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9.

18 Metal Complexes as Drugs and Chemotherapeutic Agents


N. FARRELL Virginia Commonwealth University, Richmond, VA, USA
9.18.1 INTRODUCTION 9.18.1.1 Biological Assays 9.18.2 PLATINUM COMPLEXES AS THERAPEUTIC AGENTS 9.18.2.1 Clinically Used Anticancer Agents. Cis-platinum Compounds 9.18.2.2 Platinum Compounds in Clinical Trials 9.18.2.2.1 AMD473 (ZDO-473) 9.18.2.2.2 JM-216 (Satraplatin) 9.18.2.2.3 Poly (di and tri)-nuclear platinum complexes 9.18.2.2.4 Transplatinum compounds 9.18.3 NONPLATINUM ANTICANCER AGENTS 9.18.3.1 Ruthenium Complexes 9.18.3.2 Arsenic Trioxide 9.18.3.3 The Mitochondrion as Target. Goldphosphane Complexes 9.18.3.4 Manganese-based Superoxide Dismutase Mimics 9.18.3.5 Titanium Compounds 9.18.3.6 Gallium Nitrate 9.18.4 ANTIBACTERIAL AGENTS 9.18.4.1 Silver and Mercury Salts 9.18.4.2 Bismuth-containing Antiulcer Drugs 9.18.4.3 Metal-containing Drugs as Antiparasitic Agents 9.18.5 PHARMACODYNAMIC USES OF METAL COMPLEX DRUGS 9.18.5.1 Lithium Carbonate 9.18.5.2 Vanadium Complexes in Diabetes 9.18.5.3 Gold Compounds as Antiarthritic Agents 9.18.5.4 Nitric Oxide in Physiology and Medicine 9.18.5.5 Lanthanum Carbonate 9.18.6 REFERENCES 809 810 812 812 817 817 818 819 823 825 825 826 827 827 829 830 830 830 831 831 832 832 833 833 834 834 834

9.18.1

INTRODUCTION

The medicinal uses and applications of metals and metal complexes are of increasing clinical and commercial importance. Monographs and major reviews, as well as dedicated volumes, testify to the growing importance of the discipline.111 Relevant reviews are to be found throughout annual series, for example Metal Ions in Biological Systems12 and Coordination Chemistry Reviews.13 The field of inorganic chemistry in medicine may usefully be divided into two main categories: firstly, ligands as drugs which target metal ions in some form, whether free or protein-bound; and secondly, metal-based drugs and imaging agents where the central metal ion is usually the key feature of the mechanism of action.14 This latter class may also be conveniently expanded to include those radionuclides used in radioimmunoimaging and radioimmunotherapy (Chapter 9.20). A reasonable estimate of the commercial importance is approaching US$5 billion annually 809

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Metal Complexes as Drugs and Chemotherapeutic Agents

for the whole field. A list of clinically used chelating agents may be found in most pharmacopoeia,15 while new chelating agents continue to be sought.15,16 The use of chelating agents in the treatment of Wilsons disease is a good example of how medical problems due to free metal ion (CuII) toxicity may be ameliorated by chelating agents.17 The extensive work on matrix metalloproteinases likewise represents a case study in design of small organic ligands as drugs to inactivate a metalloenzyme.18,19 Overexpression of these zinc-containing enzymes is associated with several diseases including arthritis and cancer, so inhibition of the zinc active site is a reasonable drug development strategy. Indeed, enzymatic zinc is an attractive target because of the diversity of its structural and catalytic roles in enzymes.20,21 This chapter is restricted to the uses of well-defined inorganic compounds as drugs and chemotherapeutic agents. Current uses and prospective uses, as well as those of essentially historical relevance, are covered. An important distinction to be made is between drugs as chemotherapeutic agents, whose function is to kill cells, and drugs acting by a pharmacodynamic mechanismwhose action must be essentially reversible and/or short-lived.22

