Bioinorganic Medicinal Chemistry E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 825

Veröffentlichungsjahr: 2011

Beschreibung

Edited by a renowned and experienced lecturer, this handbook and reference provides an in-depth overview of this key area in medicine and bioinorganic chemistry, detailing such topics as targeting strategies, mechanism of action, Pt-based antitumor drugs and radiopharmaceuticals.

Leseprobe

Contents

List of Contributors

Chapter 1 : Medicinal Inorganic Chemistry: State of the Art, New Trends, and a Vision of the Future

1.1 Introduction

1.2 Antimicrobial Agents

1.3 Antiviral Agents

1.4 Systemic and Metabolic Diseases Including Inflammation

1.5 Metal Chelating Agents

1.6 Antiarthritic Drugs and Inflammation

1.7 Bipolar Disorder

1.8 Anticancer Agents

1.9 Small Molecule Delivery and Control

1.10 Diagnostic Agents

1.11 Veterinary Medicinal Inorganic Chemistry

1.12 Conclusions and Vision

Acknowledgments

References

Chapter 2 : Targeting Strategies for Metal-Based Therapeutics

2.1 Introduction

2.2 Physiological Targeting

2.3 Molecular Targeting

2.4 Immunological Targeting

2.5 Concluding Remarks

References

Chapter 3 : Current Status and Mechanism of Action of Platinum-Based Anticancer Drugs

3.1 Introduction

3.2 Mechanism of Action of Cisplatin

3.3 Limitations of Current Platinum-Based Compounds: New Strategies

3.4 Novel Concepts in the Development of Platinum Antitumor Drugs

3.5 Concluding Remarks

Acknowledgment

References

Chapter 4 : New Trends and Future Developments of Platinum-Based Antitumor Drugs

4.1 Introduction

4.2 Mechanisms of Action and Resistance

4.3 Monofunctional Platinum(II) Complexes

4.4 Trans-Platinum(II) Complexes

4.5 Multinuclear Platinum(II) Complexes

4.6 Platinum(IV) Complexes

4.7 Delivery of Platinum Drugs

4.8 Concluding Remarks and Future Perspectives

Acknowledgments

References

Chapter 5 : Ruthenium and Other Non-platinum Anticancer Compounds

5.1 Introduction

5.2 Ruthenium Anticancer Compounds

5.3 From Gallium Nitrate to Oral Gallium Complexes

5.4 Titanium Anticancer Compounds

5.5 Ferrocene-Derived Anticancer Agents

5.6 The Main Group Organometallics Spirogermanium and Germanium-132

5.7 Arsenic in Cancer Chemotherapy

5.8 Overcoming the Resistance of Tumors to Anticancer Agents by Rare Earth Element Compounds

5.9 Conclusions

Acknowledgments

References

Chapter 6 : The Challenge of Establishing Reliable Screening Tests for Selecting Anticancer Metal Compounds

