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Exploration of the medical periodic table: towards new targets

Nicolas P. E. Barry and Peter J. Sadler*
University of Warwick, Department of Chemistry, Gibbet Hill Road, Warwick, UK. E-mail:;

Received 11th February 2013, Accepted 3rd April 2013

First published on 1st May 2013

Metallodrugs offer potential for unique mechanisms of drug action based on the choice of the metal, its oxidation state, the types and number of coordinated ligands and the coordination geometry. We discuss recent progress in identifying new target sites and elucidating the mechanisms of action of anti-cancer, anti-bacterial, anti-viral, anti-parasitic, anti-inflammatory, and anti-neurodegenerative agents, as well as in the design of metal-based diagnostic agents. Progress in identifying and defining target sites has been accelerated recently by advances in proteomics, genomics and metal speciation analysis. Examples of metal compounds and chelating agents (enzyme inhibitors) currently in clinical use, clinical trials or preclinical development are highlighted.

Peter Sadler

Peter Sadler

Peter Sadler obtained his BA, MA and DPhil at the University of Oxford. Subsequently he was a Medical Research Council Research Fellow at the University of Cambridge and National Institute for Medical Research. From 1973–1996 he was Lecturer, Reader and Professor at Birkbeck College, University of London, and from 1996–2007 Crum Brown Chair of Chemistry at the University of Edinburgh. In June 2007 he took up a Chair in Chemistry at the University of Warwick. He is a Fellow of the Royal Society of Edinburgh (FRSE) and the Royal Society of London (FRS), and a European Research Council Advanced Investigator. His research interests are centred on the chemistry of metals in medicine.

Nicolas Barry

Nicolas Barry

Nicolas Barry received his MSc degree in Chemistry from the Université de Rennes, France in 2008. From 2008 to 2011 he obtained his PhD in Organometallic Chemistry under the supervision of Professors Süss-Fink and Therrien at the Université de Neuchâtel, Switzerland. Presently, he is a Swiss National Science Foundation postdoctoral fellow in the laboratory of Professor Sadler at the University of Warwick.


A significant number of clinical trials now involve metal compounds, metal-chelating agents (metalloenzyme inhibitors) or other agents which interfere with metabolic pathways for metals, both for therapy and for diagnosis. Some of the areas of current clinical interest are listed in Table 1.
Table 1 Some examples of industries/sponsors with metallodrugs or chelating agents in development or clinical trials or approved for clinical use. In many cases more details can be found on the clinical trials website:
Metal-based anticancer therapeutics
Bioplatin AGDicycloplatin (Pt)Bronchial carcinomaChina Phase I
Liver cancer
Blend TherapeuticsPt complexes including nanoparticlesTargeted and combination therapyPre-clinical
Regulon Inc.Lipoplatin (Pt) (liposomal cisplatin)Lung cancerPhase III
Lipoxal (Pt) (liposomal oxaliplatin)Colorectal cancerPhase II
SanofiOxaliplatin (Eloxatin) (Pt)Colorectal cancerApproved
Cell Therapeutics Inc.Dinuclear-platinum complex CT-47463Various cancersPre-clinical
Solasia Pharma K.K.Darinaparsin (As) (Z10-101/SP-02)Peripheral T-cell lymphomaApproved US and some other countries
Solid tumours (oral)Phase I
Ziopharm/TevaTrisenox (As)Acute promyelocytic leukaemiaApproved
Lung and othersPhase II
Cancer Research UKGSAO (As)Advanced solid tumours that have not responded to therapyPhase I
SigeaNAMI-A (Ru) in combination with gemcitabineAnti-metastatic agentPhase I/II accomplished
NIIKIPHARMANKP-1339 (Ru)Various cancers, e.g. neuroendocrine and NSCLCPhase I
NKP-2235 (Ga)Cancers with high incidence of bone metastases e.g. NSCLC, breast and prostate cancers, and multiple myelomaPhase I
Virginia Commonwealth UniversityBelinostat (PXD101): histone deacetylase inhibitor (chelates Zn)Relapsed or refractory acute leukaemia or myelodysplastic syndromePhase I
Patheon Inc.Vorinostat: HDAC inhibitor (chelates Zn)Cutaneous T cell lymphomaApproved
Asan Medical CenterGastric cancerPhase I
Ohio State University Comprehensive Cancer CenterAdvanced staged oropharyngeal squamous cell carcinomaPhase I
GenentechBrain cancerPhase I
ItalfarmacoGivinostat: HDAC inhibitor (chelates Zn)Chronic myeloproliferative neoplasmsPhase II
Boneca CorporationBoronophenylalanine-based boron neutron capture therapy in combination with cetuximab (B)Head and neck cancerPhase I
Weill Medical College of Cornell UniversityTetrathiomolybdate (Mo)Breast cancerPhase II
University of Michigan Cancer CenterEsophageal carcinomaPhase II
SanofiMozobil (plerixafor): (potential chelator-Zn)Stem cell mobilisationApproved
Viamet Pharmaceuticals, Inc.VT-464 (lyase selective metalloenzyme inhibitor (Fe in CYP17))Prostate cancerPhase I
Mayo ClinicAuranofin (Au)Recurrent fallopian tube, ovarian epithelial, peritoneal cavity cancerPilot
Univ KansasChronic lymphocytic leukaemia (CLL)Phase II
Small lymphocytic lymphoma
Prolymphocytic leukaemia
Other metal-based therapeutics
SanofiFerroquine (Fe) (SSR97193)AntimalarialPhase II
VPS-1, Inc.VT-1161 (lanosterol demethylase metalloenzyme (CYP51) inhibitor)AntifungalPhase I
Prana BiotechnologyPBT2: hydroxyquinoline derivative – metal chelatorAlzheimer'sPhase II
Shire PharmaceuticalsLanthanum carbonate (Fosrenol) (La)HyperphosphatemiaApproved
Smith & NephewActicoat Absorbant™ Silver Eluting Dressing (Ag)Prevention of lower extremity revascularization wound complicationsPhase IV
Ceva (Nature Vet Pty Ltd)Cu-Algesic (CuII indomethacin) (Cu)Anti-inflammatory (veterinary-horses, dogs)Approved
Redox Pharmaceutical CorporationDoxovir (CTC-96) CoIII bis(2-methylimidazole) acacen complex (Co)Ophthalmic herpetic keratitis and adenoviral conjunctivitisPhase I completed
Herpes labialisPhase II completed
The University of Texas Health Science CenterBismuth subcitrate potassium, metronidazole, tetracycline hydrochloride and omeprazole (Bi)Helicobacter pylori infectionPhase IV
UCSF/UC San DiegoAuranofin (Au)Treatment of amoebiasis and parasite Giardia intestinalisTrials planned
Photodynamic therapy agents
Steba Biotech S.A.Palladium bacteriopherophorbide photosensitizer TOOKAD (Pd)Localised prostate cancerPhase III
University of Oxford/Steba Biotech S.A.Predetermined small renal tumour targetsPhase I/II
Diagnostic radiopharmaceuticals
American College of Radiology Imaging NetworkCopper Cu 64-ATSM and PET/CT Scan (Cu)Cervical cancerPhase II
LantheusCardiolite (99mTc-sestamibi) (Tc)Folate-receptor-positive tumoursApproved
Neurite (99mTc-disicate) (Tc)
Endocyte Inc.Etarfolatide (EC20-99mTc) (Tc)Folate-receptor-positive tumoursPhase III
Molecular Insight Pharmaceuticals, Inc.99mTc-MIP-1404 (Tc)Prostate cancerPhase II
Peking Union Medical College Hospital68Ga-DOTA-TATE PET/CT Scan (Ga)Mesenchymal tumoursPhase 0

In development

Oncogenic osteomalacia
Vanderbilt UniversityNeuroendocrine CancerPhase I
Therapeutic radiopharmaceuticals
Actinium PharmaceuticalsActinium-225-Labeled Humanized Anti-CD33 Monoclonal Antibody HuM195 (Ac)Leukaemia myelodysplastic syndromePhase I
Lintuzumab-Ac225 (Ac)Acute myeloid leukaemiaPhase I/II
Lintuzumab-Bi213 (Bi)Acute myeloid leukaemiaPhase II
Algeta ASA (Bayer)Alpharadin (223Ra chloride) (Ra)Bone metastasis from castration-resistant prostate cancerPhase I/II
Radiation therapy oncology group and National Cancer InstituteSamarium-153-lexidronam pentasodium (Sm)Prostate cancerPhase II
UMC UtrechtHolmium-166 polylactic microspheres (Ho)Liver neoplasmsPhase II
Centre René GauducheauRadiation: IMP-288-lutetium (Lu)Small cell lung cancerPhase II
Contrast agents and others
OHSU Knight Cancer InstituteFerumoxytol and gadolinium magnetic resonance imaging (Fe, Gd)Malignant brain tumoursPhase II
Lantheus Medical ImagingBMS753951 (Gd)MRI contrast for coronary arterial wall imagingDevelopment
PharmacyclicsMotexafin gadolinium (Gd)Radiation and chemotherapy sensitiserDevelopment
Alexion PharmaceuticalsCyclic pyranopterin monophosphate replacement therapy (precursor to Mo cofactor)Markers for Mo cofactor deficiencyDevelopment
Isolated SOX deficiency

These areas have been stimulated by recent successes with platinum anticancer drugs (used as a component of nearly 50% of all cancer treatments), with gadolinium complexes as MRI contrast agents (about 20 million doses administered per year) and 99m-technetium radiopharmaceuticals for γ-ray imaging (used in about 20 million radiodiagnostic procedures each year). However, many other diseases and conditions are of current interest including neurodegeneration, microbial and parasitic (and other neglected tropical diseases) infections and inflammation.1–4 About 24 elements are essential for man, Fig. 1. In principle, we should consider the roles of all essential elements in therapy (control of homeostasis), but this is currently hampered in many cases (e.g. Si, V, Ni, Sn) because their natural biochemistry is poorly understood and we do not know how to diagnose conditions associated with their metabolism. For some elements it is already possible to use genomics to understand medical conditions related to them (e.g. Fe, Cu, Zn), but in other cases it is not clear how, or if, genomes code for these elements. Genomes do not code for the elements themselves, but for particular chemical forms (e.g. vitamin B12 for cobalt). Genomic codes for metals are usually codes for proteins, proteins which are highly, but not totally, selective for particular metal ions. As is evident from the above examples of Pt, Gd and Tc, inorganic medicinal chemistry can make use of non-essential as well as essential elements for the design of drugs and diagnostic agents, Fig. 1.4

A medical periodic table: essential elements for man (symbols in white font); medical radioisotopes (green fill); elements currently used in therapy (blue fill) or diagnosis (orange fill). The entries (limited to 2 fill colours, illustrative and not comprehensive) are mainly restricted to elements/compounds which are clinically approved or on current clinical trials (e.g. as listed on Some entries for implants are included (e.g. Ti, Ta). The basis for some of the entries is given in Table S1 (ESI).
Fig. 1 A medical periodic table: essential elements for man (symbols in white font); medical radioisotopes (green fill); elements currently used in therapy (blue fill) or diagnosis (orange fill). The entries (limited to 2 fill colours, illustrative and not comprehensive) are mainly restricted to elements/compounds which are clinically approved or on current clinical trials (e.g. as listed on Some entries for implants are included (e.g. Ti, Ta). The basis for some of the entries is given in Table S1 (ESI).

