-mediated contacts. This is supplemented
by a set of hydrophobic contacts between methylene
groups of EDTA and Met27, Tyr22, Trp100, and
Trp398. Especially the two tryptophans serve as wedges
that complement the shape of the iron EDTA complex.
Importantly, the iron does not form any direct coordinative
bond with NikA residues and thus has mainly the purpose
to organize the structure of the EDTA ligand. However,
one can postulate an unshielded cation-p interaction between the iron ion and Trp398, with an indole-to-metal
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Biologically relevant metal complexes Meggers 291
Figure 4
of the most potent members of this family is the bicyclam
AMD3100 (Figure 2), which is in clinical trials for the
treatment of AIDS. The anti-HIV activity correlates with
its binding to the coreceptor protein CXCR4. Interestingly,
the complexation of Zn(II) enhances the binding strength
to CXCR4 and also its anti-HIV activity [28].
Conclusions
Binding of the iron complex [Fe(EDTA)(H2O)] to the periplasmic
nickel transporter NikA (PDB code 1ZLQ). Important amino acids are
highlighted. W, water.
distance of 5.5 Å [23]. Interestingly, NikA has the natural
function to bind to Ni(II) ions; however, the affinity to
[Fe(EDTA)(H2O)] exceeds substantially the affinity to
Ni(II) ions, and thus the authors suggest that a similar
natural metallophore is involved in periplasmic Ni(II)
transport by NikA.
A promising strategy for the recognition of proteins by
metal complexes makes use of a combination of recognition through the ligand sphere with direct coordination
to the target site. Only two examples will be discussed
here. Reboud-Ravaux and coworkers developed copper
complexes as substrate competitive inhibitors for HIV-1
protease [24,25]. For example, [bis-(2-pyridylcarbonyl)amido] copper(II) nitrate dihydrate (Figure 2g) binds
with an inhibition constant of 480 mM [24]. Molecular
modeling suggests that the catalytic water between Asp25
and Asp125 of HIV-1 protease is directly coordinated to
the Cu(II) ion. A current drawback of this class of compounds is the hydrolytical instability of the Cu(II) complexes. One could potentially overcome this problem by
designing suitable multidentate ligands or by choosing
more kinetically inert metal ions.
Sadler and coworkers investigated the binding of metal
complexes of 1,4,8,11-tetraazacyclotetradecane (cyclam)
macrocycles to the CXCR4 coreceptor and lysozyme as a
model protein (Figure 2h) [26,27]. In such metallocyclam
complexes, the metal is supposed to function by controlling
the conformation and configuration of the macrocycle.
Additional direct coordinative bonds with the target protein
can be formed with the vacant axial coordination sites. One
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Metal compounds provide new opportunities for building
structures with unique and defined three-dimensional
globular shapes in an economical fashion, and thus complement molecular diversity created by purely organic
scaffolds. This access to unexplored chemical space could
lead to the discovery of molecules with unprecedented
properties. A key aspect for using metal-containing compounds as structural scaffolds is the kinetic stability of the
coordination sphere in the biological environment. This
can be accomplished with multidentate ligands or, more
generally, by employing kinetically inert metals such as
ruthenium. Future work will increasingly rely on combinatorial chemistry of metal complex libraries followed by
screening against selected targets or even phenotypic
assays. Furthermore, it is also appealing to complement
the structural role of metals with their special physicochemical, reactive, and/or catalytic properties in one
molecule to yield compounds with new abilities to probe
and modulate biological processes.
Acknowledgements
EM thanks the University of Pennsylvania and the US National Institutes
of Health (R01 GM071695) for financial support.
References and recommended reading
Papers of particular interest, published within the annual period of
review, have been highlighted as:
of special interest
of outstanding interest
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Current Opinion in Chemical Biology 2007, 11:287–292
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