6.1 Introduction

6.2 Tumor Cell Growth Inhibition and Cell Death Screening Assays

6.3 Metal-Based Anticancer Compounds and Gene Expression Microarray Technologies

6.4 Metal-Based Anticancer Compounds and the Proteomic Approach

6.5 Concluding Remarks

Acknowledgments

References

Chapter 7 : Gold-Based Therapeutic Agents: A New Perspective

7.1 Introduction

7.2 Biological Chemistry of Gold

7.3 Gold Antiarthritic Drugs

7.4 Gold Complexes as Anticancer Agents

7.5 Gold Complexes as Antiparasitic Agents

7.6 Concluding Remarks

Acknowledgments

References

Chapter 8 : MRI Contrast Agents: State of the Art and New Trends

8.1 Introduction

8.2 T1 Agents

8.3 T2-Susceptibility Agents

8.4 CEST Agents

8.5 Concluding Remarks

References

Chapter 9 : Metal-Based Radiopharmaceuticals

9.1 Introduction

9.2 Selected Examples: Therapeutic Radiopharmaceuticals

9.3 Diagnostic Metal-Based Radiopharmaceuticals

9.4 Perspectives and Conclusion

References

Chapter 10 : Boron and Gadolinium in the Neutron Capture Therapy of Cancer

10.1 Introduction

10.2 Boron Neutron Capture Therapy

10.3 Role of Medicinal Inorganic Chemistry in BNCT

10.4 Gadolinium Neutron Capture Therapy

10.5 Conclusions and Future Outlook

References

Chapter 11 : Essential Metal Related Metabolic Disorders

11.1 Introduction: What is Essentiality?

11.2 Iron Metabolic Diseases: Acquired and Genetic

11.3 Copper Metabolic Diseases

11.4 Zinc Metabolic Diseases

11.5 Diseases Related to Imbalances in Electrolytic Metabolism: P, the Alkali Metals, and the Alkaline Earths

11.6 Metabolism of Other Trace Elements

11.7 Conclusions

References

Chapter 12 : Metal Compounds as Enzyme Inhibitors

12.1 Introduction

12.2 Kinase Inhibitors

12.3 Proteasome Inhibitors

12.4 Carbonic Anhydrase Inhibitors (CAIs)

12.5 Cyclooxygenase Inhibitors

12.6 Acetylcholinesterase Inhibitors

12.7 Protein Phosphatase Inhibitors

12.8 Trypsin and Thrombin Inhibitors

12.9 Cysteine Protease Inhibitors and Glutathione Transferase Inhibitors

12.10 HIV-1 Reverse Transcriptase and Protease Inhibitors

12.11 Telomerase Inhibitors

12.12 Zinc Finger Protein Inhibitors

12.13 CXCR4 Inhibitors

12.14 Xanthine Oxidase Inhibitors

12.15 Miscellaneous Protein Inhibitors and Conclusions

Acknowledgments

References

Chapter 13 : Biomedical Applications of Metal-Containing Luminophores

13.1 Introduction: Luminescence in Diagnostics and Imaging

13.2 Transition-Metal Containing Luminescent Agents

13.3 Lanthanide-Based Luminophores

13.4 Nanoparticle-Based Luminophores

13.5 Conclusions and Perspectives

References

Index

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The Editor

Prof. Dr. Enzo Alessio

Università di Trieste

Dipt. di Scienze Chimiche

Via L.Giorgieri 1

34127 Trieste

Italy

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List of Contributors

Silvio Aime

University of Torino

Department of Chemistry IFM & Molecular Imaging Center

Via.P. Giuria 7

10125 Torino

Italy

Roger Alberto

University of Zürich

Institute of Inorganic Chemistry

Winterthurerstr. 190

8057 Zürich

Switzerland

Enzo Alessio

University of Trieste

Department of Chemical Sciences

Via Giorgieri 1

34127 Trieste

Italy

Susan J. Berners-Price

The University of Western Australia

School of Biomedical, Biomolecular and Chemical Sciences

35 Stirling Highway, Crawley

Perth WA 6010

Australia

Angela Boccarelli

University of Bari

Department of Biomedical Sciences and Human Oncology

Piazza Giulio Cesare 11

70124 Bari

Italy

Ioannis Bratsos

University of Trieste

Department of Chemical Sciences

Via Giorgieri 1

34127 Trieste

Italy

Daniela Delli Castelli

University of Torino

Department of Chemistry IFM & Molecular Imaging Center

Via.P. Giuria 7

10125 Torino

Italy

H.Y. Vincent Ching

The University of Sydney

School of Chemistry

Sydney NSW 2006

Australia

Mauro Coluccia

University of Bari

Department of Biomedical Sciences and Human Oncology

Piazza Giulio Cesare 11

70124 Bari

Italy

Ellen L. Crossley

The University of Sydney

School of Chemistry

Sydney NSW 2006

Australia

Shanta Dhar

Massachusetts Institute of Technology

Department of Chemistry

Room 18-498

Cambridge, MA 02139

USA

Nicola J. Farrer

University of Warwick

Department of Chemistry

Coventry, CV4 7AL

UK

Teresa Gianferrara

University of Trieste

Department of Pharmaceutical Sciences

Piazzale Europa 1

34127 Trieste

Italy

Eliana Gianolio

University of Torino

Department of Chemistry IFM & Molecular Imaging Center

Via.P. Giuria 7

10125 Torino

Italy

Gilles Gasser

University of Zürich

Institute of Inorganic Chemistry

Winterthurerstrasse 190

8057 Zürich

Switzerland

Zijian Guo

Nanjing University

School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination Chemistry

Nanjing, 210093

P.R. China

Trevor W. Hambley

University of Sydney

School of Chemistry

Sydney NSW 2006

Australia

Christian G. Hartinger

University of Vienna

Institute of Inorganic Chemistry

Waehringer Str. 42

1090, Vienna

Austria

Joseph A. Ioppolo

The University of Sydney

School of Chemistry

Sydney NSW 2006

Australia

Michael A. Jakupec

University of Vienna

Institute of Inorganic Chemistry

Waehringer Str. 42

1090, Vienna

Austria

Bernhard K. Keppler

University of Vienna

Institute of Inorganic Chemistry

Waehringer Str. 42

1090, Vienna

Austria

Stephen J. Lippard

Massachusetts Institute of Technology

Department of Chemistry

Room 18-498

Cambridge, MA 02139

USA

Yasmin Mawani

University of British Columbia

Medicinal Inorganic Chemistry Group, Department of Chemistry

2036 Main Mall

Vancouver, V6T 1Z1

BC

Canada

Nils Metzler-Nolte

Ruhr-University Bochum

Faculty of Chemistry and Biochemistry

Universitätsstrasse 150

44801, Bochum

Germany

Julia F. Norman

University of Sydney

School of Chemistry

Sydney NSW 2006

Australia

Chris Orvig

University of British Columbia

Medicinal Inorganic Chemistry Group

Department of Chemistry

2036 Main Mall

Vancouver V6T 1Z1

BC

Canada

Alessandra Pannunzio

University of Bari

Department of Biomedical Sciences and Human Oncology

Piazza Giulio Cesare 11

70124 Bari

Italy

David N. Reinhoudt

University of Twente

Faculty of Science and Technology (TNW) and MESA + Institute for Nanotechnology

7500 AE, Enschede

The Netherlands

Louis M. Rendina

The University of Sydney

School of Chemistry

Sydney NSW 2006

Australia

Albert Ruggi

University of Twente

Faculty of Science and Technology (TNW) and MESA + Institute for Nanotechnology

7500 AE, Enschede

The Netherlands

Peter J. Sadler

University of Warwick

Department of Chemistry

Coventry, CV4 7AL

UK

Aldrik H. Velders

University of Twente

Faculty of Science and Technology (TNW) and MESA + Institute for Nanotechnology

7500 AE, Enschede

The Netherlands

Xiaoyong Wang

Nanjing University

School of Life Sciences, State Key

Laboratory of Pharmaceutical Biotechnology

Nanjing, 210093

P.R. China

Chapter 1

Medicinal Inorganic Chemistry: State of the Art, New Trends, and a Vision of the Future

Nicola J. Farrer and Peter J. Sadler

1.1 Introduction

Inorganic chemistry is an essential part of life. It is not just the chemistry of dead or inanimate things. It was probably even inorganic chemistry that started it all off. For example, iron sulfides may have been the energy sources for early forms of life [1]. There is currently emerging interest in the medicinal chemistry of the elements of the periodic table (Table 1.1).

Table 1.1 Some areas of medical interest in the elements of the periodic table. Entries are restricted to a few comments about each element and no attempt is made to be comprehensive. Elements thought to be essential for man are in italics.

Currently 24 elements are thought to be essential for mammalian biochemistry (H, C, N, O, F, Na, Mg, Si, P, S, Cl, K, Ca, V, Mn, Fe, Co, Ni, Cu, Zn, Se, Mo, Sn, and I). However the biochemistry of some elements, particularly F, Si, V, Ni, and Sn is poorly understood. It has even been suggested that the biological requirement for Si is merely to protect against Al toxicity [2]. Interestingly, aluminum compounds are widely used as adjuvants in human and veterinary vaccines (helping and enhancing the pharmacological effect) although the chemical basis of the mechanism for this effect is not understood [3].

This situation with aluminum serves to illustrate the problem we face with inorganic medicines. They are often used on a mass scale, but with little rational basis and limited understanding of their molecular mechanism of action. Often we find this is because the methods and techniques available for the study of inorganic agents are either inadequate or are not fully exploited. In particular, determining the speciation of inorganic compounds under biological conditions remains a major challenge. Inorganic and metal compounds are often prodrugs that may not only be transformed on the way to target sites but also when attempts are made to extract the biologically active form from biological media.

This list of essential elements is probably not complete; for example, Cr and B may prove to be essential but the current evidence is unclear. Importantly, essentiality is not just about the element itself, but particular compounds of that element. For example, we need cobalt, but probably only in the form of the vitamin B12. Similarly, toxicity (often used as an argument against using metal compounds as drugs) is typically related not just to the metal itself but also to the ligands and to the type of complex.

Whilst a given metal does exhibit recurring features peculiar to itself (e.g., a preference for particular oxidation states and ligand geometries) the ligand environment can have a marked effect on the overall reactivity of the complex. Furthermore, the behavior of a metal complex is dependent on both its composition and the environment in which it finds itself. Predicting and controlling that behavior is one of the challenges for advancing the rational design of inorganic pharmaceuticals.

In this chapter we discuss transformations of metallodrugs by ligand exchange and/or redox processes, drawing on a wide range of examples. We attempt to relate these transformations to mechanisms of action with the aim of introducing rational design concepts to as many areas of medicinal inorganic chemistry as possible.

1.1.1 Metals in the Body: Essential Elements and Diseases of Metabolism

The homeostasis and control of metal ions in the body is an area of research in itself [4, 5]. Evolution has incorporated many metals into essential biological functions, using the variable oxidation states exhibited by the metal center (e.g., FeII/FeIII in heme) to control reversible binding of small molecules (e.g., O2) and implement structural changes. The ligand binding in a typical coordination M–L bond (50–150 kJ mol−1) is much weaker than covalent bonding (the energy of a single C-C bond is 300–400 kJ mol−1) [6]; for hemes and vitamin B12, for example, this allows much more flexibility in small molecule binding and dissociation (signaling) under biological conditions; the energies involved are much smaller. Other, even weaker, interactions such as hydrogen bonding (20–60 kJ mol−1) and van der Waal’s interactions (<50 kJ mol−1) are crucial for correct structure and functioning of biological systems. For metallodrugs such non-covalent interactions can play vital roles in target recognition.

A knowledge of the transport of metals and their complexes in vivo (particularly cell uptake and efflux) is important for understanding the metabolism of inorganic (and organic) drugs, and also for understanding the nature of diseases caused by erroneous metal transport.

1.1.2 Metals as Therapeutic Agents

Medicinal inorganic chemistry is a relatively young, interdisciplinary research area that has grown primarily due to the success of cisplatin, a Pt-based anticancer drug developed in the late 1960s. In addition to metal-centered therapies, metals may also be used to enhance the efficacy of organic drugs (such as the cyclams, e.g., AMD3100) and as small-molecule delivery vehicles (e.g., for NO, CO).

Organic compounds used in medicine may be activated by metal ions or metalloenzymes, and others can have a direct or indirect effect on metal ion metabolism. Since many organic drugs follow conventional design rules (e.g., Lipinski’s rule of 5), they typically incorporate groups with the ability to act as electron donors (H-bond acceptors), endowing them with potential metal-binding sites. This bioinorganic reactivity needs to be considered when new organic drugs are designed. The rational design of metal-based drugs is a relatively new concept, bolstered by improvements in characterization and imaging techniques. In general a metal complex that is administered is likely to be a “prodrug” that undergoes a transformation in vivo before reaching its target site. Such transformations can include reduction or oxidation of the metal ion, ligand substitution, or reactions of the ligands at sites remote from the metal. Elucidating the precise mechanisms of action of these new drugs is perhaps the most challenging and complicated aspect of the research; it requires drawing together knowledge concerning the reactivity of the metal complex (outlined in Figure 1.1 and Table 1.2) to control features such as biochemical stability, coupled with an appreciation of the biochemical pathways governing cell uptake, metabolism, and excretion. By appropriate choice of the ligands and metal oxidation state, it is possible to control the thermodynamic and kinetic properties of metal complexes and to attempt to control their biological activity [7].