For many centuries the use of metallodrugs has been driven by empiricism. Whilst random screening is still a useful weapon in drug discovery, these days it should be guided largely by rational design. This implies that target sites (usually gene products – proteins) should be identified and verified early in the design process. Immediately this presents challenges for medicinal metal coordination chemistry: either the synthesised complexes need to be inert to redox and ligand substitution reactions, or these reactions need to be controlled under biological conditions en route to the target. In turn, metal- and/or ligand-centred redox reactions provide a unique platform for drug design with concepts quite distinct from those for purely organic drugs.

In this article we highlight some areas of current interest in metallodrugs. We focus especially on their interactions with (proposed) target sites, including DNA and proteins. Despite the fact that successful clinical platinum anticancer drugs have DNA as their major target, DNA is nowadays not considered to be a favoured target site. This is partly because DNA is also likely to be attacked in normal healthy cells as well as in cancer cells. However, downstream processing of platinated DNA can differ in normal and cancer cells so differential cytotoxicity can still be achieved. Moreover, it is becoming evident that anticancer drugs that target a single protein or enzyme are not always successful, since cells readily become resistant to such drugs and utilise alternative metabolic pathways. Metallo-anticancer drugs have the potential advantage of attacking several sites (multi-targeting), which can be an highly effective strategy. It is important to identify these target sites and elucidate the molecular mechanisms of action. As we shall see, a range of new target sites are being proposed for metallodrugs but there is still much progress to be made on target-site validation. Tailoring the design of metallodrugs to treat specific diseases and conditions is likely to be a major part of future personalised medicine, which will include genomic and proteomic profiling of individuals.

1. Metal-based anticancer drugs

1.1. DNA targeting

1.1.1. A traditional approach for designing metallodrugs. Direct coordinative DNA binding. It is well established that the target site for the anticancer drug cisplatin (1), cis-[PtCl2(NH3)2] (Chart 1, FDA approval 1978), is nuclear DNA.5–15 More than 4000 Pt compounds have now been tested as potential anticancer drugs, with the worldwide approval for clinical use of carboplatin (2, 1989) and oxaliplatin (3, 2002), and of three others – nedaplatin (4), lobaplatin (5) and heptaplatin (6) (Chart 1) for clinical use only in Japan, China and South Korea, respectively. The ability to form DNA adducts is important for the activity of all of these drugs. Table 2 lists the X-ray structures of cis-diam(m)ine Pt–DNA adducts registered in the Protein Data Bank by January 2013. Dicycloplatin (7) is a new complex developed at the University of Beijing by Yang et al. that has passed through Chinese clinical phase I trials. This compound is composed of one molecule of carboplatin and one molecule of cyclobutane-1,1-dicarboxylic acid interacting via hydrogen bonds (see Chart 1).16 The mechanism by which the presence of free ligand affects the activity of this platinum drug is not clear.
Molecular structures of some platinum anticancer drugs that are approved or undergoing clinical trials.
Chart 1 Molecular structures of some platinum anticancer drugs that are approved or undergoing clinical trials.
Table 2 X-ray and solution NMR structures of coordinative platinum cis-diam(m)ine PtII–DNA adducts registered in the Protein Data Bank in January 2013
Platinum complexType of Pt–DNA adductDNA structural changesPDB ID and Ref.
Cisplatin1,2-cis-{Pt(NH3)2}2+-d(GpG) intrastrand cross-linkBending (kinking) of duplex; rolling of the adjacent guanines; unwinding of the helix at platination site; widening and flattening of the minor groove opposite the platinum adduct3LPV;173M9M, 3M9N, 3M9O;182R8J, 2R8K;192R7Z;201AIO;211A84;221AU523
1,3-cis-{Pt(NH3)2}2+-d(GpTpG) intrastrand cross-link2WTF;241KSB;251DA4, 1DA526
1,3-cis-{Pt(NH3)2}2+-d(GpTpG) intrastrand cross-link in a nucleosome3O6227
Interstrand cross-link1A2E;281DDP29
Oxaliplatin1,2-{Pt(dach)}2+-d(GpG) intrastrand cross-linkStronger duplex bending than with cisplatin302K0T, 2K0U, 2K0V;311PG9, 1PGC;321IHH33
PyriplatinMonofunctional platinum–DNA adduct (Pt-N7G binding)Markedly different transcription inhibition mechanism compared to cisplatin or oxaliplatin3CO334
[PtCl(en) (ACRAMTU-S)] (NO3)2Dual modePlatinum-N7G binding in the major groove + ACRAMTU intercalation leading to inhibition of damaged DNA transcription by RNA polymerase II1XRW35

Compounds based on cis-diam(m)ine PtII structures tend to produce very similar types of adduct on target DNA – as exemplified in Table 2. It is therefore not surprising that they induce similar biological consequences, although protein recognition of the DNA adducts is dependent on the ligands. This consideration led to the hypothesis that development of Pt compounds structurally different from cisplatin which form different types of DNA–Pt adducts, may lead to a different spectrum of biological activity, perhaps complementary to cisplatin.36 In the late 1980s, Farrell began a fruitful investigation of linear multi-platinum complexes, where the platinum centres are separated by aliphatic chains, and the chlorido ligands are cis or trans at the extremities of the complex.37–40 These poly-platinum complexes are generally highly positively-charged. This leads to a stronger initial electrostatic recognition of DNA in comparison with monomeric species. Another critical feature of these multinuclear complexes is flexibility. The potent multi-platinum complex [(trans-PtCl(NH3)2)2-trans-Pt(NH3)2(NH2(CH2)6NH2)2}]4+, BBR3464 (8, Chart 2),41 completed a phase I trial,42 but failed phase II due to instability in blood.43–47

Molecular structure of complex 8.
Chart 2 Molecular structure of complex 8.

It seems to be the only Pt compound not based on the cisplatin chemotype to have entered human clinical trials.48 Hydrolysis of BBR3464 and DNA adduct formation are well documented.49,50 In general polynuclear platinum compounds bind rapidly to DNA (t1/2ca. 40 min).47 The most relevant feature of the special BBR3464–DNA binding is the lack of severe DNA distortions such as a kink, or significant unwinding of the helix, which are characteristics of DNA adducts of mononuclear platinum complexes. One of the direct consequences of this mild Pt-induced DNA conformational change is that these adducts are poor substrates for recognition by proteins, such as those containing the HMG domain, which binds to rigidly-bent DNA, as induced by cisplatin.51 Overviews of multi-nuclear platinum drugs52,53 and DNA binding to polynuclear platinum complexes54 have been published.

Low-spin octahedral 5d6 PtIV complexes have potential advantages as anticancer drugs because they are more inert to substitution reactions than square-planar PtII complexes and so are expected to undergo fewer side reactions en route to the tumour. Also they often have higher aqueous solubility, a feature exploited long ago by Tobe et al. who synthesised iproplatin (CHIP, JM9, cis,trans,cis-[PtCl2(OH)2(isopropylamine)2]).55 Iproplatin entered phase I and II clinical trials,56,57 and even phase III,58 but ultimately was found to be less active than cisplatin and so not registered for clinical use.59 Tetraplatin (ormaplatin) [PtCl4(D,L-cyclohexane-1,2-diamine)], also showed promise in preclinical studies but caused severe neurotoxicity in treated patients, and trials were subsequently abandoned at phase I.60 The unpredictability of the rate, extent and localisation of in vivo reduction of these PtIV complexes to the active PtII species may be a complication in clinical use.

The need to overcome platinum resistance, to reduce toxic side-effects and broaden the spectrum of activity has also focussed attention on the potential of anticancer drugs containing other metals. Among them, Ru-based-drugs are promising.61 The RuIII anticancer drug imidazolium-trans-dimethylsulfoxide-imidazole-tetrachlororuthenate (NAMI-A) (9) developed in Trieste by Mestroni, Alessio, et al. has reached phase I/II trials in combination with gemcitabine. Another octahedral RuIII complex indazolium-trans-bis(1H-indazole)-tetrachlororuthenate (KP1019) (10), developed by Keppler et al. in Vienna (Chart 3), has completed phase I clinical trials.62,63 Organometallic arene RuII complexes such as [(η6-biphenyl)Ru(en)Cl]+ (en = ethylenediamine)61 (11) and [(η6-p-cymene)Ru(PTA)Cl2]64 (p-cymene = para-cymene and PTA = 1,3,5-triaza-7-phosphaadamantane) (12) (see Chart 3) have been widely studied and several others also show promise.65–76

Molecular structures of RuIII anticancer complexes 9 and 10, and RuII arene complexes 11 and 12.
Chart 3 Molecular structures of RuIII anticancer complexes 9 and 10, and RuII arene complexes 11 and 12.

The antimetastatic activity of NAMI-A is thought to be due to combined effects on the control of angiogenesis (possibly because it interferes with NO metabolism)77,78 and anti-invasive properties towards tumour cells and blood vessels, and not to interaction with nucleic acids, although it can interact with DNA in vitro.79 DNA has been proposed as one of the biological targets of KP1019, and it also triggers apoptosis.80 However, the cellular mechanism of the activation of apoptosis is not understood.81 These RuIII complexes may undergo activation by reduction to RuIIin vivo.82

Different mechanisms of action have been investigated for explaining the anticancer activity of arene ruthenium complexes. Interactions between complexes containing reactive Ru–Cl and nuclear DNA can occur, through the formation of intermediary aqua complexes able to ruthenate DNA specifically at guanine residues.83,84 If the arene is extended (e.g. biphenyl, dihydroanthracene), DNA binding can involve not only direct coordination to G bases but also arene intercalation (see Section Ligand oxidation can provide a way to activate thiolato complexes of RuII arenes, which may be of importance when the intracellular thiol glutathione binds to them. Mono- (to give the sulfenate) and bis- (sulfinate) oxygenation appear to be facile, but surprisingly do not weaken the Ru–S bond85 even though this provides a route to nucleobase binding.86 Protonation of the sulfenate oxygen on the other hand does labilise this bond.87