9.18.1.1

Biological Assays

Most therapeutic agents and drugs will first be tested in tissue culture on a suitable model system. For prospective anticancer drugs, for example, in vitro data obtained by proliferation or colony formation assays give useful initial information on the cytotoxicity of the agents. The preponderance of human tumor tissues now available with well-defined genetic makeup and detailed information of up- or downregulation of critical genes now means that the relevance of murine (mouse-derived) tumor models such as P388 and L1210 leukemias is somewhat diminished, although useful for preliminary data and also for historical and comparative purposes. In vivo assays also rely initially on the murine models for determination of pharmacokinetic properties, but the use of human tumor xenografts, while significantly more expensive than murine models, is also considered more relevant to the real situation. In evaluating true drug efficacy, attention must also be paid to routes of administration: a method where drug is delivered intraperitoneally to a tumor growing in the intraperitoneal cavity (ip/ip) is common but not as relevant to a clinical situation as intravenous administration to a tumor growing subcutaneously (sc/iv). The term antitumor activity should be reserved for data obtained on tumor regression in animals and not used for cytotoxicity data obtained from tissue cultures. Phase I clinical trials assess safety and dose-limiting toxicity of prospective drugs and may be achieved with a relatively small number of patients. phase II clinical trials usually assess single-agent efficacy in defined diseases, i.e., ovarian cancer or relapsed ovarian cancer etc.; they generally involve many patients and may take a significant amount of time before statistically useful data are obtained. phase III studies may assess efficacy in combination regimens, as the chemotherapy of most cancers is treated in this manner. An overview of the drug development and approval process is available through web sites of agencies such as the US Food and Drug Administration23 and the National Cancer Institute Developmental Therapeutics program.24 The application of inorganic compounds to medicine requires detailed examination of the fundamental aqueous chemistry of the proposed drug, including its pharmacokinetics, the metabolic fate in blood and intracellularly, and the effects of the drug on the target of choice. Coordination and organometallic complexes present a wide variety of coordination spheres, ligand designs, oxidation states, and redox potentials, giving the ability to systematically alter the kinetic and thermodynamic properties of the complexes toward biological receptors. The toxicology of inorganic compounds in medicinal use, especially those containing the heavy metals, confronts the stigma of heavy metal toxicity; but therapeutic windows are rigorously defined to minimize such side effectsthe usefulness of any drug is a balance between its toxicity and activity. The toxicity of a compound may derive from its metabolism and unwanted random protein interactions. Human serum albumin is of fundamental importance in the transport of drugs, metabolites, endogenous ligands, and metal ions.25 The crystal structure, combined with physical and biophysical studies, allows visualization of likely binding sites of many potential inorganic drugs.26 Abundant cysteine-rich small peptides, especially glutathione (GSH) (Figure 1a), and proteins such as metallothionein27 represent detoxifying but also deactivating pathways for inorganic drugs. A further source of metal ion/protein interactions is provided by transferrin, whose natural iron-binding site is accessible to many metal ions of similar radius and charge including Ru2, Ga3, and Al3.28 The nature of the target to be attacked by any drug obviously depends on the specific application. Many cytotoxic metal complexes target DNA because of its importance in replication and cell viability. Coordination compounds offer many binding modes to polynucleotides, including outer-sphere noncovalent binding, metal coordination to nucleobase and phosphate backbone

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(a)
O

HS H N O

O N H

O O NH3+

Glutathione O O H2N HS Cysteine OH S Methionine H2N OH

NH2 (b) N O
O

NH2 N

N N
O

N O H OH H

O P O O H

O O

P O O

H OH

2'-Deoxyadenosine-5'-Monophosphate O N O
O

2'-Deoxycytidine-5'-Monophosphate O

NH N NH2
O

HN O P O O H OH 2'-Deoxythymidine-5'-Monophosphate O O H N

N O H OH H

P O O

2'-Deoxyguanosine-5'-Monophosphate
Figure 1

(a) Structures of common sulfur-based amino acids and tripeptides. (b) Structures of nucleic acid monophosphates capable of metal binding.

sites, as well as strand cleavage induced by oxidation using redox-active metal centers. The purine and pyrimidine mononucleotide building blocks are depicted in Figure 1b. The later transition metals such as platinum and ruthenium favor binding to electron-rich nitrogens on the bases, especially guanine N7. Titanium and early metals may display a mixture of nucleobase and

812
Table 1 Element

Metal Complexes as Drugs and Chemotherapeutic Agents


Medical and prospective medical uses of inorganic compounds.a Uses Trade names/comments

Compound

Approved agents (mostly US or worldwide): Li Li2CO3 Manic depression Fe [Fe(NO)(CN)5]2 Vasodilation Ga Ga(NO3)3 Hypercalcemia of malignancy As As2O3 Anticancer agent Ag AgNO3 Disinfectant Ag(sulfadiazene) Antibacterial Sb Pt Au Bi Hg SbIII(tartarate) cis-[Pt(amine)2X2] Au(PEt3)(acetylthioglucose) Bi(sugar) polymers Hg-organic compounds Antiparasitic, leishmaniasis Anticancer agents Rheumatoid arthritis Antiulcer; antacid Antibacterial Antifungal Agents in clinical trials: Pt Polynuclear PtIV species Mn Ru V Ln Mn chelates trans-[RuCl4 (Me2SO)(Im)] VO(maltate)2 Ln(CO3)3 Anticancer agents

Camcolit; Cibalith-S; Lithane (of many) Nipride. For acute shock. NO release Ganite. Possible anticancer agent. In clinical trials for use in lymphomas Trisenox. Use in acute promyelocytic leukemia Neonatal conjunctivitis Flamazine; Silvadene; treatment of burns. 1% cream Tartar Emetic Stibophen; Astiban Platinol; Paraplatin; Eloxatine Testicular, ovarian, colon cancers Ridaura. Orally active Pepto-Bismol; Ranitidine Bismutrex; De-Nol Thiomersal; mercurochrome (amongst many) Slow release of Hg2 BBR3464, Satraplatin, AMD-473 Expands spectrum of activity of cisplatin; overcomes resistance; oral activity? SOD mimics NAMI-A; antiangiogenic? BMOV; insulin mimetic Fosrenol; phosphate binder