Figure 1.1 Some features of metal coordination complexes that can play a role in biological activity. Control of these characteristics is important in rational design.

Table 1.2 Features of metals and metal complexes that can be used in the design of therapeutic and diagnostic agents.

FeatureComments (examples)Coordination numberFull range 2–10; transition metals typically 4–6, can be more variable for main group metals (e.g., Bi) and larger for Ln (e.g., 9)GeometryExamples; linear (AuI), square-planar (PtII), tetrahedral (e.g., TiIV in TiCp2Cl2, distorted), trigonal bipyramidal, octahedral (TiIV, RuIII, PtIV), possible metal-centered chirality (CoIII, RhIII)Oxidation stateWide range (typically 0–7 in biological media), with different oxidation states favoring different coordination numbers and rates of exchange (e.g., PtIV vs. PtII)Ligand typeWide range of donors, e.g., C, N, O, halides, P, S, Se. Chelating ligands; denticity, e.g., (κ2) 1,2-diaminoethane, (κ6), EDTA; hapticity, e.g., η6 and η4 binding for benzeneThermodynamic stabilityWide range of M–L bond strengths (typically 50–150 kJ mol−1)Kinetic stabilityLifetimes of M–L bonds cover wide range (ns–years). Highly dependent on metal oxidation state and other ligands, can be stereospecific, e.g., trans effect in PtIIProperties of ligandsOuter sphere interactions, e.g., H-bonding, hydrophobic interactions (<50 kJ mol−1) for receptor recognition (including use of chirality); may undergo transformation in vivo, e.g., by redox, hydrolysis, enzymatic reactions (e.g., by P450 in the liver).Nuclear stabilityRadioactive nuclides can be used to track metabolism of drugs, e.g., 195mPt (t½ = 4 d) and 99mTc (t½ = 6 h). Appropriate nuclide depends on decay pathway (α, β, γ) and half-life

The use of metals in medicine is varied [8–12] (Figure 1.2). Fundamental wide-reaching medical problems such as bacterial, viral (particularly HIV), and parasitic infections such as malaria are being addressed by research on metal-based medicines. There are also promising developments for tackling the main diseases affecting an affluent, aging western population: cardiovascular, age-related inflammatory diseases, neurological diseases (e.g., Parkinson’s, Alzheimer’s), cancer (Chapters 3–5) [13–15], diabetes, and arthritis (Chapter 7). Bipolar and gastrointestinal disorders are addressed by metal-based medicines and metal-based diagnostic agents for MRI and X-ray are in routine clinical use; for example, gadolinium MRI contrast agents have now been administered to ∼50 million patients worldwide (Chapter 8).

Figure 1.2 Some key areas of medicinal inorganic chemistry.

In the following sections, using selected examples, we provide an overview of the uses of metal-based drugs in these aforementioned diverse medical fields and, where appropriate, we guide the reader to chapters that provide a more in-depth analysis.

1.2 Antimicrobial Agents

Many metal compounds show appreciable antimicrobial activity, some established examples are based on silver, bismuth, mercury, and antimony.

Under an inert atmosphere, silver has no effect on microorganisms; however, in the presence of oxygen it exhibits a broad spectrum of antimicrobial activities. Several different mechanisms are thought to be responsible: (i) Ag+ interacts with thiol groups of l-cysteine residues of proteins, inactivating their enzymatic functions; (ii) Ag+ causes potassium release [16]; (iii) Ag+ binds to nucleic acids [17]; and (iv) Ag+ generates superoxide (O•−2) intracellularly [18]. This interaction with bacterial proteins and nucleic acids causes structural changes in membranes (blocking respiration), and nucleic acids (blocking transcription). Morphologically, treatment of Escherichia coli and Staphylococcus aureus (model strains for Gram-negative and Gram-positive bacteria, respectively) with AgNO3 has been shown to cause detachment of the bacterial membrane from the cell wall, condensation of the nuclear DNA, and deposition of S- and Ag-rich granules both around the cell wall and within the cytoplasm [19]. The same effects are not seen in mammalian systems.

Simple compounds of silver (e.g., AgNO3) have long been used as antibacterial agents, with particular efficacy in the treatment of burn wounds. Although the use of silver diminished in the 1940s following the development of penicillin, there has been a recent resurgence of interest due to the emergence of strains of bacteria resistant to the current organic-based drugs [20]. The combination of silver with a sulfonamide antibiotic in 1968 produced silver sulfadiazine (SSD) cream (an insoluble polymeric Ag+ compound, see Figure 1.3a), a broad spectrum silver-based antibacterial that also exhibits antiviral and antifungal properties. Wound dressings and materials for medical devices such as catheters are often manufactured with the incorporation of silver to improve sterility.

Figure 1.3 Structures of polymeric silver sulfadiazine (a) and (1,3-dimethyl-4,5-dichloroimidazole-2-ylidene)silver(I) acetate (b). The latter shows bacteriostatic and bacteriocidal properties against a panel of pathogens associated with cystic fibrosis and chronic lung infections.

Since silver acts biologically as “Ag+,” the main role of the ligands is to tailor the solubility and pharmacokinetic profile (i.e., release and distribution of Ag+). Recent developments in silver-based antimicrobials have focused on the use of sophisticated ligands (e.g., imidazolium N-heterocyclic carbenes, NHC) and also on the potential offered by silver nanoparticles.

Silver complexes of NHC with electron-withdrawing groups in the 4- and 5-positions [such as (1,3-dimethyl-4,5-dichloroimidazole-2-ylidene)silver(I) acetate, see Figure 1.3b] have demonstrated activity against bacterial strains associated with cystic fibrosis and chronic lung infections [21]. Typically, NHC-Ag complexes decompose rapidly in aqueous solution, but incorporation of Cl in the 4,5 positions of the imidazole ring withdraws electron density from the carbene carbon, making it less susceptible to attack and slowing the rate of hydrolysis. Silver nanoparticles appear to possess greater antimicrobial activity (nM vs. μM) than conventional forms of silver [22, 23]. Although the mammalian response to silver nanoparticles is not well-characterized, they have been shown to be toxic towards a mouse spermatogonial stem cell line [24].

Development of bacterial resistance to silver is thought to be due to increased use of efflux pumps [25]. Silver toxicity in humans is seen in the form of argyria (a permanent blue-tinting of the skin) following administration of particularly high doses.

Bismuth is regarded as a borderline metal and typically exists as BiIIIin vivo. Bismuth exhibits variable coordination numbers (3–10) with irregular geometries, the structure of the aqua complex [Bi(H2O)9]3+ is similar to those of LnIII complexes. Bismuth compounds show low toxicity towards mammalian cells (probably due to the protection afforded by the thiol-rich proteins, metallothioneins) and have been in use for over 200 years as antimicrobial agents, for treating syphilis and other infections, including colitis, gastritis, and diarrhea [26–30]. Various Bi compounds – colloidal bismuth sub-citrate, ranitidine bismuth citrate, bismuth sub-salicyclate (Pepto-Bismol), and ammonium potassium BiIII citrate (De-Nol™) – are used, often in combination therapy with other antibiotics, for the treatment of gastrointestinal disorders caused by Helicobacter pylori. This bacterium causes inflammation of the stomach lining and is linked to the development of duodenal and gastric ulcers [31]. Bismuth salts also show activity against several other gastrointestinal tract pathogens, including Escherichia coli, Vibrio cholerae, Campylobacter jejuni, and those of the Yersinia, Salmonella, and Shigella genera [32]. The major biological targets for BiIII are proteins; BiIII is known to bind to both FeIII- and ZnII-coordination sites of proteins [33] and, in particular, is thought to inhibit the nickel-binding protein urease and bind to the histidine-rich and cysteine-rich metal-binding domains of heat-shock protein A, which are both crucial to the survival of H. pylori in the gut [34]. In addition to the antibacterial action shown by BiIII, the derivatives formed in the acid environment of the stomach bind strongly to the proteins in ulcerated tissue to form a protective layer, allowing it to heal. They also cause an increase in local prostaglandin levels, which stimulates the production of bicarbonate and mucin thereby protecting the stomach [32].