Osmium, the heavier congener of ruthenium and a third row transition metal, commonly exhibits slower kinetics than ruthenium, and is often considered to be relatively inert. However, it is possible to tune the biochemical reactivity of the arene OsII complexes through understanding their aqueous solution chemistry. The rates of hydrolysis of [(η6-arene)Os(XY)Cl]n+ complexes can be controlled by the choice of the chelating ligand XY (faster for XY = O,O, followed by O,N and slowest for N-donor chelating ligands, especially when N,N is a strong π-acceptor such as azopyridine). The pKa values of the aqua adducts also follow this order, being highest for O,O ligands, with coordinated water tending to be more reactive than coordinated hydroxide.88 Ligand substitution rates on arene OsII are often ca. 100× slower than for RuII and coordinated aqua ligands ca. 1.5 pKa units more acidic. Thus, active arene OsII complexes have been designed.89–99 In particular chlorido OsII picolinate complexes can bind to DNA, but interestingly some inert iodido OsII azopyridine complexes exhibit nanomolar potency to a wide range of cancer cells and are also active in vivo.100 The azopyridine complexes appear to have redox mechanisms of action.101 Interestingly injected OsO4 has a long history of use in therapy in Scandinavia for chemical synovectomyin the treatment of chronic synovitis.102

In addition to binding to DNA,103 IrIII Cp* anticancer complexes can also have redox mechanisms of action, readily forming hydride complexes on reaction with coenzyme NADH, and even producing H2 catalytically.104 These findings highlight the existence of new potential targets for such complexes. Non-covalent DNA binders. Metal complexes of an appropriate shape and polarity can intercalate between DNA base pairs.105 Intercalators can be potent mutagens, due to their ability to induce structural and therefore functional changes in duplex DNA, leading to inhibition of transcription, replication and DNA repair processes. Intercalators are potential antibiotics, antibacterials, trypanocides, schistosomicides, and antitumour agents.106,107 Several metallo-intercalator complexes have been reported recently, Table 3.
Table 3 Examples of DNA-intercalators and groove-binding metal complexes reported in 2011 and 2012
a dppz = dipyrido[3,2-a:2′,3′-c]-phenazine.
ZnIISchiff bases;108 trihydroxy-isoflavones109
AgIbis-Benzimidazole ligands112
CuIIDipyrido-phenazine and glycinato ligands;113 (phenyl(pyridine-2-yl)methylidene)-benzohydrazides;114 trihydroxy-isoflavones;109 terpyridine ligands115
CuII–PbIVPhenanthroline derivatives116
PtIICarbenes;117 ethylenediamine, diaminocyclohexane and phenanthroline derivatives;118 phenylpyridine;119 bipyridyl-thiourea ligands;120 phenanthroline derivatives121
NiIITrihydroxy-isoflavones;109 (phenyl(pyridine-2-yl)methylidene)-benzohydrazides;114 phenanthroline derivatives122
IrIIIPolypyridine ligands;126,127 cyclopentadienyl ligands123
RhIIIPolypyridine ligands124
CoIII(Phenyl(pyridine-2-yl)methylidene)-benzohydrazides;114 quinoline derivatives;125 phenanthroline derivatives122
RuIIDppza ligands;131,132 allopyranoside-grafted ruthenium(II) complex;126 quinone derivatives;127 phenanthroline derivatives118,119,128

Besides intercalation and groove binding, highly charged multinuclear complexes can bind strongly to the phosphate backbone of DNA, forming a “phosphate clamp. The trinuclear complex triplatinNC [{trans-Pt(NH3)2(NH2(CH2)6(NH3)}2-μ-{trans-Pt(NH3)2(NH2(CH2)6NH2)2}](NO3)8 (13, see Chart 4) exclusively utilises backbone functional groups to interact with DNA, and can associate with DNA even in the absence of direct coordination to DNA bases.129

Molecular structure of triplatinNC.
Chart 4 Molecular structure of triplatinNC. Coordination plus intercalation: dual mode DNA binders. Metal complexes with σ-bonded aromatic side arms or organometallic complexes with extended π-bonded arenes can act as dual-function complexes, binding to DNA both by direct metal coordination to a DNA base and intercalation between DNA bases through an attached aromatic ligand.105 The utilisation of σ-bonded side arm-containing platinum complexes acting as intercalators was reported in the late 1980s.130,131 For example, Pt complexes incorporating planar aromatic ligands such as acridine orange, 9-aminoacridine, ethidium bromide, and acridinylthiourea (ACRAMTU) bind to DNA by both coordination and intercalation.131–133 The dual mode interaction causes a strong structural modification by increasing the length and unwinding the DNA duplex. On the other hand, helical bending, C3′-endo deoxyribose puckering and rolling are not observed, which distinguishes the dual mode-induced damage from intrastrand cross-link damage.35 The adducts formed by the potent complex [PtCl(en)(ACRAMTU-S)](NO3)2 (14) (Fig. 2) inhibit transcription of the damaged DNA by RNA polymerase II.134
X-ray crystal structure showing the dual mode coordination/intercalation interaction between complex 14 and DNA (PDB ID 1XRW). Adapted from ref. 35.
Fig. 2 X-ray crystal structure showing the dual mode coordination/intercalation interaction between complex 14 and DNA (PDB ID 1XRW). Adapted from ref. 35.

Additionally, biphenyl RuII complex 11 (Chart 3) not only binds strongly and preferentially to G bases in DNA but also intercalates via the phenyl substituent on the η6-arene.135,136 In monofunctional adducts of {(η6-biphenyl)Ru(en)}2+ with the 14-mer (ATACATGGTACATA)·(TATG*TACCATGTAT) ruthenation occurs at N7 of each guanine residue. At one site (G*), not only was intercalation of the arene between G* and adjacent T observed, but also stacking of a non-intercalated arene on a tilted adjacent thymine on the surface of the major groove.137 Other dual-function coordination complexes have also been investigated,138,139 such as the di-RhII complex cis-[Rh2(dap)(μ-O2CCH3)2-(η1-O2CCH3)(CH3OH)](O2CCH3) (dap = 1,12-diazaperylene).

A series of low-spin 5d6 cyclopentadienyl IrIII organometallic half-sandwich complexes has been shown to form adducts with 9-ethylguanine and/or 9-ethyladenine readily, depending on the chelating ligands. Moreover, in the case of complexes incorporating extended Cp* ligands, the ability to intercalate into DNA appears to contribute to the anticancer potency of these IrIII complexes.123

Combining Pt and other metal ions also provides a strategy for designing complexes able to bind DNA both by coordination and by intercalation. For example, in heterobimetallic complexes containing Pt and Ru centres joined by a linker,140 PtII offers coordinative binding through ligand substitution, and octahedral RuII chelated by terpyridine or extended pyridyl ligands can act as an intercalator as well as possessing useful optical properties.140 Alternatively, the Pt unit is capable of interacting with DNA by π–π stacking or coordination through Cl substitution, and the Ru unit can bind to DNA by electrostatic or surface binding, or partial intercalation.141 G-quadruplex binders. Telomeres in human genes contain many repeats of the sequence d(GGTTAG) (G-quartets) and are responsible for maintaining cell division. In these G-rich strands, four-stranded G-quadruplexes can be formed consisting of planar G-quartets stabilised by K+ or Na+. These inhibit the enzyme telomerase. Targeting either telomerase or stabilising G-quartets is an effective strategy for the design of anticancer agents.

The first, and only example to date, of an X-ray crystal structure of human telomeric G-quadruplex DNA bound to a metal complex was reported in 2012.142 NickelII and copperII salphen metal complexes were co-crystallised in the presence of human telomeric DNA and the effective binding of these metal–salphen complexes to human telomeric quadruplexes by direct end-stacking was demonstrated (see Fig. 3). Other methods have also been used to demonstrate the binding of metal complexes to quadruplex DNA. Table 4 lists examples of coordinative and non-coordinative metal-based G-quadruplex DNA binders reported between 2009 and 2012.

X-ray crystal structure of human telomeric G-quadruplex DNA bound to a salphen–NiII complex (PDB ID 3QSF). Adapted from ref. 142.
Fig. 3 X-ray crystal structure of human telomeric G-quadruplex DNA bound to a salphen–NiII complex (PDB ID 3QSF). Adapted from ref. 142.
Table 4 Coordinative and non-coordinative metal complexes which bind to G-quadruplex DNA
AuIIIPorphyrins;143 pyrazolylpyridine144
CuIISalphen derivatives;142 terpyridine-based ligands145
PtIICarboxamide phenanthrolines and bis-carboxamide pyridines;146 terpyridines;145,147,148 Schiff bases;149 phenanthroimidazoles;150 triarylpyridines;151 perylene derivatives152
Tetranuclear PtIIQuinoxalines153
PtII–ZnIIPorphyrazine derivatives154
Dimetallic CuII, PtII and ZnIITerpyridine-based ligands155
PdIITerpyridine-based ligands;145 carboxamide phenanthrolines and bis-carboxamide pyridines146
NiIISalphen derivatives142
CoIII, MnIII, Octanuclear RuIIPorphyrins157,158
RuIIPolypyridyl ligands;159 phenanthroline derivatives;160,161 Dppz ligands162
RuIIPhenanthroline derivatives
Dinuclear RuIIBipyridines and tetrapyrido-phenazines;163 tetraazaphenanthrenes and tetrapyridoacridines164

1.1.2. Selective DNA-targeting. Metallodrugs with sequence specificity. New metal drug candidates should (ideally) interact with a specific biological target. For DNA, incorporation of ligands possessing sequence specificity can provide a strategy to enhance the selectivity of binding. For example, mononuclear and dinuclear PtII complexes incorporating linear and hairpin polyamide ligands (imidazole, pyrrole and β-alanine subunits, see Chart 5) are capable of recognising sequences up to seven base-pairs in length, providing a foundation for the synthesis of hairpin polyamides with multiple platinum groups leading to high DNA-sequence-selectivity, water-solubility and potentially highly active complexes.165,166
Molecular structures of some mononuclear and dinuclear PtII complexes incorporating linear and hairpin polyamide ligands.
Chart 5 Molecular structures of some mononuclear and dinuclear PtII complexes incorporating linear and hairpin polyamide ligands.

Specific recognition of DNA sequences can be also used to overcome side-effects and resistance to platinum drugs. Similarly incorporation of an oligonucleotide into a Pt complex allows sequence recognition within double stranded DNA by the formation of triple helices.167 Various pathways to metal-containing oligonucleotides have been designed, such as conjugation of an end-functionalised oligonucleotide, chelation of an oligonucleotide to the metal or incorporation of metal-containing phosphoramidites or hydrogenophosphonates. Oligodeoxynucleotide-tethered bifunctional cis-dichlorido Pt complexes168 can retain cross-linking ability. Protein-mediated DNA recognition. The design of metallodrugs incorporating groups capable of interacting specifically with DNA sequences is a challenge. An elegant strategy is to use a presenter protein and a small molecule that can bind to both protein and target.169 The formation of such ternary complexes has been described for organic drugs, such as the immunosuppressive antibiotic rapamycin,170 and has been illustrated as a concept for metallodrugs by an arene-Ru-biotin derivative171 embedded in the tetrameric streptavidin protein (Fig. 4).172 The supramolecular structure binds G-quadruplex DNA with selectivity towards DNA telomeres, even in the presence of competing targets (such as glutathione). However, because of a poor cellular uptake, the in vivo activity of the system was not investigated.
Presenter protein strategy for targeting telomeric DNA with Ru metallodrugs. The Ru drug embedded into tetrameric streptavidin in a 2 : 1 molar ratio forms a supramolecular complex that may allow extensive interactions with DNA (here depicted as G-quadruplex telomeric DNA; G4A). Reprinted from ref. 172 with permission. Copyright (2010) John Wiley & Sons.
Fig. 4 Presenter protein strategy for targeting telomeric DNA with Ru metallodrugs. The Ru drug embedded into tetrameric streptavidin in a 2[thin space (1/6-em)]:[thin space (1/6-em)]1 molar ratio forms a supramolecular complex that may allow extensive interactions with DNA (here depicted as G-quadruplex telomeric DNA; G4A). Reprinted from ref. 172 with permission. Copyright (2010) John Wiley & Sons.