Anticancer agents Anticancer agent Type II diabetes Hyperphosphatemia

a Principal uses as medicinal agents. Other trivial or topical uses as ointments; antacids and skin desiccants for individual elements (especially Zn, Mg, and Al) may be found throughout.14

phosphate backbone binding. The accessibility of different oxidation states of metals such as Fe, Cu, Co, Ru, Mn, etc. may allow for redox chemistry resulting in strand breakage. Noteworthy in this respect is the anticancer antibiotic bleomycin, whose mode of action on target DNA is strand scission mediated by Fe binding to the drug.29,30 Cytotoxic agents reduce the proliferation of a tumor but lack of selectivity between normal and malignant tissue may render many agents of little clinical utility. Drug discovery in general has been transformed by rapid advances in the understanding of the cells molecular biology coupled with information sciences.31 Cancer treatment strategies especially have evolved in favor of agents targeted toward specific pathways, notably those involved in cell signaling.32 A challenge for the medicinal inorganic chemist is the placement of coordination chemistry within this new paradigm. This section reviews both established and evolving approaches to uses of inorganic-based drugs with emphasis on the most recent literature. The major clinical application and promising preclinical areas are summarized in Table 1.

9.18.2 9.18.2.1

PLATINUM COMPLEXES AS THERAPEUTIC AGENTS Clinically Used Anticancer Agents. Cis-platinum Compounds

Cisplatin, (cis-[PtCl2(NH3)2], also known as cis-DDP) ((1), Figure 2) is perhaps the best known example of a small molecule metal-containing drug. The clinically used platinum complexes are shown in Figure 2. The history of the discovery and development of cisplatin remains a remarkable scientific story.33 Its use and effectiveness in cancer chemotherapy since the entry into the clinic in the late 1970s has been thoroughly documented.3436 Cisplatin is cited for treatment of

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O H3N Pt H3N (1) Cl Cl H3N Pt H3N O (2) O O

H2 N O Pt O N H2 (3)

H3N Pt H3N

O O (4)

H2 N Pt N H2

O O ( 5)

Figure 2 Structures of the clinically used platinum anticancer agents.

germ-cell cancers, gestational trophoblastic tumors, epithelial ovarian cancer, and small cell lung cancer as well as for palliation of bladder, cervical, nasopharyngeal, esophageal, and head and neck cancers.3739 The use of cisplatin (usually as a principal component of combination regimens) has rendered at least one cancer, testicular cancer, curable and is significant in treatment of ovarian and bladder cancers. Typical doses range from 20 mg/m2 to 100 mg/m2, usually for up to five consecutive days. Despite this success, there is still a limited range of tumors sensitive to cisplatin interventionsome cancers are inherently resistant.40,41 A further disadvantage is the onset of clinical (acquired) resistance after treatment with the drug. The side effects of cisplatin treatment are severe and include the dose-limiting nephrotoxicity, neurotoxicity, ototoxicity, and emetogenesis. The second-generation compounds based on the cisplatin structure were developed in attempts to improve toxicity and/or expand the range of useful anticancer activity. Carboplatin (2) entered the clinic in 1998, principally in response to the necessity to reduce the toxic side effects of the parent drug. Despite this lower toxicity, carboplatin is essentially active in the same set of tumors as cisplatin and a broader spectrum of activity is not indicated.42 For some tumors, cisplatin appears to be therapeutically more effective than carboplatin (germ cell tumors, head and neck, and bladder) whereas for lung cancer and ovarian cancer effectiveness is comparable.43 The choice of the most appropriate analog is a function of the cancer being treated, treatment intention (palliative or curative), and other component drugs used in combination. Since the advent of cisplatin in the clinic, the consistent goals for drug development have been improvement of toxicity profile, circumvention of resistance, and expansion of the tumors sensitive to treatment by cisplatin. The importance of circumventing resistance was recognized very early on and reports of the activity of complexes containing 1,2-diaminocyclohexane (dach) in murine L1210 resistant to cisplatin date back to 1978.44 After approval and use in Europe for a number of years, oxaliplatin (3) was finally granted approval for use in the US in August 2002 for colorectal cancer in combination with 5-fluorouracil (5-FU).45,46 Little information is available on nedaplatin (4) and lobaplatin (5), which have been approved for use in Japan and China, respectively. DNA is accepted to be the cellular target of cisplatin. The natural sequence of scientific understanding has developed from a detailed structural understanding of the cisplatinDNA interaction to the biological consequences of these adducts. In this respect, the field has also kept pace with the understanding of cellular cancer biology over the same period. Thus, it is not the DNA adduct per se but the downstream effects of protein recognition and cell signaling events that are the ultimate causes of cell death. In essence, the two major pathways a cell must take upon receiving an insult such as a chemotherapeutic drug, or indeed a mutagenic lesion in any fashion, are (i) to repair the damage, or (ii) or initiate the pathway to apoptosis (programmed cell death). The factors that affect cisplatin cytotoxicity, whether in sensitive or resistant cells, are summarized in Figure 3. DNA damage by chemotherapeutic agents is in many cases mediated through the p53 pathway.47 Cisplatin damage to DNA stimulates apoptosis via a p53-dependent pathway, although in some cell lines or tumor types a p53-independent pathway has been observed.48,49 Resistance to cisplatin is multifactorial and has been shown to be due to a combination of decreased cellular accumulation of cisplatin, increased efflux of platinum from the cell,

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Figure 3 A general scheme for cellular response to platinum-induced DNA damage.