Bismuth complexes have shown inhibition of HIV-1 virus production and activity against SARS coronavirus [35]. In other applications, the radioactive nuclide 212Bi (α-emitter, t½ ≈ 1 h) is used in targeted radiotherapy through complexation to monoclonal antibodies. A long unsolved mystery in bismuth pharmacology is the nature of so-called bismuth inclusion bodies found in the nuclei of kidney tubular proximal cells, hepatocytes, and pneumocytes, usually assumed to be associated with toxic side-effects of Bi therapy [36].

Compounds of mercury show significant variation in bioavailability, bioaccumulation, and metabolism in humans and as such can be divided into three groups: elemental mercury (Hg), organometallic complexes (i.e., containing at least one Hg—C bond), and non-organometallic (often called “inorganic” complexes, e.g., sulfides). Here we focus on the latter two groups, discussing their use in medicine and briefly exploring the suggested mechanisms of toxicity towards both humans and microorganisms.

The antibacterial and antifungal properties of organometallic mercurials have resulted in their application as topical disinfectants (thiomersal and merbromin), preservatives in vaccines (thiomersal), and grain products (methyl and ethyl mercurials). Despite several high-profile fatalities (Iraq and China in 1970s, Minamata Bay, Japan in 1950s and 1960s) organometallic mercurial compounds are still in widespread use; thiomersal (sodium ethylmercurithiosalicylate) (Scheme 1.1) is contained in GlaxoSmithKline’s recently released influenza pandemic (swine flu) vaccines Pandemrix and Arepanrix. In Pandemrix, thiomersal is present at 5 μg per 0.5 ml dose [37], falling well within the World Health Organization (WHO) recommended maximum limit for the similar but more toxic organometallic mercurial compound, methyl mercury (1.6 μg per kg body weight per week) [38]. After injection, thiomersal rapidly dissociates to produce ethyl mercury, which binds to the available thiol ligands present in tissue proteins – a mechanism that is corroborated by the fact that the nature of the ligand attached to the ethyl mercury group (thiosalicyclate in the case of thiomersal) makes little difference to the ultimate bodily distribution of mercury. Merbromin (Mercurochrome) (Figure 1.4) is thought to react in a similar fashion. The toxicology of methyl mercury is better understood than that of ethyl mercury; methyl mercury is generated in nature by microorganisms in aquatic environments from mercury salts, and its bioaccumulation up the food chain has long been known; the mean level of Hg in tinned white tuna in one US study was found to be 0.407 μg per g of tuna [39]. In the body, methyl mercury is typically found attached to the sulfur of thiolate ligands, entering the endothelial cells of the blood–brain barrier complexed to l-cysteine. It is removed from mammalian cells as a complex of reduced glutathione, but is then recycled in vivo to the l-cysteine complex. If any is converted into inorganic complexes of mercury (which are typically insoluble in biological fluids) it can be accumulated in the CNS in the inert form of mercury selenide, or excreted in the feces. The precise mechanism of damage to the brain is still unclear but it appears to involve inhibition of protein synthesis with specific damage to the granule cells in the cerebellum, which have a critical absence of protective mechanisms exhibited by neighboring cell types. Thiomersal has been demonstrated to cause oxidative stress in leukemia cells, leading to the activation of execution caspases and apoptotic cell death [40]. Organometallic mercurials are slowly metabolized to inorganic complexes of mercury mainly by microflora in the intestines, although some demethylation also occurs in phagocytic cells.

Scheme 1.1 Thiomersal is degraded rapidly in vivo to ethyl mercury, which in turn is slowly metabolized to non-organometallic mercurial compounds and excreted in the feces.

Figure 1.4 Structure of merbromin.

Several thiol-containing complexing agents, including the orally-available N-acetyl-l-cysteine (Figure 1.5), have shown promise in enhancing methyl mercury excretion [41]. There is evidence that administration of selenium compounds can delay the onset of the toxic effects of methyl mercury in animals.

Figure 1.5 Structure of N-acetyl-l-cysteine.

Mercurous chloride (calomel, Cl-HgI-HgI-Cl) has been used for centuries as a diuretic, laxative, antiseptic, skin ointment, and to treat vitiligo, although its use has largely been superseded by modern medicines [42]. The traditional Chinese medicine Cinnabar, which is used to achieve sedative and hypnotic effects, contains mercury sulfide (HgS). Since purified mercury sulfide shows poor bioavailability and low absorption from the gastrointestinal tract, it is postulated that the major medicinal benefit of cinnabar might be due to its interactions with other components of traditional Chinese medicines. Once absorbed into the blood, mercury disposition from cinnabar follows the pattern for other inorganic mercury complexes and it is preferentially distributed to the kidneys, with a small portion to the brain [43].

Aquaporins (first reported by Benga and co-workers in 1985) are attractive targets for the development of novel drug therapies for disorders that involve aberrant water movement, such as edema and kidney disease. Compounds such as mercurous chloride are known inhibitors of aquaporins, sterically blocking the water transport pore by binding to a cysteine thiolate sulfur (Cys189 in CHIP28/AQP1) [44–46].

As with silver, the antibacterial action of mercury is attributed largely, but not exclusively, to the strong affinity of the metal for thiol groups of proteins. Evidence suggests that mercurials cause structural and functional changes of bacterial cell walls and inhibit membrane bound proteins, interfering with respiration, ATP synthesis, and transport processes [47]. Bacterial resistance to mercury antimicrobial agents involves induction of enzymes (such as mucuric reductase) that are capable of converting HgII in the cytoplasm into the less toxic and more volatile Hg [48].

Antimony (SbV) compounds such as sodium stibogluconate (Pentostam) and meglumine antimonite (Glucantime) are used to treat leishmaniasis, a disease caused by a parasite that is transmitted by the bite of a certain species of sand fly. The parasites replicate within mammalian macrophage phagolysosomes, initially causing skin sores, although some forms of the disease exhibit graver effects such as anemia and damage to the spleen and liver, which can be fatal. The precise mechanism of action of these SbV drugs, which have been in use for 60 years, is still unclear. Several effects have been noted: inhibition of glycolysis and fatty acid oxidation, fragmentation of parasitic DNA, and externalization of phosphatidylserine on the outer surface of membranes via a caspase-independent pathway [49]. In the parasite, reduced trypanothione T(SH)2 rapidly reduces SbV to SbIII, which is thought to be the active form. New insights into the molecular basis for the antiparasitic activity of SbIII come from the recent X-ray crystal structures of reduced trypanothione reductase (TR) from Leishmania infantum with NADPH and SbIII. TR is essential for parasite survival and virulence and is absent from mammalian cells. SbIII is coordinated by the two redox-active catalytic cysteine residues, a threonine residue, and a histidine, and has been shown to strongly inhibit TR activity, blocking trypanothione reduction [50]. Toxicity of the drugs, as well as increasing resistance, are leading to more research into their mechanism of action [51]. In one study, resistance towards sodium stibogluconate has been attributed to the upregulation of multidrug resistance-associated protein 1 (MRP1) and permeability glycoprotein (P-gp) in host cells, resulting in a non-accumulation of intracellular Sb and favoring parasite replication. Co-administration of the drug lovastatin (Figure 1.6) has been shown to inhibit this resistance in vivo, restoring the curative properties of the Sb agent [52]. The exact formulation of the antimony drugs is not well defined; sodium stibogluconate is a mixture of SbV and carbohydrate. Improvement of efficacy of SbV-based antiparasitic agents is anticipated to focus on controlling the activation-by-reduction step of SbV to SbIII.

Figure 1.6 Structure of lovastatin.

The arsenic-based antimicrobial agent Salvarsan ({RAs}n, R = 3-amino-4-hydroxyphenyl, Figure 1.7) was used historically to treat syphilis and trypanosomiasis, although in recent times it has been superseded by penicillin. 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 [53].

Figure 1.7 Structure of 3-amino-4-hydroxyphenylarsenic(III) (Salvarsan). This has been the subject of much debate, but in solution it is now thought to consist of cyclic species (AsR)n (R = 3-amino-4-hydroxyphenyl) where n = 3 and n = 5 are the most abundant species.