1.2. Protein targeting

A number of proteins (e.g. kinases, bacterial Zn enzymes) have been proposed as potential biological targets for metal complexes or chelating agents in the case of metalloprotein targets.173–187 Modern bioanalytical techniques with high sensitivity and selectivity have facilitated the discovery of potential protein targets for metal complexes.188 However, as for DNA, the ability of a metallodrug to interact with amino acids, peptides or proteins in vitro does not necessarily imply a direct involvement in the cellular mechanism of action of this metallodrug. The involvement of particular targets has to be validated (e.g. by knockdown experiments, silencing gene expression by RNAi techniques). This involves blocking production of the protein in the cell and observing the effects on the activity of the drug candidate. So far, this has been rarely done for metallodrugs. Correlations of activity with protein binding (including inverse) can be useful for structure–activity relationships.189

We now illustrate recent work on interactions of metallodrugs with potential protein targets. The examples are illustrative and not comprehensive.

1.2.1. Hormone receptors. Prostate cancer is the most common cancer for men and the second killing-cancer after lung cancer. The majority of prostate cancers are initially androgen-dependent and might be treatable by hormone therapy. This therapy aims to block androgen receptors (AR) by binding antagonists (antiandrogens) to these receptors instead of the endogenous testosterone.190 Three are currently in clinical use for treatment of prostate cancer: flutamide,191 nilutamide,192 and bicalutamide,193 (Chart 6). Despite promising results, resistance acquired by cancer cells (possibly due to mutations of the androgen receptor) is one of the major limitations of the use of hormone therapy.194 The discovery of new antiandrogen compounds effective for both hormone-dependent and hormone independent prostate cancers is therefore of major importance. Among these potential antiandrogens, are steroid hormones progestogens (and synthetic derivatives progestins).
Molecular structures of flutamide, nilutamide, bicalutamide, tamoxifen, and hydroxyferrocifen.
Chart 6 Molecular structures of flutamide, nilutamide, bicalutamide, tamoxifen, and hydroxyferrocifen.

Ferrocenyl organometallic complexes incorporating steroidal androgens testosterone and dihydrotestosterone (DHT) exhibit a strong antiproliferative effect on the hormone-independent prostate cancer cells PC-3 with IC50 values in the low micromolar range.195

Tamoxifen ((Z)-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine, Chart 6) is a bioavailable selective estrogen receptor modulator commonly prescribed for preventing and treating hormone-dependent breast cancers. Its metabolite, hydroxytamoxifen, is the active form which competitively binds to estrogen receptors. Despite this clinical success, tamoxifen suffers from critical limitations: ineffectiveness towards ER-tumours (a third of hormone-dependent tumours), development of resistance mechanisms (another third), and increases of uterine and endometrial cancer risks.196

Ferrocenyl tamoxifen derivatives, obtained by substitution of the β-phenyl ring of hydroxytamoxifen by a ferrocenyl fragment (Chart 6), show promise for the treatment of both hormone-dependent and independent breast cancer cells.197 The replacement of the phenyl group by ferrocene reduces receptor affinity by about 40%, whilst the increase in length of the dimethylaminoalkyl chain has an adverse effect on receptor binding. In addition to tamoxifen-like binding to the estrogen receptors, ferrocifens are likely to be activated by oxidation to quinone methides in cells, suggesting a dual biological mode of action. The mechanism of formation of these quinone methides from ferrocenyl phenols is a two-step pathway involving two successive single-electron oxidations, accompanied by deprotonation which stabilises the quinone radical, resulting in the quinone methide structure.88 The proposed quinone methides have been characterised, and indeed appear to be the active metabolites of ferrocifens.198

Ruthenocenyl tamoxifen analogues behave essentially as antiestrogens.199 Electrochemical studies of such complexes showed that the oxidation of the ruthenocenyl fragment is irreversible and leads to rapid decomposition of the organometallic entity.197 Similarly, cyclopentadienyl Re analogues do not exhibit antiproliferative activity, ({CpRe(CO)3} acting as a spectator group).200 Therefore, the redox activity of the ferrocenyl group is of central importance, along with the antiestrogenic properties of the hydroxytamoxifen derivative, for providing a unique dual mechanism of action of these ferrocenyl tamoxifen derivatives.

The anticancer activity of titanocene dichloride has been known for decades, but its efficacy in Phase II clinical trials in patients with metastatic renal cell carcinoma201 or metastatic breast cancer202 was too low to be pursued. The titanocenyl-derivative of tamoxifen203 has estrogenic effects on hormone-dependent breast cancer cells in the nanomolar range. Unfortunately, hydrolysis of the titanocene fragment leads to the generation of TiIV species that behave in a similar way to estradiol towards the estrogen receptor. This explains the estrogenic effect observed for Cp2TiCl2 and precludes the use of Cp2TiCl2 derivatives of tamoxifen as drug candidates for the treatment of breast cancer. It also poses the problem of the possible role of titanium salts as endocrine disruptors.197 Nonetheless, the recent development of highly active water-soluble ring-substituted cationic titanocene dichloride derivatives has reactivated interest in such organometallic complexes.204–206

Another promising way of targeting hormonal receptors is utilisation of carboranes as estrogen receptor agonists and antagonists. Estrogen receptors are over-expressed in estrogen-receptor-positive tumours, such as in some breast cancers.207 Carboranes are versatile pharmacophores and possess unique properties that make them useful in inorganic chemistry.208,209 Compounds incorporating carborane cages structurally close to estradiol,210 can act as efficient estrogen receptor agonists.211Closo carborane tamoxifen is more stable than tamoxifen itself, and the Z carborane tamoxifen isomer exhibits similar inhibition properties as tamoxifen.

1.2.2. Mitochondrial protein targeting. Mitochondria in cells regulate energy production and modulate redox potentials as well as generating reactive oxygen species (ROS e.g. O2˙ and H2O2). In cancer cells, mitochondria have hyperpolarised membranes and over-produce ROS. Their defective function in cancer cells makes them potential targets for anticancer drugs.

Mitochondrial proteins are potential targets for arsenic compounds which can bind strongly to vicinal (Cys) thiol groups, increase ROS production and induce apoptotic signalling pathways. Several studies have highlighted the potential of arsenic metallodrugs in cancer therapy. Arsenic(III) trioxide (As2O3) has been used as a therapeutic agent for over 2000 years.212–214 More recently Ehrlich screened hundreds of organoarsenic compounds for biological activity and in 1910 introduced Salvarsan (arsphenamine) for the treatment of syphilis. Currently, As2O3, (ATO, ‘Trisenox’, Table 1) is the most effective single agent for the treatment of acute promyelocytic leukaemia.215 In aqueous solution ATO exists as the trihydroxide As(OH)3 and is taken up into cells via the aquaporins (especially aquaglyceroporins216)-membrane transport proteins.

GSAO (4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid) is a promising new compound, known to inhibit adenine nucleotide translocase (ANT) in the inner membrane of mitochondria. A phase I clinical study is in progress in patients with solid tumours refractory to standard therapy (Table 1).217 Metabolism of GSAO is required for biological activity. This metabolism involves a two-step mechanism, first cleavage by γ-glutamyltranspeptidase at the cell surface to give GCAO (4-(N-(S-cysteinylglycylacetyl)amino) phenylarsonous acid). Then GCAO enters cells via an organic ion transporter and is metabolised by dipeptidases to CAO (4-(N-(S-cysteinylacetyl)amino) phenylarsonous acid) in the cytosol (Fig. 5). Finally, CAO enters the mitochondrial matrix and AsIII cross-links cysteine residues 57 and 257 of human ANT1,218 so inhibiting this enzyme.

Metabolism of GSAO and molecular structure of PENAO. Adapted from ref. 218.
Fig. 5 Metabolism of GSAO and molecular structure of PENAO. Adapted from ref. 218.

The analogue of CAO, PENAO (4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid) (Fig. 5), is accumulated in cells ca. 85-fold faster than GSAO, has a 44× higher antiproliferative activity and 20× higher antitumour efficiency in mice. In 2012, patients with solid tumours refractory to standard therapy were recruited for Phase I/IIa dose escalation studies.218

In general, many positively-charged lipophilic complexes are taken up by mitochondria, for example cartionic gold(I) phosphines and carbenes.219,220 Another example is inert polypyridyl RuII complexes which target mitochondrial function and induce apoptosis. A strategy for combinatorial parallel coordination chemistry has been recently used, giving access to a library of more than 500 monocationic polypyridyl ruthenium complexes.221 These complexes were screened for cytotoxicity towards cancer cells, and structure–activity relationships led to the discovery of a lead complex [Ru(tBu2bpy)2(phox)]PF6 (tBu2bpy = 4,4′-di-tert-buty-2,2′-bipyridine and Hphox = 2-(2′-hydroxyphenyl)oxazoline) (15, Chart 7), which is active at submicromolar concentrations in clinically relevant Burkitt-like lymphoma cells. This complex strongly reduces the mitochondrial membrane potential, suggesting involvement of the intrinsic pathway of programmed cell death. These complexes are chiral, but all compounds in this study were formed as mixtures of enantiomers or diastereoisomers. It would be interesting to test the separated enantiomers for activity.

Molecular structures of complexes 15 and 16. Only one enantiomer is shown.
Chart 7 Molecular structures of complexes 15 and 16. Only one enantiomer is shown.