increased cytoplasmic detoxification (through increased levels of cellular thiols such as GSH), or enhanced repair/tolerance of platinum-DNA adducts.50,51 Cellular accumulation of cisplatin is a much more complicated process than previously thoughtboth active and passive diffusion pathways are now thought to exist.52 The establishment of resistant cell lines with characterized and calibrated mechanisms of action has aided greatly in advancing a molecular approach to overcoming resistance.53,54 Coupled with this understanding has been the necessity to understand the fate or metabolism of cisplatin in the biological milieu and explain the pharmacokinetic profile of the drug. For the purposes of this review, the major outlines of the biological understanding will be reviewed with reference to key understandings and most recent comprehensive reviews. The rate-limiting step in DNA binding is aquation of the PtCl bonds. The major products of the aquation of cisplatin are the mono- and bisaqua species cis-[Pt(NH3)2(H2O)Cl] and cis-[Pt(NH3)2(H2O)2]2, respectively (Figure 4). Deprotonation gives inert hydroxo species, which may also form dinuclear and trinuclear hydroxo-bridged species in concentrated solution. Calculation of the pKa of the coordinated water molecules coupled with equilibrium constants for both aquation and deprotonation reactions allows calculation of speciation in biological medium.55,56 The compound, and its direct structural analogs, form adducts between neighboring guanine residues on DNA, forming d(GG) 1,2-intrastrand and d(GC) interstrand cross-links, shown schematically in (Figure 5). Minor lesions, which have consequently received somewhat less attention, are 1,2-intrastrand crosslinks formed between an adenine and a guanine in a d(AG) adduct as well as a 1,3-intrastrand crosslink where two platinated guanines are separated by one base paird(GNG).
1+

L Pt k1a L Pt L' Cl k1b L Pt L' Cl L'

OH2 Cl

k2a
2+

L Pt L' Cl 1+ k2b

OH2 OH2

OH2

Figure 4 Hydrolysis scheme for cisplatin-based anticancer agents. Where L L0 NH3 cisplatin is indicated. When L NH3 and L0 2-picoline or cha the rates of aquation of the trans-chloride ligands are different.

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Bifunctional cisplatinum DNA adducts

1,2-Intrastrand cross-link

1,3-Intrastrand cross-link

Interstrand cross-link

Bifunctional transplatinum DNA adducts

Interstrand cross-link

Interstrand cross-link

Figure 5

Schematic depiction of cross-links formed by both cis- and trans-platin.

The application of {1H,15N}HSQC NMR techniques has proven to be very informative in elucidating detailed kinetic parameters for both aquation and DNA-binding processes. Platinated DNA may be observed at low (mM) concentrations because only 1H and 15N resonances derived from platinum am(m)ine species are seen and the 15N shifts are strongly influenced by the trans ligand.57,58 The monoaquated species is the most likely reactant with DNA, although evidence has also been put forward for the importance of the cis-[Pt(NH3)2(H2O)2]2 species in this regard.59 The hydrolysis of carboplatin involves the displacement of the chelating cyclobutane-1,1-dicarboxylate from the coordination sphere and is unsurprisingly very slow. In the presence of acid, the process resembles the successive displacement of two monodentate carboxylates.60 In keeping with the kinetic inertness of carboplatin, significantly higher doses are required for both equivalent levels of DNA platination compared to cisplatin and also to generate equitoxic and equivalent antitumor effectsclinical doses are 800900 mg/m2.36 The benefit, of course, is reduced nephrotoxicity as the drug may be excreted essentially intact. The well-known affinity for sulfur binding of PtII has led to detailed study of interactions with GSH, metallothionein, and human serum albumin.61,62 Interestingly, direct substitution of the PtCl bonds by sulfur donors such as cysteine and GSH, without the necessity for prior aquation, is indicated from kinetic studies.63,64 Eventually, binding of the thiolate also results in displacement of the ammonia ligands by chelation of the tripeptide moiety.65 Novel binding modes involving N-ligation from deprotonated amide bonds as well as sulfur have been deduced from the reaction of [PtCl2(en)] (where en ethylene 1,2 diamine) and GSH.66 Platinum-thiolate species [Pt-RS] display a great tendency to form dinuclear bridging structures {Pt-"(RS)-Pt} as the bound thiolate is even more nucleophilic than free ligand.67 The crystal structure of [Pt2("-Nacetylcysteine)2(2,20 -bipyridine)2] confirms the bridging propensity of thiolate.68 Methionine metabolites such as [Pt(Met-S,N)2] have been identified from the urine of cisplatin-treated patients, emphasizing the importance of this amino acid in the biotransformation of the drug.69 The mechanism of formation has been studiedthe metabolite exists predominantly as the cis isomer (cis:trans 87:13).70 Methionine interactions with carboplatin and the formation of a stable ringopened species may provide a chemical understanding of the activation of this inert drug.71 A combination of 2D NMR techniques, chemical modification of the protein, and gel filtration chromatography identified the dominant binding site on Human Serum Albumin (HSA) as involving methionine rather than the expected Cys-34.62 The propensity of platinum binding to sulfur has also led to use of sulfur compounds as rescue agents in cisplatin toxicity.63 In these cases, a balance must be found between overcoming toxicity and reduction of antitumor efficacy through competitive binding. The binding of Pt to DNA is irreversible and is kinetically controlled. Platinum may be removed from DNA by strong nucleophiles such as CN. NMR methods have also provided new insight into