Malaria is caused by a protozoan parasite of the genus Plasmodium and is responsible for about 2 million deaths per year [54]. The most commonly used antimalarial drug is chloroquine (CQ), which accumulates within the parasite and interferes with the function of its digestive vacuole (where the host hemoglobin is digested). Cases of malaria are on the increase, and it is as yet unclear whether climatic changes may [55] or may not [56] be responsible. These increases may also be attributed to increased resistance towards established antimalarials [54].

Metal complexation of established antimalarials shows promise in overcoming resistance. The ferrocene derivative Ferroquine (FQ, see Figure 1.8b), a 4-aminoquinoline antimalarial that contains a quinoline nucleus similar to chloroquine (for structure of CQ see Figure 1.8a), is being developed by Sanofi-Aventis and has recently entered phase II clinical trials (2007), showing excellent activity against CQ-resistant Plasmodium falciparum, both in vitro and in vivo. Its mechanism of action is probably similar to that of chloroquine itself, involving hematin as the target and inhibition of hemozoin formation [57]. The metal fragment in the RuII chloroquine complex [RuCl2(CQ)]2 has been shown to alter the structure, the basicity, and most importantly the lipophilicity of CQ, to make it less recognizable to the parasite’s defense mechanism [58]. Metal complexes of the form [M(madd)]+ (M = Al, Ga, FeIII; madd = 1,12-bis(2-hydroxy-3-methoxybenzyl)-1,5,8,12-tetraazadodecane) show high activity against CQ-resistant P. falciparum (the strain that accounts for most instances of morbidity and mortality) and inhibit heme polymerization in the digestive vacuole of the parasite [59].

Figure 1.8 (a) Structure of the antimalarials chloroquine (CQ), a component of [RuCl2(CQ)]2, and (b) ferroquine.

1.3 Antiviral Agents

Polynuclear, early-transition metal oxyanions (polyoxometalates or POMs [60] have demonstrated antiviral, anticancer, and antibacterial activity [61]. The anti-HIV activity stems from the binding of the anionic POM to the viral envelope glycoprotein (gp120); the negative charge on the POM shields positively-charged sites on the glycoprotein that are necessary for viral attachment to a cell surface glycopolysaccharide, heparan sulfate. Because POMs prevent viral entry to cells, it is suggested that their main role in the management of HIV infections may reside in the prevention of sexual transmission of HIV infection, blocking HIV infection through both virus-to-cell and cell-to-cell contact [62]. Furthermore, Nb-containing POMs α1-K7[P2W17(NbO2)O61], α2-K7[P2W17(NbO2)O61], α1-K7[P2W17NbO62], and α2-K7[P2W17NbO62] selectively inhibit HIV-1 protease (HIV-1P) with IC50 values of 1–2 μM and display high activity in cell culture against HIV-1 (EC50 = 0.17–0.83 μM) [63]. The heteropolyoxotungstate K7[PTi2W10O40].6H2O (PM-19) (Figure 1.9) inhibits the replication of herpes simplex virus (HSV) strain 169 both in vitro and in vivo [64].

Figure 1.9 POMs: (a) structure of [NH3Pri]6[Mo7O24]·3H2O (PM-8), which shows potent antitumor activity, and (b) K7[PTi2W10O40]·6H2O (PM-19), which shows both antiviral and antibacterial activity.

Figure reproduced with permission from Reference [61].

Polyoxotungstates such as PM-19 also have been shown to enhance the effect of β-lactam antibiotics on methicillin-resistant S. aureus (MRSA) by depressing the formation of a protein (PBP2′) that is selectively expressed in the resistant strain, and which is essential for cell wall construction. They also suppress the production of β-lactamase which hydrolyzes the β-lactam antibiotics.

Cyclams are 14-membered tetraamine macrocycles that bind strongly to a wide range of metal ions [65]. Medical interest has centered on clinical trials of a bicyclam for the treatment of AIDS and for stem cell mobilization, and on adducts with Tc and Cu radionuclides for diagnosis and therapy. Other potential applications, particularly for Cr, Mn, Zn, and Ru cyclams, are also emerging. Macrocyclic bicyclams ligands such as AMD3100 (Figure 1.10) are amongst the most potent inhibitors of HIV ever described. AMD3100 targets the early stages of the retrovirus replicative cycle and blocks HIV-1 cell entry by interacting with the seven-helix transmembrane, G-protein coupled, coreceptor protein CXCR4 [66].

Figure 1.10 Structure of AMD3100 (previously also known as JM3100).

Although clinical trials of AMD3100 for the treatment of AIDS were halted due to adverse side-effects, it has been clinically approved (as the drug Plerixafor, Mozobil) for mobilization of stem cells and stem cell transplantation in cancer patients [67]. The same coreceptor CXCR4 that mediates cell entry of HIV-1 also anchors stem cells in the bone marrow. It is possible that a metalated form of the drug is the active species in vivo, constraining the macrocycle configuration, which is important in receptor recognition. Configurationally-restricted metallomacrocycles can be even more potent anti-HIV agents than AMD3100 [68, 69]. Both zinc and nickel cyclams can also interact with carboxylates to give unusual folded cis configurations [70].

The CXCR4 transmembrane receptor protein is widely expressed on cells of the immune, central nervous, and gastrointestinal systems, and also on many different types of cancer cells, besides playing a central role on the anchorage of CD34+ stem cells in bone marrow. Thus, cyclam derivatives may find use in the treatment of various pathogenic disorders, including HIV infections, rheumatoid, allergic and malignant diseases, and in other diseases that can benefit from stem-cell mobilization.

The CoIII bis(2-methylimidazole) acacen complex [acacen = bis(acetylacetone)ethylenediimine] CTC-96 (Doxovir, Figure 1.11) has been shown to be a potent topical microbicide and has successfully completed phase II clinical trials for treatment of herpes simplex virus (HSV) [71]. It has also shown activity against epithelial herpetic keratitis, adenovirus keratoconjunctivitis, and HIV [71, 72]. A range of CTC-96 analogs has been shown to inhibit human α-thrombin by substitution of an axial ligand at the CoIII centre with an active site histidine residue in the protein [73]. Interestingly, [CoIII(NH3)6]3+ also possesses antiviral activity [74].

Figure 1.11 Cobalt(III) Schiff base complexes that have been shown to inhibit human α-thrombin by substitution of an axial ligand for an active site histidine residue. Doxovir (CTC-96) has groups X = 2-methylimidazole, Y = H.

1.4 Systemic and Metabolic Diseases Including Inflammation

In this section we discuss treatments for diabetes, obesity, Alzheimer’s, Parkinson’s, arthritis, and bipolar disorder. Passivation and removal of aberrant metal ions in disease, including Parkinson’s, Friedreich’s Ataxia, iron overload, and Wilson’s disease, have recently been reviewed [75]. Metabolic disorders related to essential metals are also discussed later in this book (Chapter 11).

1.4.1 Diabetes and Obesity

Orally-available vanadium complexes can be used to mitigate insufficient insulin response in diabetes. Although they cannot entirely substitute for lack of insulin (a feature of type 1 diabetes), they can reduce reliance on injected insulin. They can also substitute for oral hypoglycaemic agents that are currently used to treat type 2 diabetes, a condition that is characterized by resistance to insulin. Early investigations of purely inorganic vanadyl salts such as vanadyl sulfate (VOSO4) were hampered by gastrointestinal distress and low absorptive efficiency [76]. The five-coordinate complex bis(2-ethyl-3-hydroxy-4-pyronato)oxovanadium(IV) (BEOV, see Figure 1.12) has been developed specifically to overcome these problems; inclusion of ionizable ligands allowed formation of a neutral complex, with the use of oxygen-rich ligands contributing to enhanced water solubility. BEOV is currently in Phase IIa clinical trials as an insulin-enhancing agent for treatment of diabetes. It has an intermediate stability in vivo, dissociating within hours after ingestion, but is stable enough to avoid potential gastrointestinal intolerance and demonstrates a bioavailability two to three times higher than vanadyl sulfate. It is suggested that the oxidation state of the administered drug is crucial; VIV compounds, as a group, have been found to be more potent than complexes of VIII and VV. Eventual ligand dissociation is necessary for the activity of the complex, and so non-toxic ligands are essential. BEOV has been suggested to be a multifactorial insulin sensitizer, inhibiting phosphotyrosine phosphatase 1B (PTP1B) within the insulin signaling cascade, and affecting insulin signaling to regulate glucose homeostasis favorably [77]. Other VIV complexes such as bis(allixinato)oxovanadium(IV) are also being investigated. [78].