Another example of mitochondrial targeting is the complex [Ru(dppz)2(CppH)]2+ (CppH = 2-(2′-pyridyl)pyrimidine-4-carboxylic acid; dppz = dipyrido[3,2-a:2′,3′-c]phenazine, 16, Chart 7), which impairs the mitochondrial membrane potential in HeLa cells as early as 2 h after treatment and induces apoptosis.222

1.2.3. Kinases, TNF-α and thioredoxin. The selective targeting of enzyme kinases is a particularly complex task, since more than 500 proteins belong to this family, although they all possess highly conserved ATP binding sites.223 Inert octahedral metal complexes are emerging as promising scaffolds for targeting kinase active sites,224 thanks to their rigid and globular shapes, and high synthetic versatility.225 Meggers and co-workers have demonstrated that specific RuII,226 OsII,227 RhIII,228 and IrIII (ref. 229) complexes can serve as highly potent (micromolar to nanomolar range) and selective inhibitors of kinases. In most cases, the racemic complexes were resolved into the enantiomers by chiral HPLC (Δ/Λ−, or R/S-enantiomers), and the individual isomers were tested against different kinase enzymes. The affinities of the isomers for kinase ATP-binding sites are markedly different (for instance, the Λ-enantiomer of a ruthenium complex (FL-172) 27-fold more potent for kinase PAK1 compared to the Δ-enantiomer226). The Ru centre is not involved in any direct interactions and has solely a structural role.230 A striking example of this work is the crystal structure of PIM2 (a serine/threonine kinase over-expressed in human leukaemia and lymphomas) with a bound R-configuration organoruthenium inhibitor (17, see Fig. 6 for molecular structure), which shows the good shape complementarity between the Ru complex and the ATP site of kinase PIM2, Fig. 6. An interesting strategy is the combination of kinase inhibition and photoactivity demonstrated for an angiogenic octahedral organoiridium complex. This can undergo substitution of a selenocyanate ligand on irradiation with visible light and induces apoptosis in cancer cells.231 There are good prospects for further improving the selectivity of photoactivated metallodrugs by conjugation to targeting vectors such as peptides.232
Molecular structure of complex 17 and X-ray crystal structure showing its interactions in the ATP pocket of PIM2 kinase (PDB ID 2IWI). Adapted from ref. 233.
Fig. 6 Molecular structure of complex 17 and X-ray crystal structure showing its interactions in the ATP pocket of PIM2 kinase (PDB ID 2IWI). Adapted from ref. 233.

Aberrant activity of tumour necrosis factor-α (TNF-α, a pro-inflammatory cytokine involved in the regulation of many key biological processes, e.g. haematopoiesis, immunity, and inflammation)234 is associated with a number of diseases, such diabetes, tumourigenesis, and autoinflammatory diseases. Clinical trials in ovarian cancer suggest that synthetic therapeutic antibodies (e.g. infliximab), which bind directly to TNF-α, may be effective in blocking its interaction with the tumour necrosis factor receptor (TNFR).235–237 Despite this success, synthetic antibodies suffer from limitations, such as development of anti-antibody response, which has led to the search of alternative small-molecule-based therapies as inhibitors of TNF-α. Based on the approach developed for kinase inhibition, inert octahedral metal complexes, such as the cyclometalated biquinoline iridium(III) complex 18 (see Chart 8), hold potential as direct TNF-α inhibitors.238

Molecular structure of complex 18. One enantiomer is shown.
Chart 8 Molecular structure of complex 18. One enantiomer is shown.

Interest in targeting the thioredoxin system – including thioredoxin (Trx), thioredoxin reductase (TrxR) and NADPH – led in 2006, to the submission of a New Drug Application to the FDA for Motexafin gadolinium, an inhibitor of thioredoxin reductase and ribonucleotide reductase, for the treatment of lung cancers with brain metastases. This compound is currently in clinical development as a radiation and chemotherapy sensitiser (Table 1). Thioredoxin reductase remains an attractive target for metallodrugs (Table 5), particularly for gold complexes,239–243 although there is a need to validate this as a target for these metal complexes in vivo. Thioredoxin reductase (TrxR) contains FAD and NADPH binding domains and a redox-active disulphide (Cys–Cys) bond in its active site. It transfers electrons to thioredoxin which, in turn, reduces disulphide bonds and other substrates. Mammalian TrxRs contain a second redox-active site, a C-terminal –Cys-SeCys– (where SeCys is selenocysteine).244

Table 5 Recent examples of metal (and metalloid) complexes which interact with isolated thioredoxin reductase
SeOrganic selenium-containing amino acids245
AsArsenic trioxide246
AuICarbene derivatives;240,242,248,249 Auranofin;250 thiosemicarbazones;242 Benzimidazol-2-ylidene;251N,N′-disubstituted cyclic thiourea252
AuI and AuIIIGlyoxaldehyde-bis(thiosemicarbazones)253
AgICarbene derivatives;249 silver-nanoparticles254
PtIVcis-[Pt(NH3)2Cl4] and trans-[PtCl2(CN)4]2−;256
PdK2PdCl4, and K2PdCl6;257
RuIICarbene derivatives258

1.3. Metallodrug delivery and activation

1.3.1. Light activation of PtIV prodrugs. Spatially-targeted activation by light is a possible way of increasing the efficiency of PtIV prodrugs, avoiding unnecessary damage to normal tissues, and delivering the active drug mainly to the tumour itself to enhance activity or activate the drug specifically in the cancer cells.260 The metal complexes used are generally stable to thermal activation so that they reach the target site intact. However the excited singlet and triplet states (which are often reached very quickly, in pico–nano seconds) have different electron distributions to the ground state and hence different geometries and different reactivities.261 Excited state drugs offer the prospect of novel mechanisms of action.262 The wavelength of activation is important because longer wavelengths (e.g. red light) penetrate tissues more deeply than shorter wavelengths (e.g. blue light).

Platinum(IV) complexes of the type [Pt(OH)2(N3)2(amine1)(amine2)] have strong azide-to-PtIV charge-transfer bands, are stable in the dark, and towards the intracellular reducing agent glutathione.263 After short treatment and short irradiation times (e.g. 1 h), they react rapidly with DNA bases such as guanine and are potently cytotoxic. Interestingly, the trans diam(m)ine diazido complexes appear to be more effective as photoactivatable anticancer agents than the cis isomers (Fig. 7).264 These complexes are also more effective than cisplatin when used under conditions appropriate for clinical phototherapeutic drugs (short treatment times, short irradiation times).

Photocytotoxicity of trans-diam(m)ine PtIV diazido complexes versus their cis-isomers, with associated IC50 values.
Fig. 7 Photocytotoxicity of trans-diam(m)ine PtIV diazido complexes versus their cis-isomers, with associated IC50 values.

The DNA lesions are unusual and include interstrand crosslinks. Trans,trans,trans-[Pt(OH)2(N3)2(NH3)(py)] is active in vivo on activation with blue light in an oesophageal cancer model.265Trans,trans,trans-[Pt(OH)2(N3)2(py)2] (py = pyridine) undergoes photoreduction when irradiated by UVA, blue or green light,266 and also produces azidyl radicals which can be quenched by L-Trp.267 Therefore these diazido complexes may have a dual mechanism of action involving the production of reactive PtII and radicals from the PtIV prodrug. Unlike conventional photosensitizers (which convert 3O2 to excited 1O2: photodynamic therapy), these complexes would not rely of O2 for activity, a potential advantage since tumours are often relatively hypoxic.

Other metal complexes are potent light activated anticancer agents. For instance, strained octahedral tris-bipyridyl ruthenium(II) complexes have been shown to be inert until triggered by visible light.268 Under irradiation, a light-activated ligand release mechanism occurs, leading to DNA binding, and to an increase in cytotoxicity of 2 orders of magnitude in cancer cells (with potencies superior to cisplatin against 3D tumour spheroids). The use of intramolecular strain is a promising strategy for developing light-activated Ru complexes for PDT applications.

1.3.2. Photo-release of biologically-active small molecules. Photoactivation is also a promising strategy for the release of biologically-active small molecules such as NO, CO, and H2S. NO is an important signalling molecule with a wide range of functions in the cardiovascular, nervous, and immune systems.269 The interactions of NO with metal complexes in vivo – heme and non-heme Fe in particular – are of prime importance to its physiological role. Metal complexes show promise for both controlled release and scavenging of NO.270 Examples include [Ru(terpy)(bdqi)NO]3+ (terpy = terpyridine, bdqi = 1,2-benzoquinone diimine) which can release NO on irradiation with visible light. This complex can be delivered in lipid nanoparticles via topical administration and provides a possible treatment for skin cancer.271

CO is also a natural signalling molecule which can be released from a metal centre by light activation,272 and metal carbonyls have been extensively investigated as potential CO-donating pharmaceuticals.273,274In vivo, CO appears to have a role as a messenger, has anti-inflammatory properties and an ability to suppress organ graft rejection. The design of metal complexes that can release CO at a predicable rate is therefore valuable as a relatively non-toxic source of CO. Cell viability studies of HT29 colon cancer cells treated with the CO-releasing compound [Mn(CO)3(tpm)]PF6 (tpm = tris(pyrazolyl)methane) have revealed a significant photoinduced cytotoxicity, comparable to that of the established anticancer agent 5-fluorouracil.275

1.3.3. Anticancer platinum drug delivery. The limitations of PtIV drug candidates might also be overcome by the utilisation of drug cargos. In principle, these transporters can carry a large number of platinum centres, shield the drug from premature activation, and deliver platinum specifically to cancer cells. Moreover, cancer cells divide rapidly and have a higher demand for nutrients than normal cells. Because of this need for nutrients, the vascular endothelial growth factor (VEGF) is expressed and induces angiogenesis (formation of new blood vessels for the tumour cells) which increases the permeability of the cell membrane. The increased permeability leads to a higher uptake of large molecules and proteins. However the major difference from normal cells resides in the lymphatic drainage, which is severely impaired for cancer cells, thus leading to the retention of large molecules and lipids inside the cell.276 This enhanced permeability and retention (EPR) effect of cancer cells is an excellent target for the development of anti-cancer agents:277 Large molecules might be selectively taken up by cancer cells and retained whereas excretion by normal cells through their healthy lymphatic system might occur.

A large number of carrier systems have been developed in recent years, spanning functionalised carbon nanotubes, nanorods, metal–organic frameworks, metalla-cages, nanoparticles, liposomes, nanogels, proteins, and polymers. This wide diversity of systems offers an interesting pool of carriers, and each system possesses unique advantages.260 The delivery system can also influence the activity of metallodrugs. For example, a PtIV complex has been recently tethered via amide linkages to gold nanoparticles (AuNPs) functionalized with thiolated oligonucleotides. The resulting systems exhibit 12-fold higher activity than free cisplatin towards A549 lung cancer cells.278 The delivery of a lethal dose of cisplatin to prostate cancer cells by the encapsulation of PtIV prodrug in prostate-specific membrane nanoparticles (NPs) has also been recently reported.279 The utilisation of prostate-specific membrane antigen to target aptamers overexpressed in tumour cells, allows an specific delivery of the active drug into cancer cells. The release of the PtIV complex from the nanoparticles is followed by reduction to PtII (cisplatin), which can subsequently form 1,2-d(GpG) intrastrand cross-links on nuclear DNA.