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the kinetics and mechanism of DNA binding by cisplatin and other mononuclear analogs. The sequence dependence on the rate constants for monofunctional and bifunctional adduct formation have been cataloged.72 The structural consequences of bifunctional binding for the major intrastrand and interstrand adducts have now been elucidated in great detail (Figure 6).73 The requirement to bind two adjacent guanines on the same strand of DNA to form the intrastrand adduct, whilst maintaining the square-planar geometry of PtII, places considerable steric restraints on the final structure. Molecular and biological studies have confirmed that the principal effect of bifunctional intrastrand binding to DNA is a bending of the helical axis toward the major groove exact measurements of bending angle vary to some extent with technique but a typical value of approximately 3035 is often quoted from gel electrophoresis studies.72 The high resolution X-ray crystal structure of the 1,2-intrastrand adduct in the sequence d(CCTCTG*G*TCTCC)_d(GGAGACCAGAGG) shows the helix bending of approximately 50 toward the major groove.75 The DNA is a mixture of conformationsB-form on the 30 -side of the adduct and the more condensed A-form on the 50 -side. In agreement with the possibility that the A-form is induced by crystal packing forces or the concentrations of cations in the crystallization procedure, the DNA remains in the B-form in solution.76 The d(ApG) adduct appears to be similarly kinked.77 Spectroscopic (especially NMR) studies on the sequence dependence of the adduct have been reviewed.72,78,79 Carboplatin, as might be expected, gives the same adducts on DNA as cisplatin since loss of the dicarboxylate produces the same cis-{Pt(NH3)2}2 moiety. Interestingly, the crystal structure of the oxaliplatin adduct of the same dodecanucleotide shows the overall geometry to be very similar to the cisplatin case, with a bending of approximately 30 toward the major groove. The enantiomerically pure (R,R)-dach ligand results in a hydrogen bond between the pseudoequatorial NH hydrogen and the O-6 atom of the 3-guanine, emphasizing the importance of chirality in mediating biological properties.80 These results confirm the findings that the oxaliplatin-induced damage of cellular DNA and its consequences are very similar to those of cisplatin.81,82 The interstrand cross-link also induces DNA bending.72 X-ray and NMR studies on this adduct show that platinum is located in the minor groove and the cytosines of the d(GC) base pair involved in interstrand cross-link formation are flipped out of the helix stack and a localized Z-form DNA is observed.8385 This is a highly unusual structure and very distortingimplications for differential repair of the two adducts have been addressed. Alternatively, the interstrand cross-link of the antitumor inactive trans-DDP is formed between a guanine (G) and its complementary cytosine (C) on the same base pair.86,87trans-DDP is sterically incapable of producing 1,2-intrastrand adducts and this feature has been cited as a dominant structural reason for its lack of antitumor efficacy. It is clear that the structural distortions induced on the DNA are very different and likely to induce distinctly different biological consequences. Cisplatin-adducted DNA is recognized by a host of proteins.52,72,73,88,89,90 Two general classes of protein may be identifiedthose that specifically recognize the platinated sites as a first step in their repair, and those that bind to such sites because of structural similarity to the proteins natural binding sites. DNA repair occurs primarily through the nucleotide excision repair pathway and proteins of the first class include the human excision repair complex, mismatch repair proteins, XPA, and RPA (single stranded binding proteins involved in DNA replication and repair) proteins. DNA damage induced by cisplatin is recognized by proteins containing the

B-DNA

1,2-Intrastrand cross-link

1,2-Interstrand cross-link

Figure 6 (see color plate 10) Structures of the major cisplatin/DNA adducts.

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so-called high mobility group (HMG) domain motif. The exact function of these nuclear but extrachromosomal DNA binding proteins is still a matter of debate but they bind strongly to unusual noncanonical DNA structures, such as cruciform DNA.91 A common feature of all HMG domain proteins is their ability to bend DNA. Several HMG domain proteins recognize cisplatin-DNA adducts but not those of the clinically ineffective adducts of trans-DDP or the monofunctional [PtCl(dien)] (where dien diethylenetriamine). This preferential recognition has led to the suggestion that proteins with high binding affinity for cisplatin-damaged DNA may shield the polynucleotide from cellular repair. The structural characterization of the recognition motifs of HMG protein and cisplatin-adducted DNA give insight into the molecular details of protein recognition.92 Domain A of the structure-specific HMG-domain protein, HMG1, binds to the widened minor groove of a 16-base pair DNA duplex containing a site-specific 1,2-GG intrastrand cross-link. The DNA in the protein complex is bent significantly further than in the Pt-DNA adduct alone, and a phenylalanine moiety intercalates into a hydrophobic notch created at the platinated d(GpG)-binding site. The importance of an intercalating protein residue such as phenylalanine in forming the bend and in contributing to the affinity toward platinated DNA was confirmed by sitedirected mutagenesis where removal of the intercalating moiety reduced binding affinity.93

9.18.2.2

Platinum Compounds in Clinical Trials

The need for new agents in cancer chemotherapy is apparent from the inability to predictably cure or induce remissions in common tumors such as breast, lung, colon, or prostate cancer. New cytotoxic agents building on our experience and knowledge of the current armamentarium continue to play an important role in the clinical management of cancer. Approximately 28 direct structural analogs of cisplatin entered clinical trials but most have been abandoned through a combination of unacceptable toxicity profile and/or lack of improved or expanded anticancer efficacy.38 For new, direct structural analogs of cisplatin to find clinical use exceptional properties would need to be found.38 Currently, there are three principal drugs ((6)(8); Figure 7) in clinical trialsthe approaches to their development represent examples of steric control of reactivity, control of oxidation state and ligand lipophilicity aimed at producing orally active agents, and manipulation of new structures to produce structurally new DNA adducts.