Figure 1.12 Structure of bis(2-ethyl-3-hydroxy-4-pyronato)oxovanadium(IV) (BEOV) which is in Phase II trials for treating diabetes.

Sodium tungstate (Na2WO4·2H2O) is a novel agent in the treatment of obesity. Oral administration of tungstate significantly decreases body weight gain and adiposity without modifying caloric intake, intestinal fat absorption, or growth rate in obese rats [79]. Sodium tungstate reduces glycemia and reverts the diabetic phenotype in several induced and genetic animal models of diabetes. Importantly, tungstate has also shown promise as an effective treatment for diabetes. Tungstate appears to mimic most of the metabolic effects of insulin and exerts insulin-like actions in primary cultured rat hepatocytes by increasing glycogen deposition [80]. The in vivo transport of tungstate is thought to be mediated by plasma proteins such as human serum albumin [81].

1.4.2 Metal Homeostasis and Related Diseases

Several neurological disorders may result from errors in the distribution of metal ions in the brain, including Zn, Cu, Fe, and Mn (see Chapter 11 for more detail). Zinc is a cofactor for many proteins involved in cellular processes such as differentiation, proliferation, and apoptosis. Zinc homeostasis is tightly regulated; one mechanism of control includes storage in, and retrieval from, vesicles, so-called zincosomes [82]. Disturbance of zinc homeostasis due to genetic defects or dietary availability influences the development of diseases such as diabetes (insulin is stored as a zinc complex), cirrhosis of the liver, cancer, asthma, bowel diseases, and rheumatoid arthritis. Because zinc is important in cell division, zinc deprivation during the development of T-lymphocytes impairs their polarization into effector cells, and their function, leading to a reduction in T-cell numbers. As a consequence, zinc deficiency can also affect the immune system, increasing susceptibility to bacterial infections [83]. Zinc homeostasis in the brain is integral for normal brain function. Alterations in zinc levels can have devastating results with zinc becoming a pathogenic agent that mediates neuronal death in conditions such as Alzheimer’s disease, amyotrophic lateral sclerosis, and ischemia (a shortage of blood supply). Although zinc-chelating agents are being investigated to treat these neurological disorders, zinc homeostasis needs to be better understood to aid rational intervention [84].

Copper, Zn and Fe are known to promote the aggregation of amyloid beta (Aβ) deposits that cause Alzheimer’s disease. [85]. Furthermore, copper binds to both the prion protein, the amyloid precursor protein and alpha-synuclein [86]. In addition, vanadium compounds have been shown to have interesting properties for treatment of Alzheimer’s [87].

1.5 Metal Chelating Agents

Chelating agents can be used either to deliver metal ions for medical applications or for the removal of unwanted metals from the body. In diagnostic applications, the metal ions can be radioactive (γ-emitter), paramagnetic, or luminescent, whereas therapeutic applications generally require metals that either emit ionizing radiation (α- or β-emitter) or are chemically active. The stability of the chelate in vivo is crucial for the metal ion to be delivered safely and effectively to its target. (See later section on diagnostic agents and Chapters 8 and 9.) The use of macrobicyclic caged metal complexes (clathrochelates) is one avenue that is currently being explored [88].

It is useful to be able to reduce the levels of unwanted forms of metals in the human body; for example, long-term exposure to manganese particulates through inhalation can be neurotoxic, with deficits in neuromotor and cognitive domains [89]. Chelating agents vary widely according to metal-binding properties: dithiocarbamate derivatives have shown promise in polonium chelation in vivo [90], whereas catechol-3,6-bis(methyliminodiacetic acid) (CBMIDA) has been used to chelate and increase excretion of uranium [91]. Iron chelators such as Desferal (Desferrioxamine mesylate) are neuroprotective against iron-overload. However, since Desferal is not able to cross the blood–brain barrier (BBB), there is a need for further development if chelating agents such as these are to be used to treat cases of abnormal iron accumulation in the brain, such as Parkinson’s disease [92].

A potential therapy for Alzheimer’s involves targeting Cu and Zn in the brain with chelators. The antifungal drug and antiprotozoal drug clioquinol (5-chloro-7-iodo-quinolin-8-ol, Figure 1.13) has been on clinical trial for treatment of Alzheimer’s disease but is likely to be replaced soon by a related 8-hydroxy quinoline, PBT2, which lacks the iodine (structure not explicitly reported) [93], a once per day, orally bioavailable, second-generation derivative of clioquinol [94]. Phase IIa studies of PBT2 [95] have established a favorable safety profile for the drug and suggest a central effect on Aβ metabolism. PBT2 may not act as a metal chelator, but rather as an ionophore that makes copper and zinc more available for normal neuronal function [96].

Figure 1.13 Structure of clioquinol.

Tetrathiomolybdate ([MoS4]2−) has anticancer and anti-angiogenic activities, and acts through copper chelation and NF-kappa-B inhibition. Phase I and II clinical trials in solid tumors have demonstrated efficacy with a favorable toxicity profile [97]. Although initially used for treatment of neurologically-presenting Wilson’s disease [98], [MoS4]2− has efficacy in animal models of fibrotic [99], metastatic colorectal cancer [100], inflammatory, autoimmune, and neoplastic diseases, as well as Alzheimer’s disease. A CuI ion can bind strongly to a pair of MoS42− sulfurs. Additional coordination of CuI to sulfur of glutathione may facilitate transport from the liver to the kidney [101].

1.6 Antiarthritic Drugs and Inflammation

Gold-based drugs, including the injectable thiolate polymer aurothiomalate and oral triethylphosphine complex auranofin (Figure 1.14), are widely used to treat rheumatoid arthritis (see Chapter 7 for more detail). In the blood, AuI is transported by albumin on Cys34, and inside cells binds to the thiol of glutathione. It is thought that the pharmacologic effect may be achieved through inhibition of the selenoenzyme thioredoxin reductase [102]. The use of thiol-reactive probes and photocrosslinking methods for detecting gold binding sites on proteins has recently been proposed [103]. The finding that [Au(CN)2]− is excreted not only by patients receiving gold therapy who are smokers (about 35 μg HCN/cigarette) but also by non-smokers, emphasizes that strong small ligands such as cyanide can play a role in the metabolism of metallodrugs. [Au(CN)2]− is readily taken up by cells (and also has anti-HIV activity). Whitehouse et al. have recently reported that colloidal (purple) gold exhibits potent antiarthritic activity in rats, approximately ten-times that of the clinically-used drug sodium aurothiomalate (Myocrisin) [104].

Figure 1.14 Structure of triethylphosphine gold-2,3,4,6-tetra-o-acetyl-l-thio-d-glucopyranoside (auranofin).

Metaphore Pharmaceuticals Inc. has investigated M-40403 (Figure 1.15) [105], a Mn-based superoxide dismutase (SOD) mimetic, for the potential treatment of post-operative ileus, oral mucositis [106], pain, dermatological disease, inflammation [107], and arthritis [108]. M-40403 is said to improve the effectiveness and predictability of morphine. A potential target indication for M-40403 is the treatment of cancer pain and post-operative pain in patients in acute care settings who are on, or are candidates for, opioid therapy. In Metaphore’s earlier Phase II trial (completed May 2003) the company found that 20 mg of M-40403 as a single agent was significantly superior to placebo for up to one hour (p < 0.05) following molar tooth extraction. No serious adverse events were reported. Results from the trial provided clinical proof of concept that SOD mimetics are well-tolerated and have therapeutic potential [109]. It is suggested that M-40403 removes superoxide anions without interfering with other reactive species known to be involved in inflammatory responses, for example, nitric oxide (NO) and peroxynitrite (ONOO−). M-40403 treatment prevents activation of poly (ADP-ribose) polymerase – having an anti-inflammatory effect – in the gingivomucosal tissue during ligature-induced periodontitis [110]. Other Mn complexes such as MnIII salen chloride [salen = N,N′ bis(salicylidene)ethylenediamine] also show SOD and catalase mimetic functionality [111].