Ruthenium metalla-cages also show promise as drug delivery systems. Supramolecular metalla-prisms based on arene ruthenium complexes can encapsulate square-planar acetylacetonato PdII and PtII complexes in their cavities and deliver them into cells, (e.g. [19]6+, see Chart 9).280,281 The activity of these carceplexes towards human ovarian cancer cell lines is more than an order of magnitude higher than the empty metalla-cage.281 Metalla-prisms can be synthesised with larger portal sizes (e.g. [20]6+, [21]6+, and [22]6+, see Chart 9).282,283 The guest can be released from such metalla-cages without rupture of the cage,284–288 and the extent of drug release correlates with the portal size of the cage.289 The host–guest capability of these systems has been used for encapsulating hydrophobic pyrenyl-cycloplatinate complexes,290 pyrenyl-containing dendrimers of different generations, for targeting cancer cells via the EPR effect,291–293 and for incorporating guests having affinity for G-quadruplex DNA.294 They can also be used as vehicles for intracellular delivery of photosensitisers, with possible use in photodynamic therapy.295 These systems being robust, highly water-soluble, and versatile are promising for drug delivery.

Molecular structures of metalla-cages [19]6+, [20]6+, [21]6+, and [22]6+.
Chart 9 Molecular structures of metalla-cages [19]6+, [20]6+, [21]6+, and [22]6+.

2. Anti-viral, anti-microbial and anti-diabetic metallodrugs

2.1. Anti-viral metallodrugs

2.1.1. Hepatitis. According to The World Health Organization, hepatitis C viral infection (HCV) affects 150 million people with consequences spanning from a mild illness lasting a few weeks to a serious, lifelong condition that can lead to cirrhosis of the liver or liver cancer. Every year, more than 350[thin space (1/6-em)]000 people die from hepatitis.296 This disease can be treated by combination therapy involving pegylated recombinant interferon and ribavirin. However, interferon is not always well tolerated, some HCV genotypes respond better to interferon than others, and both interferon and ribavirin are not selective for HCV or viral disease in general.297 Moreover, the absence of an effective vaccine is stimulating the search for new drugs. A possible strategy for such development is to target specifically the critical RNA sequences present in hepatitis C virus but rare in the genome of infected host cells, For instance, the synthesis of a catalytic metallodrug that targets stem-loop IIb of the internal ribosomal entry site (IRES) RNA of hepatitis C virus has been recently reported.298 This metal complex incorporates an amino-terminal copper and nickel binding motif (ATCUN) that is found naturally at the N-terminus of many albumins299 as well as natural peptides such as histatin 5300 and neuromedin,301 and which binds copper and nickel with very high affinity.302 The ATCUN ligand provides a stabilisation of the redox states Cu(III)/Cu(II) and prevents the formation of the labile Cu(I) state. A C-terminal tetrapeptide (YrFK-amide) targeting domain is also coordinated to the metal centre in order to provide a selective recognition of the HCV IRES stem-loop IIb domain (Chart 10). Interestingly, neither the targeting peptide alone YrFK-amide, lacking the metal binding ATCUN motif, nor the metal binding ATCUN domain alone show any cellular efficacy. However, the complex reacts in vitro with the HCV IRES stem-loop IIb domain and inactivates catalytically and irreversibly the replication of hepatitis C virus with a turnover number of about 32.298 Despite this low turnover number, this preliminary study represents a promising new approach to the design of anti-hepatitis drugs.
Molecular structure of Cu(ii)-YrFK-amide complex.
Chart 10 Molecular structure of Cu(II)-YrFK-amide complex.
2.1.2. Human immunodeficiency virus. Drugs for treatment of the Human Immunodeficiency Virus (HIV) are targeted to various pathways and enzymes: nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and integrase inhibitors.303

The enzyme integrase (IN) catalyses the integration of viral DNA into the host cell DNA and is a particularly interesting target for HIV inhibitors. The active centre of the enzyme possesses two MgII ions held in place by a triad of protein carboxylate side chains, as well as an HHCC zinc finger site. Ligands which can chelate to the MgII ions might be effective enzyme inhibitors and drugs. Such a drug is raltegravir, approved by the FDA in 2007 (see Fig. 8). Despite its clinical success it suffers from an overall dose burden, and a lack of potency. To help to overcome rising raltegravir resistance, Cohen et al. have synthesised a series of raltegravir-chelator derivatives (RCD) as HIV integrase inhibitors in order to assess the role of the metal-binding group.304 The binding mode for this series of RCD molecules was elucidated by docking simulations, based on a crystal structure of prototype foamy virus (PFV) integrase in complex with raltegravir (PDB ID 3OYA). The docking of raltegravir and of RCD-1 (structure in Fig. 8) into PFV IN gives identical binding modes (Fig. 8), showing that the O,O,O donor atom triad of both raltegravir and RCD can bind to the MgII ions, forming 5- and 6-membered chelate rings.

Molecular structures of raltegravir and RCD-1. Comparison of the computational docking of RCD-1 (magenta) in the PFV IN versus the reported crystal structure of raltegravir (green) bound to PFV IN (PDB ID 3OYA). Adapted from ref. 304.
Fig. 8 Molecular structures of raltegravir and RCD-1. Comparison of the computational docking of RCD-1 (magenta) in the PFV IN versus the reported crystal structure of raltegravir (green) bound to PFV IN (PDB ID 3OYA). Adapted from ref. 304.

Carbamoyl pyridine scaffolds can also chelate two MgII ions in the active site of HIV-1 IN with nanomolar affinity.305 Carcelli et al. have shown that incorporation of RuII arene substituents can increase the potency of quinolone and hydroxypyrimidine-carboxamide HIV-1 IN inhibitors.306

An effective anti-HIV strategy is to target the membrane protein CXCR-4, a seven-helix transmembrane G-protein-coupled receptor and one of the several chemokine receptors that HIV uses to infect CD4+ T cells. The bis-macrocycle xylyl-bicyclam has potent anti-HIV activity but its use in the treatment of HIV was hindered by its lack of oral availability and cardiac disturbances.307 During clinical trials, its effectiveness in mobilising stem cells from the bone marrow was discovered, which led to clinical approval by the FDA in 2008 for this purpose (e.g. in transplant therapy) as the drug Mozobil.308

Metal ions such as ZnII and CuII bind to cyclam strongly309 and relatively rapidly,310 and it seems likely that metal complexation by xylyl-bicyclam is involved in the mechanism of action of the drug in vivo. The affinity of xylyl-bicyclam for the CXCR4 receptor is enhanced by factors of 7, 36, and 50 by incorporation of CuII, ZnII, or NiII, respectively, into the cyclam rings. Dizinc xylybicyclam tetraacetate forms the unusual folded cis-V configuration with an acetate carboxylate bound to ZnII on one side of the cyclam ring and acetate forming a double H-bond to cyclam NH groups on the other side of the ring.311 In a model of the Zn drug docked onto human CXCR4, a similar coordination can be achieved involving the carboxylates of Asp171, Asp162 and Glu288. Hydrophobic interactions involving Trp side chains and the periphery of the cyclam rings together with metal–carboxylate binding and H-bonding are observed in the X-ray crystal structure of CuII–cyclam and CuII2–bicyclam adducts of the protein lysozyme (Fig. 9).312

X-ray crystal structure of a CuII–cyclam adduct of lysozyme (PDB ID 1YIK). A different viewing point is adopted in the enlargement on the right side, for clarity. Adapted from ref. 312.
Fig. 9 X-ray crystal structure of a CuII–cyclam adduct of lysozyme (PDB ID 1YIK). A different viewing point is adopted in the enlargement on the right side, for clarity. Adapted from ref. 312.

Configurationally constrained metal–cyclam complexes have potential as even more potent antiHIV agents. For example, ZnII hexyl-dimethyl-cyclam complexes are active, but more active are Zn2((5-5′-[1,4-phenylenebis(methylene)]-bis(1,5,8,12-tetraazabicyclo[10.2.2]hexadecane))(OAc)4,313 and Ni2(1-[4-aminomethylbenzyl]-1,4,8,11-tetraazabicyclo-[10.2.2]hexadecane)(NO3)2.314 These studies illustrate that direct metal coordination, H-bonding and hydrophobic interactions with the ligands can all play important roles in metallodrug-protein target recognition.

2.2. Anti-microbial agents

2.2.1. Tuberculosis. Tuberculosis (TB) remains a major global health problem, with almost 9 million new cases in 2011 and 1.4 million TB deaths (990[thin space (1/6-em)]000 among HIV-negative people and 430[thin space (1/6-em)]000 HIV-associated TB deaths).315 Moreover, 27[thin space (1/6-em)]000 cases of extremely drug-resistant TB in both developed and underdeveloped countries were reported in 2005; The most recently developed anti-tuberculosis drug is more than 40 years old. New anti-tuberculosis drugs with different biological mechanisms are needed, and although metal complexes might provide efficient alternatives, very few examples of such complexes have been reported, and in most cases, their mechanisms of action have rarely been thoroughly studied.

Nonetheless, some recent studies have demonstrated the potential of metal-based drugs for the development of anti-tuberculosis agents. Among them, the redox activation of isoniazid iron(II) complexes is of interest.316 Indeed, isoniazid has been used as a front-line drug in the treatment of TB, although resistant TB strains have limited its use. Isoniazid is a prodrug that needs to be activated by an electron transfer reaction. This reaction is catalysed by the catalase-peroxidase KatG, and leads to the formation of an intermediate isonicotinic acyl radical that promptly reacts with NADH, generating a NAD–isoniazid adduct. This adduct is an efficient inhibitor of the enoyl reductase enzyme InhA, a major target for anti-Mycobacterium tuberculosis agents.317

About 50% of isolated isoniazid-resistant strains have either a deletion or mutations in the katG gene and this KatG enzyme disruption (blocking electron transfer reactions) has been shown to be the major cause of isoniazid resistance.318 For overcoming such resistance, the coordination of isoniazid to metal complexes (e.g. cyanoferrates) might allow a rapid oxidation of the metal centre, triggering isoniazid activation intramolecularly, independently of the activation by KatG enzymes (see Fig. 10 for a possible mechanism of action). This hypothetical mechanism still needs to be supported by experimental evidence, but preliminary studies on an isoniazid-containing pentacyanoferrate complex show that an inner-sphere electron transfer reaction occurs between the metal and isoniazid, thereby activating this prodrug and overcoming the necessity for KatG. This metal complex inhibits both wild-type InhA and its isoniazid-resistant mutant InhA I21V, even in the absence of KatG and NADH, bypassing the enzymatic activation. Interestingly, the ruthenium analogue (isoniazid)pentacyanoruthenate(II) complex does not inhibit InhA, probably because its very high electrochemical potential is outside the biological range.