9.18.2.2.1

AMD473 (ZDO-473)

As understanding of the mechanisms of platinum resistance has increased, more rationally designed platinum derivatives have been synthesized. One approach has been to insert steric

O O H3N Pt N H2 O Cl Cl O (6) (JM-216) H3N Pt N Cl CH3 (7) Cl

4+ H3N Pt Cl NH3 H 3N NH2(CH2)6H2N Pt NH2(CH2)6H2N NH3 H3N Pt NH3 Cl

( 8) (BBR3464)
Figure 7 Platinum-based drugs in clinical trials.

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bulk at the platinum center to retard the kinetics of substitution in comparison to cisplatin.94,95 AMD473 (cis-[PtCl2(NH3)(2-methylpyridine)], also known as ZDO-473 (7)) (AnorMED; http:// www.anormed.com) is a molecule that was designed specifically to circumvent thiol-mediated drug resistance by sterically hindering its reaction with GSH while retaining the ability to form cytotoxic adducts with DNA.96 GSH competes for platinum binding and may diminish DNA platination, thus reducing cytotoxicity. The rate of aquation of AMD473 is 23 times slower than that of cisplatin,97 and interstrand cross-link formation is much slower. The DNA binding is similar to cisplatin, and the complex forms a highly stereoselective adduct on DNA, but not for reactions with mono- and dinucleotides.98 In cell lines with previously determined mechanisms of cell resistance, AMD473 showed little cross-resistance compared with cisplatin or carboplatin. This partial or complete circumvention of acquired platinum drug resistance makes this a promising compound for clinical development. It is currently undergoing phase II trials where it has shown linear pharmacokinetics and evidence of antitumor activity in ovarian cancer patients. It has a manageable side effect profile; the dose-limiting toxicity was a reversible, dose-dependent thrombocytopenia. Nonhematological toxicities (nausea, vomiting, and metallic taste) were mild. No nephrotoxicity, peripheral neurotoxicity, or ototoxicity has been observed.99

9.18.2.2.2

JM-216 (Satraplatin)

Another avenue in platinum chemistry is to manipulate chemical and biological properties through oxidation number. Indeed, the early Rosenberg studies recognized the PtIV complex cis-[PtCl4(NH3)2] as an active anticancer agent.33 A number of PtIV compounds have since undergone clinical trialsincluding cis-[PtCl4(1,2-dach)], known as tetraplatin, and cis,cis,cis[PtCl2(OH)2(PriNH2)2], known as CHIP or Iproplatin. These compounds have been abandoned because of either undesirable side effects or lack of a significantly enhanced therapeutic range compared to cisplatin.38 Potential oral activity of JM-216 (6) is achieved by carboxylation of the Pt-OH groups as well as replacement of one NH3 group by the more lipophilic cyclohexylamine (cha). Interestingly, trans-PtIV compounds were also tested because their kinetic inertness give more reasonable in vivo activity than their analogous PtII compounds (see Section 9.18.2.2.4).100 The cytotoxicity is dependent on the reduction potential of the PtIV compound, allowing suitable modification of pharmacokinetic parameters.101 Biological reducing agents, however, such as GSH, reduce PtIV readily.102,103 The general synthetic scheme for JM-216 is shown in Figure 8104 In practice use of I in the first step to give cis-[PtCl(I)(NH3)(cha)] (mixture of isomers) followed by conversion to the dichloride greatly facilitates synthesis.

H3N Pt Cl

Cl Cl

cha

H3N Pt cha

Cl Cl

H2O2 O O H3N Pt cha O Cl Cl O (6) (JM-216)


Figure 8 Preparation of JM-216.

O R O

O R OH H3N cha OH Pt Cl Cl

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Despite the reputed inertness of PtIV compounds, JM-216 undergoes rapid biotransformation in human red blood cells.105 The PtII complex cis-[PtCl2(NH3)(cha)] is the major metabolite.106 The consequences of DNA binding are again similar to those of cisplatin, as expected from the general similarity of the cis-dichlorodiam(m)ineplatinum structure.107 An interesting difference between the cha and pyridine groups is that in the former case stereoisomers are seen in the 1,2intrastrand adductthe cha group may reside either on the 30 or 50 end of the duplex. The cytotoxicity of both the PtII and PtIV compounds has been examined extensively. The compound was well tolerated orally.108,109 Interest has recently been revived in this agent.