Figure 1.15 Structure of the pentagonal bipyramidal complex M-40403, which shows potential as a superoxide dismutase (SOD) mimetic.

1.7 Bipolar Disorder

Lithium salts such as Li2CO3 have been widely used for treating bipolar disorder since the early 1950s, and are administered in near-gram quantities on a daily basis. Millimolar levels of Li+ build up in the blood significantly reducing intracellular sodium concentration in electrically activated cells, a marker that is typically elevated (two to five times higher) in bipolar patients as compared to control subjects [112]. Lithium may also modify monoamine neurotransmitter concentrations in the CNS, inducing changes in neurotransmitter signaling and attenuating fluctuations of cAMP levels (by raising the lowest basal levels and decreasing the highest stimulated increases), stabilizing the activity of this signaling system [113]. Response to lithium appears to cluster in families and can be used to predict the recurrence of bipolar disorder symptoms [114]. Li+ is similar in size to Mg2+ and can therefore inhibit Mg-activated enzymes such as myo-inositol monophosphatase. As a consequence it can also interfere with calcium signaling, since Ca2+ is mobilized by inositol phosphates [115].

1.8 Anticancer Agents

The discovery of the anticancer activity of cisplatin (cis-[PtII(NH3)2Cl2]) by Rosenberg and coworkers some 40 years ago and its subsequent approval for clinical use ten years later has done more for the advancement of inorganic medicinal chemistry than almost any other development in the field. It is worth considering what has happened since and where platinum drugs are heading in the future (see also Chapters 3 and 4).

1.8.1 PtII Cytotoxic Agents

Both the thermodynamics (ligand arrangement, trans influences) and kinetics (rates of ligand substitution, trans effects) are crucial for the rational design of platinum anticancer drugs. Clearly, both the metal and the ligands determine the biological activity, not just the metal (Pt). Platinum occupies a unique place in the recent development of inorganic medicinal chemistry due to the clinical success of cisplatin, subsequently carboplatin, and more recently oxaliplatin (Figure 1.16a). The latter is currently a billion-dollar (“blockbuster”) drug, even though it is used mainly only for colorectal cancer in combination with organic drugs [116]. These successes have provided enormous incentive for exploration of the chemistry of platinum, which has uncovered new and interesting findings, both thermodynamic and kinetic. The ligands on PtII play important roles not only in determining the activation of the administered complex (e.g., by hydrolysis) but also in the recognition of the drugs and their DNA adducts by proteins and repair enzymes, and hence the ligands play a pivotal role in the development of resistance mechanisms.

Figure 1.16 Structures of (a) cisplatin, carboplatin, and oxaliplatin; (b) BBR3464; and (c) trans,trans,trans-[Pt(N3)2(OH)2(py)(NH3)].

The precise mechanism of cell uptake of platinum complexes remains a topic of great curiosity. The copper transporter Ctr1 has been implicated in the transport of cisplatin, (carboplatin and oxaliplatin) across the cell membrane [117] and Ctr2 has been shown to regulate the cellular accumulation and cytotoxicity of cisplatin and carboplatin [118]. In general, copper transporters appear to regulate the cellular pharmacology and sensitivity to Pt drugs [119]. However, reactions of cisplatin with the extracellular methionine-rich N-terminal domain of Ctr1 can lead to the release of the ammine ligands, thus deactivating the drug [120]. This has precedent, stemming from the high trans effect of sulfur (l-methionine) [121] and such reactions have also been detected in cancer cell extracts [122]. The hypothesis put forward by Arnesano and Natile [123] – that interaction of cisplatin with Ctr1 leads to pinocytosis and delivery of cisplatin into the cell in vesicles, helping to shield it from reactions with nucleophiles such as glutathione and metallothionein, which lead to drug inactivation – is therefore an attractive one.

Not only does protein recognition appear to be important in cell entry of platinum drugs, but also in the processing of platinated DNA lesions and excision-repair resistance mechanisms. For example, platinated intra-strand crosslinks are recognized by high mobility group (HMG) proteins, which shield them from repair, whereas interstrand crosslinks are recognized by the mismatch repair (MMR) family [124].

An early design rule for platinum drugs was that they should be neutral in charge to allow uptake by cells. Now there are several exceptions to this rule, notable examples being the 1+ complex cis-[Pt(NH3)2(pyridine)Cl]+ [125] and the 4+ trinuclear complex [{trans-PtCl(NH3)2}2(μ-trans-Pt(NH3)2{NH2(CH2)6NH2}2)](NO3)4 (BBR3464) (Figure 1.16b) [126], both of which contain only monofunctional Pt centers. Both examples also break one of the early rules that complexes should be bifunctional or potentially bifunctional after loss of two cis monodentate ligands or a weakly chelated (e.g., oxygen donor) bidentate ligand. The belief that the am(m)ines in square-planar PtII complexes need to be of cis geometry for activity is also no longer valid [127, 128]. It is apparent that the inactivity of transplatin is not a feature of trans diamine PtII complexes in general, and several trans-PtII complexes are being developed that rival, or improve upon, the cytotoxicity of cisplatin [127].

Recent advances in formulation of platinum drugs and means for delivery and for targeting have included attaching PtIV prodrugs to single-walled carbon nanotubes [129] and platinum–polymer conjugates, dendrimers, micelles, and microparticulates [130], including PtIV-encapsulated prostate-specific membrane antigen (PSMA) targeted nanoparticles [131].

1.8.2 PtIV Prodrugs

Several PtIV prodrugs have been on clinical trials but none has been successful enough to date to gain widespread approval. Clinical trials of tetraplatin ([Pt(DACH)Cl4]) and iproplatin ([cis,trans,cis-[Pt(i-PrNH2)(OH)2Cl2]) were abandoned some years ago although satraplatin (JM216, cis,trans,cis-[Pt(cyclohexylamine)(NH3)(acetate)2Cl2]), which is orally active, is in Phase III trials for hormone-refractory prostate cancer. One of the difficulties perhaps is the requirement for in vivo activation by reduction at the tumor; the levels of reductants such as ascorbate and thiols may be too variable for the activation to occur in a controlled and predictable way in patients.

1.8.3 Photoactivatable PtIV Complexes

Adverse side effects and development of acquired resistance to platinum diam(m)ine (PtII) complexes pose a serious problem; improved targeting is crucial for the clinical success of new anticancer agents. Octahedral PtIV complexes are typically more inert to reaction than square-planar PtII complexes; PtIV complexes that can be specifically activated only at a tumor site provide a route to a better targeted treatment. Sadler et al. have developed PtIV azido complexes that are non-toxic in the dark but which become highly toxic to cells following irradiation [132]. For example, trans,trans,trans-[Pt(N3)2(OH)2(py)(NH3)] (Figure 1.16c) has little or no dark toxicity and is an order of magnitude more potent towards human ovarian cancer cells (A2780) when photoactivated than cisplatin under similar conditions [133]. Moreover, recent work has shown that the trans bis-pyridine adduct can be activated in cells by visible light [133b]. The mechanism of action of these complexes is postulated to involve platination of nuclear DNA, but such excited state drugs can undergo unusual reactions [134] and other targets (proteins) may be involved. The use of light in this way provides a degree of spatial and temporal control over drug activation [135].

1.8.4 Ruthenium

Soon after the discovery of the anticancer properties of platinum complexes, ruthenium compounds were investigated. They often have similarly slow kinetics of substitution reactions as platinum. NAMI-A (Figure 1.17a) is a tetrachlorido imidazole/dmso RuIII compound that inhibits matrix metalloproteinases and prevents tumor invasion of nearby tissues [136]. The related bis-indazole complex RuIII (KP1019) (Figure 1.17a) showed no dose-limiting toxicity in Phase I studies [137]. It has been demonstrated to be largely protein bound in blood (to albumin and transferrin) and is found on DNA in peripheral leukocytes. The results of Phase II colorectal trials are anticipated with interest. The kinetically-inert organometallic RuII complex, DW1/2 (Figure 1.17b) (Table 1.3), which mimics staurosporine, targets a signal transduction pathway; its action involves inhibition of the beta form of glycogen synthase kinase-3 (binding to its ATP site), activation of p53, and apoptosis via the mitochondrial pathway [138].