Possible mechanism for overcoming isoniazid resistance using an FeII complex. Based on ref. 316.
Fig. 10 Possible mechanism for overcoming isoniazid resistance using an FeII complex. Based on ref. 316.
2.2.2. Other anti-microbial agents. Many metal compounds show appreciable antimicrobial activity, some established examples are based on silver, bismuth, mercury, arsenic, and antimony. For instance, the arsenic-based antimicrobial agent Salvarsan ((AsR)n, R = 3-amino-4-hydroxyphenyl, where n = 3 and 5 are the most abundant species in solution) was used historically to treat syphilis and trypanosomiasis, although in recent times it has been replaced. It is suggested that oxidation in vivo generates the active form of the drug, such that Salvarsan serves as a slow-release source of RAs(OH)2 (oxidation from AsI to AsIII).319 The importance and historical role of inorganic and organometallic complexes as antimicrobial agents have been recently reviewed.320,321

A wide range of inorganic compounds from organometallic complexes to metal organic frameworks, nanoparticles or metallic surfaces have also been recently investigated for killing or inhibiting microbial growth, including mercury,322 silver,323 gold wires324 and nanoparticles,325 copper,326 cobalt,327 platinum,326 palladium,328 ruthenium,329 iron (chelation therapy),330,331 manganese complexes,332 titanium dioxide nanoparticles,333 noble metal nanoparticles,334,335 and nanostructures as antibacterial drug delivery systems.336

2.3. Anti-diabetic metallodrugs

Diabetes mellitus (DM) is a group of chronic metabolic diseases characterised by persistent hyperglycaemia associated with absolute or relative deficiency in insulin secretion from the beta cells of pancreas. The dysfunction of insulin receptors might also be associated with diabetes. The current (285 million patients worldwide) and dramatically-increasing incidence of this disease is stimulating the search for new anti-diabetic agents.337 Potential insulin mimetic metallodrugs have received much interest in the last two decades. The aim of developing new oral insulin mimetic drugs that act independently of insulin, for both insulin-dependent and insulin-independent diabetes, is to overcome side effects such as hyperinsulinemic hypoglycaemia due to current insulin preparations and synthetic drugs used in clinic.

Zinc and vanadium complexes have been widely studied as potential metallopharmaceutics for treating diabetes mellitus. Zinc plays an essential role in the physiology, structure and function of insulin,338 and vanadium is also an essential element. The complex bis(maltolato)oxovanadium(IV) (BMOV, Chart 11), underwent phase II clinical trials but failed due to effects on the kidneys of patients. To reduce toxicity, Wei et al. have synthesised a vanadium complex which incorporates a modified pyranone derivative (BBOV, Chart 11).339 BBOV has low in vivo toxicity and oral administration of this complex to STZ-induced diabetic rats leads to a dramatic reduction of hyperglycaemia, along with an increase of the impaired glucose tolerance activity.

Molecular structures of vanadyl anti-diabetic drug candidates BMOV and BBOV.
Chart 11 Molecular structures of vanadyl anti-diabetic drug candidates BMOV and BBOV.

A third metal of interest for development of anti-diabetic drugs is chromium, an element for which there is now no good evidence that it is essential.340,341Table 6 summarises recent examples of anti-diabetic CrIII complexes and their activity.

Table 6 Examples of anti-diabetic CrIII complexes
CrIII ligandsActivity
Nicotinates, phenylalanines, histidinatesDecrease of blood glucose level342–345
PolysaccharidesNo positive effect346
PicolinatesImprovement of serum lipid metabolism
Improvement of glucose metabolism347,348
PropionatesAmelioration of insulin resistance symptoms349
Rutin, folate and stachyose ligandsControl of blood glucose350
MalateControl of blood glucose level, liver glycogen level, and of the activities of aspartate transaminase, alanine transaminase, and alkaline phosphatase351

Tetrahedral vanadate, molybdate, and tungstate complexes can compete with phosphate substrates for binding to phosphatases,352 and are potent inhibitors of muscle glycogen phosphorylases by competing with glucose-1-phosphate.353 Sodium tungstate Na2WO4 has been particularly investigated, due to the restoration of hepatic glucose metabolism by the stable oxoanion [WO4]2−.354 Moreover, [WO4]2− appears to mimic most of the metabolic effects of insulin and stimulate insulin output.355 The Keggin anion [PW12O40]3− has been also investigated for its ability to mimic insulin.356–358 Sodium molybdate Na2MoO4 is similarly effective for preventing or treating of diabetic mellitus in the early stages of the disease.359 However none of these compounds has yet received clinical approval as a new antidiabetic drug.

There is also increasing interest in the potential use of vanadium compounds for treating leishmaniasis, Chagas' disease and amoebiasis, and viral infections.360

3. Anti-parasitic, anti-inflammatory and anti-neurodegenerative metallodrugs

3.1. Anti-parasitic metallodrugs

3.1.1. Malaria. The absence of a vaccine for the prevention and/or treatment of malaria is one of the major factors stimulating the search for new anti-malarial therapeutics. Malaria is treated mainly with a combination of chloroquine and antifolate drugs, or by artemisinin derivatives. Innovative drugs having new biological mechanisms of action are needed, due to the emergence of a high number of drug-resistant Plasmodium strains. In this context, metallodrugs are a promising class of compounds that might lead to a breakthrough in antimalarial therapy.

Plasmodium falciparum is one of the five species of Plasmodium parasite that causes the most lethal form of malaria. Plasmodium falciparum is particularly sensitive to oxidative stress,361 and targeting of thioredoxin reductase is an approach that is being widely studied.362 Auranofin (Fig. 11) and a few related gold complexes strongly inhibit Plasmodium falciparum growth, probably due to a direct inhibition of Plasmodium falciparum thioredoxin reductase. In 2012, based on studies demonstrating that auranofin is a pro-drug giving rise to the active fragment {Au(PEt3)}+ (while the tetraacetylthioglucose ligand is excreted in vivo),363 molecular docking experiments364 were carried out and suggest that {Au(PEt3)}+ can bind to a N atom of an histidine in the active site of Plasmodium falciparum thioredoxin reductase, Fig. 11. This mode of binding to a protein His sidechain (despite the presence of Cys thiol sulfurs) was observed previously for {Au(PEt3)}+ in the X-ray structure of cyclophilin-3.365 Gold(I) also has a high affinity for selenocysteine which provides selectivity for inhibition of thioredoxin reductase over glutathione reductase.251

Molecular structure of auranofin. Docked conformation of {Au(PEt3)}+ in truncated SmTGR. FAD is in violet sticks. The gold atom is a yellow sphere. Residues interacting with the gold atom are in sticks. Adapted from ref. 364.
Fig. 11 Molecular structure of auranofin. Docked conformation of {Au(PEt3)}+ in truncated SmTGR. FAD is in violet sticks. The gold atom is a yellow sphere. Residues interacting with the gold atom are in sticks. Adapted from ref. 364.

Another approach for designing metallodrugs with potency against malaria is to coordinate biologically-active quinolone derivatives to metal centres. The ferrocene–quinoline conjugate ferroquine has been on clinical trials (Chart 12, Table 1).366

Molecular structures of chloroquine, ferroquine, and ruthenoquine. The intramolecular hydrogen bond facilitating membrane permeability of ruthenoquine is shown.
Chart 12 Molecular structures of chloroquine, ferroquine, and ruthenoquine. The intramolecular hydrogen bond facilitating membrane permeability of ruthenoquine is shown.

Chloroquine is thought to interfere with the digestion of haemoglobin in the blood stages of the malaria life cycle. Even though some similarities between the biological mode of action of chloroquine and ferroquine have been observed,367 ferroquine exhibits additional mechanisms.368 In particular, ferrocene can undergo a one-electron oxidation, yielding the ferrocenium cation, which may generate hydroxyl radicals under physiological solutions,369,370 leading to potential DNA371 and cell membrane damage.372 Moreover, the weaker base properties and higher lipophilicity at physiological pH of ferroquine compared to chloroquine, as well as intramolecular H-bonding with the lateral side chain of ferroquine (in non polar conditions) leads to the improved ability of ferroquine to cross membranes and a higher accumulation in the digestive vacuole.373

Ferroquine and ruthenoquine analogues possess slightly different mechanisms of action, Ruthenoquine does not produce reactive oxygen species (ROS) under the oxidative conditions of the parasitic digestive vacuole of Plasmodium falciparum.374 However, both compounds are active against drug-susceptible and drug-resistant strains of Plasmodium falciparum.375 Ruthenocenic derivatives of chloroquine with and without an intramolecular hydrogen bond have been used to study the localisation and quantification of ruthenoquine in Plasmodium falciparum-infected erythrocytes.374 This study suggested that the presence of intramolecular H-bonding (Chart 12) substantially improves the membrane permeability and transport of the drug to its target.

3.1.2. Amoebiasis. Amoebiasis is an infection of the intestine caused by the parasite Entamoeba histolytica, responsible for about 70[thin space (1/6-em)]000 deaths a year.376 The World Health Organisation estimates that amoebiasis is the fourth leading cause of death due to protozoan infections (after malaria, Chagas disease, and trichomoniasis). Current medications for the treatment of amoebiasis are based on nitroimidazole derivatives, such metronidazole, and tinidazole. However, the appearance of resistant E. histolytica strains377 and side effects associated to these drugs, are strong limitations for this family of compounds. New drugs are therefore needed with new mechanisms of action.

Metal complexes of active antiamoebiasis drugs have been investigated including AuI, RuII and CuII complexes of metronidazole ([1-(2-hydroxyethyl)-2-methyl-5-nitro-1H-imidazole]) which have higher activity than uncomplexed metronidazole.378 Cyclooctadiene RuII complexes of thiosemicarbazone derivatives are also more active than metronidazole.379 Recently, an automated, high-throughput screen has been developed to facilitate drug screening for Entamoeba histolytica.380 Interestingly, this screening identified that auranofin is 10× more potent against E. histolytica than metronidazole. The capability of this drug to inhibit E. histolytica thioredoxin reductase prevents the reduction of thioredoxin and enhances the sensitivity of trophozoites to reactive oxygen-mediated killing. This new use of auranofin represents a promising therapy for amoebiasis, and the drug has been granted orphan-drug status by the FDA (Table 1).