9.18.2.2.3

Poly (di and tri)-nuclear platinum complexes

All direct structural analogs of cisplatin produce a very similar array of adducts on target DNA and it is, therefore, not surprising that they induce similar biological consequences. This latter consideration led to the hypothesis that development of platinum compounds structurally dissimilar to cisplatin may, by virtue of formation of different types of Pt-DNA adducts, lead to compounds with a spectrum of clinical activity genuinely complementary to the parent drug.110113 In terms of cellular biology, the cell signals (structure and conformation of Pt-DNA adducts as outlined in Figure 3) must be altered to produce different cell signaling and protein recognition and induction effects downstream of the platination event, which may be eventually reflected in an altered pattern of antitumor activity. Polynuclear (dinuclear and trinuclear) bifunctional DNAbinding agents are amongst the best studied of these nonclassical structures. The class as a whole represents a second, distinctly new structural group of platinum-based anticancer agents. The first example of this class to advance to clinical trials is BBR3464 ((8), Figure 7). The dinuclear structure is extremely flexible and capable of producing a wide series of compounds differing in functionality (bifunctional to tetrafunctional DNA-binding), geometry (leaving chloride groups cis or trans to diamine bridge), as exemplified in Figure 9.114 Further systematic variations on nonleaving groups in the Pt coordination spheres (NH3 or a planar group such as pyridine or quinoline) and linker (flexible, variable chain length) are also possible.115 The patterns of DNA modification induced by the various structural motifs have been examined and further related to cytotoxicity and antitumor activity.116,117 The necessity to concentrate on a limited number of compounds identified the 1,1/t,t series (see Figure 9 for explanation of this nomenclature) as having the most promising pattern of antitumor activity and DNA-binding. Linker modifications have produced most success in terms of enhanced cytotoxicity. The presence of charge and hydrogen bonding capacity within the central linker (either in the form of a tetraamineplatinum moiety, or a charged polyamine linker such as spermidine or spermine), Figure 9b, produces very potent compounds significantly more cytotoxic than the simple dinuclear species. Their biological activity varies with chain length and charge, although the overall profile is similar.

(i) BBR3464. A trinuclear platinum clinical agent The first polynuclear drug to enter clinical trials (in June 1998), and the first platinum drug not based on the cisplatin structure, is the trinuclear compound denominated BBR3464 ((15), Figure 9b). The structure, derived from general structures of trinuclear systems118 is notable for the presence of the central Pt, which contributes to DNA affinity only through electrostatic and hydrogen bonding interactions. The 4 charge, the presence of at least two Pt coordination units capable of binding to DNA, and the consequences of such DNA binding are remarkable departures from the cisplatin structural paradigm. In tissue culture, BBR3464 is cytotoxic at 10100-fold lower molar concentrations than cisplatin and displays activity in cisplatin-resistant cell lines.119 The profile of antitumor efficacy mirrors its unique structure and is characterized by activity in human tumor (e.g., ovarian) xenografts resistant to cisplatin and alkylating agents.120 Importantly, BBR3464 also consistently displays high antitumor activity in human tumor xenografts characterized as mutant p53.121 These tumors are historically insensitive to drug intervention. This important feature suggests that the new agent may find utility in the over 60% of cancer cases where mutant p53 status is indicated. Consistently, cytotoxicity displayed in mutant cell lines would suggest an ability to by-pass this pathway. In agreement, transfection of p53 into p53-null SAOS osteosarcoma cells resulted in a marked reduction in cellular

820

Metal Complexes as Drugs and Chemotherapeutic Agents


Cl Pt Cl NH2(CH2)6H2N
(9)(2,2/c,c )

NH3

H 3N Pt

Cl

Cl

2+ H3N Pt H3N NH2(CH2)6H2N


(10)(1,1/c,c )

2+ Cl Pt NH3 H3N Pt NH2(CH2)6H2N


(11)(1,1/t,t)

Cl

Cl Pt

NH3

Cl

NH3

H 3N

NH3

1+ H3N Pt H3N NH2(CH2)6H2N


(12 )(1,2/c,c )

Cl

H3N Pt

Cl

1+ Cl Pt NH3 H 3N Pt NH2(CH2)6H2N
(13)(1,2/t,c )

Cl

Cl

H3N

Cl

NH3 Cl Pt NH3 Y

NH3 Pt NH3 Cl

2+
(14) Y =

H2N

NH2

(15 ) Y =

H2N

NH3 N Pt H2 NH3 H2 N

H2 N

4+ NH2

(BBR3464)

(16) Y =

H2N

4+ N H2 3+ NH2 NH2

(17) Y =

H2N

H2 N

Figure 9 (a) Variation of structures of dinuclear platinum complexes depending on the coordination sphere of the platinum. The structural notation describes the number of chloride ligands at each platinum center, followed by the position of the leaving group at each site (cis or trans) with respect to the N atom of the bridging diamine. (b) Variation of linker diamine within one class of dinuclear complexes producing both the trinuclear structure and polyamine-bridged species.