Figure 1.17 (a) KP1019, NAMI-A; (b) DW1/2; and (c) half-sandwich organometallic RuII complexes of the type [(arene)Ru(X)(Y)(Z)]; inclusion of a chelating ligand (1,2-diaminoethane, en) can improve aqueous stability.

Table 1.3 Some examples of the dependence of the biological activity of ruthenium, platinum, and gold complexes on oxidation state and coordinated ligands.

ComplexActivityReferenceRutheniumDW1/2 [CpRuII(pyridocarbazole)CO)]Inert ATP-competitive protein kinase inhibitorsFigure 1.17b (Meggers) [140]NAMI-A trans-[RuIIICl4(DMSO)(Im)](ImH)AntimetastaticFigure 1.17a (Alessio, Sava) [141]KP1019 trans-[RuIIICl4(Ind)2](IndH)Cancer cell cytotoxicFigure 1.17a (Keppler) [137][(η6-biphenyl)Ru(en)Cl]+Organometallic anticancer complexFigure 1.17c (Sadler) [142][RuII(CO)3Cl(glycinate)]CO delivery; cytoprotectant(Mann) [143][RuII(bpy)2(dipyridophenazine)]2+Luminescent DNA intercalator, oxidative damage(Barton) [144][RuIII(HEDTA)Cl]−NO scavenger (alleviation of NO-mediated disease states)(Review by Fricker) [145]Ruthenium red [Ru3Cl8(OH)3(NH3)12(OH2)3]Blocker of mitochondrial calcium uptake/efflux: potential application for prevention of ischemia reperfusion injury in liver transplantation.Crystal structure [146]Medical application [147]Platinum[PtCl4]2−, [PtCl6]2−Potent immunogens (allergens, skin sensitizers), but not [Pt(NH3)4]2+(General review)[148]Cisplatin cis-[PtCl2(NH3)2]Cytotoxic anticancer drug; bifunctional, crosslinks, and kinks DNAFigure 1.16a (Review) [123], [149]trans-[PtCl2(NH3)2]Inactive as anticancer agentcis-[Pt(NH3)2(py)Cl]+Monofunctional anticancer agent; substrate for organic cation transporters SLC22A1 and SLC22A2(Lippard) [125]trans-[PtCl2(iminoether)2] where iminoether is HN=C(OR)R′Active trans anticancer complex(Natile) [128]cis-[PtII(H2N(CH2)2PPh2)2]Cl2Cytotoxic, reversible chelate ring-opening, and binding to G(Sadler) [150][PtII(en)Cl(S-thiourea-acridine)]DNA intercalator; inactive in vivo(Bierbach)[151][PtII(en)Cl(N-amidine-acridine)]DNA intercalator; active in vivo (lung cancer)PtIV prodrugsOn reduction can release active agents, e.g., estrogen or enzyme inhibitors(Lippard) [152] (Dyson) [153]t,t,t-[PtIV(N3)2(OH)2(NH3)(py)]Photoactivatable anticancer complex; only cytotoxic following irradiationSee Figure 1.16c (Sadler) [133]TriplatinNC [{trans-PtII-(NH3)2(NH2(CH2)6(NH3+)}2-μ-{trans-PtII(NH3)2(NH2(CH2)6NH2)2}]Trinuclear; cytotoxic; trinuclear phosphate clamp, electrostatic binding to DNA backbone(Farrell) [154]BBR3464 [{trans-PtIICl(NH3)2}2-μ-{trans-PtII(NH3)2(NH2(CH2)6NH2)2}](NO3)4Trinuclear; cytotoxic; monofunctional centers, long-range DNA crosslinkingFigure 1.16b (Farrell) [155][PtII(S,S-dach)(phen)]2+DNA intercalator; leukemia, non-toxic in vivo, and reduces tumor growth(Aldrich-Wright) [156][(cis-{PtII(NH3)2})2(μ-OH)(μ-pyrazolate)]2+Potent cytotoxic; DNA GG crosslinks but little distortion(Reedijk) [157]GoldEt3PAuISR (Auranofin) and [AuI-S-CH(CO2Na)(CH2CO2Na)]n, (sodium aurothiomalate, Myochrysine)Oral antiarthritic and injectable antiarthriticFigure 1.14 (Review) [158][AuI(CN)2]−Stable metabolite of gold antiarthritic drugs(Graham) [159][AuI(diphosphine)2]+; [AuI(N-heterocyclic carbene)2]+Anticancer; antimitochondrial; thioredoxin and thioredoxin reductase inhibitorFigure 1.20b (Berners-Price) [160, 161][AuIII(dithiocarbamate-R)X2]Anticancer; proteasome inhibitorFigure 1.20c (Fregona) [162]

1.8.4.1 Interaction with Plasma Proteins

Binding to plasma proteins causes a drastic decrease of NAMI-A bioavailability and a subsequent reduction of its biological activity, implying that association with plasma proteins essentially represents a mechanism of drug inactivation [139]. Contrastingly, an important step in the mode of action of KP1019 is thought to be binding to the serum protein transferrin and transport into the cell via the transferrin pathway [163]. In the blood, transferrin is only one-third saturated with its natural metal ion FeIII and cancer cells have a higher density of transferrin receptors than normal cells; so hijacking this route into the cell with therapeutic agents such as KP1019 provides a potentially selective uptake mechanism.

1.8.4.2 Ruthenium Arenes

Half-sandwich organometallic RuII complexes of the type [(arene)Ru(XY)Z] provide a versatile platform for anticancer drug design (Figure 1.17c, for example). Some structure–activity relationships have been described [164–166]. If X, Y, and Z are monodentate ligands, the complexes demonstrate low cytotoxicity on account of rapid hydrolysis and weak binding to DNA [167], although some 1,3,5-triaza-7-phosphaadamantane adducts have interesting antimetastatic activity (RAPTA-C, Figure 1.17c) [168].

Activity tends to increase with the size of the arene, and extended arenes can intercalate between DNA bases [169, 170]. For XY = ethane-1,2-diamine (en, an N-chelating ligand), and Z = halide, activation occurs via aquation and the aqua adduct selectively binds to guanine (G) residues in DNA, at the N7 ring position. This is accompanied by C6O (G) hydrogen bonding to an NH group of the en ligand. Chelated ligands with X and/or Y = O (H-bond acceptor) can also bind to adenine (H-bond donor).

The half-sandwich Ru complex [(η6-biphenyl)Ru(en)Cl]Cl (ONCO4417, Figure 1.17c) exerts antiproliferative effects in H460 lung cancer cells by inducing apoptosis, with levels of DNA damage comparable to those produced by cisplatin. Cell death appears to occur prior to entry into the G2/M phase [171]. The complex is currently in preclinical development. Such complexes are non-cross-resistant with cisplatin in line with the different lesions produced on DNA. The loss of cytotoxicity in complexes of this type when XY = phenanthroline or bipyridine, both strong π-acceptor ligands, is intriguing; in the case of bipyridine activity can be restored by 3,3′-hydroxylation of the rings [172]. Use of another strong π-acceptor chelating ligand hydroxy- or N,N-dimethyl-phenylazopyridine, Z = iodide, leads to hydrolytically inert complexes that appear to kill cancer cells by a different mechanism: catalysis of glutathione oxidation and production of reactive oxygen species (ROS) in cells [173].

Ligand oxidation appears to provide a route to activation of Z = thiolato complexes, a route that may be important when the intracellular thiol glutathione binds to these ruthenium arene complexes. Mono- and bis-oxygenation appear to be facile but surprisingly do not weaken the Ru–S bond [174] even though this provides a route to nucleobase binding [175]. Protonation of the sulfenate oxygen on the other hand does labilize this bond [176].

1.8.5 Osmium

Organometallic half-sandwich OsII complexes that are isostructural with their RuII counterparts have been synthesized [166, 177]. Although structurally similar, their properties differ in some important ways, influencing their biological activity. For example, Z = Cl complexes hydrolyze about 100 times more slowly, and the resultant bound water is about 1.5 pKa units more acidic. The latter feature favors formation of hydroxo adducts that readily associate to give very stable hydroxo-bridged dimers, even in cell culture media, for example, for the OsII complex where XY = acetylacetonate (Figure 1.18