3.2. Anti-inflammatory metallodrugs

3.2.1. Arthritis. Chrysotherapy (utilisation of metallic gold and its complexes in medicine) has been used for the treatment of various diseases for many centuries. For instance, AuI cyanide was used to treat tuberculosis in the early 20th century and was replaced by AuI thiolates such as the polymer aurothiomalate. French physicians first used injectable AuI compounds to treat rheumatoid arthritis in 1929.381 In 1985 the AuI triethylphosphine complex auranofin (Fig. 11) was approved by the FDA as an oral antiarthritic agent. The mechanism of action of this compound is still not understood,382 although recent studies have shown that cathepsin B is inhibited by AuI complexes.383 Auranofin is also highly cytotoxic to cancer cells and clinical trials for certain cancers are now in progress (Table 1).
3.2.2. Ulcers. Similarly to gold, utilisation of bismuth is traditional, both in Chinese and occidental medicines. Dyspepsia, syphilis, colitis, wound infections and quartan malaria are examples of diseases in which bismuth is effective. Yang and Sun comprehensively reviewed the biological chemistry of bismuth in 2011.384 However, the use of bismuth in therapy has found its main application for the inhibition of Helicobacter pylori,385,386 a bacterium that can prevent ulcers from healing.387 Due to the development of antibiotic drug resistance by H. pylori, triple388 and quadruple389 regimens based on two antibiotics, plus an acid-suppressing agent, plus bismuth salts are nowadays investigated for the treatment of this bacterium. Time-resolved ICP-MS studies of the uptake of bismuth-based drugs suggest a competitive FeIII/BiIII transport pathway into H. pylori.390 Homoleptic tri-substituted bismuth(III) sulfonate complexes possess interesting bactericidal activity towards three laboratory strains of H. pylori (B128, 26 695 and 251), with minimum inhibitory concentration (MIC) values in the nanomolar range.

In the blood, the FeIII binding site of transferrin is also a strong site for BiIII.391 The recent 2.4 Å X-ray crystal structure of human transferrin with Bi in the N-lobe and Fe in the C-lobe shows Bi bound in a partially-opened cleft via only one of the two binding cleft Tyr side-chains together with nitrilotriacetate, carbonate and water.392

3.3. Neurodegenerative diseases

Neurodegenerative diseases (NDs), the progressive loss of structure or function of neurons – are attracting much attention due to the global increase of life expectancy in modern societies; 35 million people currently live with dementia; Alzheimer's disease (AD), Parkinson's disease (PD), and prion diseases (PrDs) are the most prevalent NDs.393 However the lack of knowledge of the origins, mechanisms, and development factors for these diseases results in poorly efficient drugs, which treat symptoms at best (for ADs and PDs, but no medication available for PrDs),394 and do not reverse or slow down disease progression.

Senile plaques, neurofibrillary tangles, neutrophil threads, amyloid-β peptide (Aβ) deposition, selective loss of neurons and decreased synaptic density in post-mortem brains are the pathognomonic indicators of Alzheimer's disease. Aberrant metal biochemistry in the pathogenesis of AD has been demonstrated.395,396 Related to the synaptic activity, Cu and Zn are of importance, since millimolar concentrations of Zn are released upon neuronal activation, whilst Cu is involved in the regulation of synaptic functions. Amyloid-β peptide (Aβ) is released upon neuronal activation, and Aβ deposition and oxidative stress may be attributed to interactions between Aβ and metal ions. Bush et al. have recently reported the post-hoc analysis of a Phase IIa double-blind, randomised, placebo-controlled clinical trial for a copper/zinc ionophore, PBT2,397 an hydroxyquinoline derivative that facilitates the clearance of Aβ aggregates in the cortex by targeting the zinc and copper ions that mediate the assembly of these aggregates in amyloid and diffuse deposits, effectively detoxifying the Aβ.398 The output of this study shows clear improvement for treated patients compared to placebo group.397

In 2012, the bioinorganic chemistry of Alzheimer's disease was surveyed by Kepp,399 and the role that metal-Aβ association species play in AD was comprehensively reviewed by Pithadia and Lim.400 Inhibition of the interactions between Aβ and metal ions is a promising therapeutic approach for developing new and effective anti-AD agents. This inhibition may be achieved by utilisation of competitive agents (for occupying the metal binding site on Aβ), or by using chelating agents. Chelation therapy is a powerful tool for metal depletion and excretion and has been extensively studied in recent years for the treatment of Wilson's disease and neurodegenerative diseases.401,402

Metal chelators, especially inhibitors of histone deacetylases (HDACs), are also of much interest in anticancer therapy, as exemplified by suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza) which inhibits Zn(II)-dependent class I and class II histone deacetylases (HDACs). Histone acetylation plays a key role in controlling the affinity of histones for DNA and gene expression. Deacetylation of Lys on histones produces a positive charge on its side chain and increases DNA affinity.

In 2013, Telpoukhovskaia and Orvig, surveyed how coordination chemistry might play a role in anti-neurodegenerative drug development, by understanding the binding preferences of metal ions for key proteins involved in the propagation of NDs, and by using the tools of inorganic chemistry for investigating the competition of synthetic ligands with proteins for metal ions.403

4. Diagnostic and therapeutic radiopharmaceuticals

There is an increasing interest in the development of both diagnostic and therapeutic radiopharmaceuticals (Fig. 1), as illustrated by the large number of ongoing clinical trials worldwide (Table 1). The development of radiopharmaceuticals is aided by their rapid passage from the laboratory into the clinic, since very small doses are usually administered, posing a negligible toxicity hazard.

Therapeutic radiopharmaceuticals are useful for delivering locally cytotoxic doses of ionising radiation. The radionuclides used emit β-particles (electrons) or α-particles (used in targeted α-therapy (TAT)). Most radiotherapeutic nuclides in the clinic are β emitters, such 32P, 47Sc, 64Cu, 67Cu, 89Sr, 90Y, 105Rh, 111Ag, 117mSn, 131I, 149Pm, 153Sm, 166Ho, 177Lu, 186Re, 188Re.404 Recent advances in this field include the first clinical trial using an α-particle emitting 225Ac complex, labelled with a humanised antibody, lintuzumab, which targets the CD33 antigen expressed on the blast cells of most cases of acute myeloid leukaemia. The phase I clinical trial was initiated by the Scheinberg group at Memorial Sloan-Kettering Cancer Center with a primary goal to define both safety and the maximum tolerated dose of 225Ac TAT in patients with advanced myeloid leukaemia (AML) through a dose escalation series.405 Promising results have led to the ongoing phase I/II clinical trial, sponsored by Actinium Pharmaceuticals (Table 1). This complex is also undergoing a phase I clinical trial for the treatment of leukaemia myelodysplastic syndrome. The Scheinberg group reported the first proof-of-concept 213Bi TAT clinical trial, again targeting CD33 with antibody lintuzumab to treat 18 patients with advanced myeloid leukaemia in a phase I trial.406 This compound is now undergoing a phase II clinical trials (Table 1). Jurcic et al. also conducted a follow up study with 213Bi TAT, wherein 13 newly diagnosed patients and 18 patients with relapsed/refractory acute myeloid leukaemia were first treated with continuous cytarabine (cytosine arabinoside) infusion for 5 days.407 They observed marrow blast reductions at all dose levels.

Two types of radioimaging are used in clinic: single-photon emission computed tomography (SPECT), and positron emission tomography (PET). SPECT is based on the utilisation of pharmaceuticals labeled with a γ-emitting radionuclide, while PET requires a radiopharmaceutical labeled with a positron β+-emitting radionuclide. Useful γ-emitting nuclides include 99mTc, 67Ga, 111In, and 201Tl; useful β+-emitting nuclides include 55Co, 64Cu, 66Ga, 68Ga, 82Rb, 86Y.404 Recent clinical developments of such radioimaging agents include for instance 68Ga-DOTA-TATE408 and 64Cu-ATSM for PET/CT scans409 (Table 1, and Chart 13 for the molecular structure of 68Ga-DOTA-TATE).

Molecular structure of 68Ga-DOTA-TATE.
Chart 13 Molecular structure of 68Ga-DOTA-TATE.

Multimodality imaging (positron emission tomography-computed tomography (PET-CT)) has been used in clinic for more than a decade, and is nowadays one of the main cancer imaging techniques.410 Following this clinical success, combined PET/magnetic resonance (MR) systems for clinical use have been recently developed. Ga-DOTATOC PET/MR imaging is feasible in patients, with a good diagnostic image quality (average visual rating PET/CT, 2.83; PET/MR, 2.08). Moreover, detectability of focal PET lesions is equivalent to PET/CT on a patient basis and organ-system basis.411 The clinical value of Ga-DOTATOC PET/MR with additional diagnostic MR protocols needs to be evaluated against PET/CT with multiphase contrast-enhanced CT protocols in future studies.


The exploration of the medical periodic table presents exciting challenges. Inorganic compounds, and metal complexes in particular, offer mechanisms of drug action that can be quite distinct from those of organic drugs. About 13 metal ions are essential for mammalian life, which can all be used in therapy. However, not only can essential metals be used, but also non-essential metals, a strategy that might be particularly important for fighting bacteria which are becoming increasingly resistant to organic drugs. Also radionuclides with suitable ligands offer targeted agents both for diagnosis and therapy. The ligands can play critical roles in the activity of all metallodrugs and diagnostic agents. It is important to identify the parts of metallodrugs which are critical for activity (the pharmacophores).

We have tried to focus here particularly on the discovery of new targets for metallodrugs. These days an understanding of targets and mechanisms of action is essential if a drug is to receive approval for clinical use. Such understanding will eventually become important when patients can be screened on a personal-medicine basis for the optimum drug to treat their particular conditions. There are signs that rapid progress is currently being made, aided by advances in metal analysis and especially speciation techniques, and by the methods of modern molecular biology (proteomics and genomics), which can be fruitfully applied to the identification of target sites and understanding of metabolic pathways.

Although many new targets are currently being proposed for metallodrugs, and provide promising new leads for development, few have been validated in vivo. Advances in controlling metallodrug activation are also needed so that metallodrugs reach target sites and do not undergo unwanted side-reactions. From a general point of view, the field will benefit greatly from the application of the drug design principles used for the development of organic drugs. In this sense, we have tried to highlight some recent and promising strategies. Specific G-quadruplex binders, metallodrugs with DNA sequence specificity, inert polypyridyl metal complexes specifically able to target kinases, catalytic metallodrugs, and multi-labeled nanoparticle drug delivery systems are striking examples of the new strategies that can be used for designing metal-based anticancer drug candidates. The potential of inorganic and organometallic complexes as antibiotics, and for the treatment of other diseases, such as viral and parasitic diseases is also apparent.

We also have highlighted some organic drugs which are targeted to metal ions, often to the metal in a metalloenzyme. Organic drugs are often designed so they contain H-bond acceptors (lone pair donors). These acceptor atoms are also potential metal binding sites but perhaps not always recognised as such.

There is an urgent need to find new and effective therapies for a wide range of diseases and conditions. As highlighted in Table 1, there is current clinical and industrial interest in such advances.


We thank the Swiss National Science Foundation (Grant No. PA00P2-145308 to NPEB), the ERC (Grant No. 247450 to PJS), EPSRC (Grant No. EP/F034210/1) and EC COST Action CM1105 for support. We also thank Roger Alberto, Enzo Alessio, Martin Brechbiel, Peter Caravan, Seth Cohen, Nicholas Farrell, Stephen Lippard, Neil Moore, Thomas O'Halloran, Christopher Orvig, Jonathan Sessler, and Holden Thorp for supplying information on current commercial and clinical developments, Thomas Ward for providing Fig. 4, and Eduardo Sousa for discussion of Fig. 10.


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