Metal Complexes as Drugs and Chemotherapeutic Agents

821

sensitivity to BBR3464 but only a slight sensitization to cisplatin. In addition, in contrast to cisplatin, the triplatinum complex was a very effective inducer of apoptosis in a lung carcinoma cell line carrying mutant p53. Cell cycle analysis showed a dose-dependent G2/M arrest by BBR3464.122 In phase I clinical trials 47 patients, all of whom had previously failed standard treatments for solid tumors, received the drug in the UK, Italy, and Switzerland on three different schedules.123,124 Dose-limiting toxicities have been defined as bone marrow depression and diarrhea. The latter is treatable with loperamide. Signs of biological activity were seen. Notably one patient with metastatic pancreatic cancer showed a partial response (for 4 months) and two further patients, one with metastatic melanoma and one with bronchoalveolar carcinoma, also showed partial responses. In a phase I trial in combination with 5-FU, a partial response in breast cancer was observed.125 Furthermore, a reduction in tumor marker levels was observed in two patients, one with ovarian cancer, and one with colon cancer. Phase II studies have shown partial responses in cisplatin-resistant ovarian and nonsmall-cell lung cancer.126,127 The indications are that the profile of clinical activity is different and complementary to the mononuclear platinum agents. Cellular pharmacology studies showed enhanced cellular uptake of the charged polynuclear platinum compounds in comparison to cisplatin.128,129 This in itself is very surprising given that the classical structureactivity paradigms for platinum agents require complex neutrality. The enhanced uptake is not sufficient to explain, by itself, the increased cytotoxicity of BBR3464. Formation of BBR3464-induced interstrand cross-links in L1210/0 (murine leukemia) and U2-OS (human osteosarcoma) cells peaks at the earliest time points observed. Their persistence over time and very slow removal suggests that they are not good substrates for DNA repair. The cellular response of HCT116 (human colon tumor) mismatch repair-deficient cells was consistent with a lack of influence of mismatch repair status on BBR3464 cytotoxicity.121

(ii) DNA binding of polynuclear platinum compounds The polynuclear platinum compounds stand in vivid contrast to mononuclear platinum complexes because the predominant DNA lesions are long-range inter- and intrastrand cross-links where the sites of platination may be separated by up to four base pairs. The consequent structural and conformational changes in DNA are also distinct.

(iii) Aquation of dinuclear and trinuclear platinum agents The hydrolysis profile of platinum complexes with monofunctional [Pt(amine)3Cl] coordination spheres (e.g., mononuclear complexes such as [PtCl(dien)] or [PtCl(NH3)3] and the 1,1/t,t and 1,1/c,c dinuclear compounds of (Figure 9) differs from that of cisplatin.130 The aquation rate constant is comparable, but the reverse chloride anation rate constant is much higher so that the equilibrium favors the chloro form.131 For the dinuclear diaqua complex [{transPt(H2O)(NH3)}2"-(H2N(CH2)6NH2)]4 the pKa of the aqua ligands (pKa 5.62) is much lower than in cis-[PtCl(H2O)(NH3)2] (pKa 6.41). For the trinuclear compound BBR3464 the aquation rate constant is comparable to the dinuclear analog, but the chloride anation rate constant is lower so that there is a significantly greater percentage of aquated species ($30%) present at equilibrium. The pKa of 5.62 for the aqua ligands is identical to the dinuclear case. Based on the calculated equilibrium and dissociation constants, and assuming physiological pH (7.2), the maximum tolerated dose (MTD) of BBR3464 in patients corresponds to 1.8 108 M and at an intracellular chloride concentration of 22.7 mM the drug will be 98.7% in the dichloro form at equilibrium. In blood plasma, at a [Cl] of 103 mM only 0.3% of the total is aquated.132

(iv) Reactions with oligonucleotides Global DNA binding of polynuclear platinum compounds is characterized by very rapid binding, a high level of DNADNA interstrand cross-links, unwinding of supercoiled plasmid DNA typical of bifunctional DNA binding, and a sequence specificity different from that of cisplatin.133,134 Strong sequence preference for single dG or d(GG) sites was found and molecular modeling suggested various possible adducts including 1,4-(G,G) and 1,6-(G,G) interstrand and 1,5-(G,G) intrastrand cross-links, which were similar in energy (Figure 10).

822

Metal Complexes as Drugs and Chemotherapeutic Agents

1,4-Interstrand cross-link

1,5-Interstrand cross-link

1,6-Interstrand cross-link

Figure 10 (see color plate 11) Structures from molecular modeling of the major DNA adducts of BBR3464.

Due to the charged nature of polynuclear platinum complexes, ranging from 2 to 4, it is not surprising that binding to DNA occurs significantly more rapidly than for cisplatin. The binding of polyamine-bridged dinuclear compounds is even faster than BBR3464, suggesting strong preassociation or electrostatic binding prior to covalent attachment. Conformational changes characteristic of the B ! A and B ! Z transitions have been observed in poly(dG)poly(dC) and poly(dG-dC)poly(dG-dC) modified by all polynuclear platinum compounds.135138 Ethidium bromide binding favors the B-form of DNA, and intercalation into Z-DNA induced by NaCl or [Co(NH3)6]3 results in reversal to the B-form.139 In contrast, intercalation into A- and Z-form DNA induced by dinuclear or trinuclear platinum compounds is inhibited indicating that the conformational changes are essentially irreversible. The ability to maintain unusual DNA conformations in solution is a unique characteristic of polynuclear platinum compounds. Induced A-like conformations in vivo are theorized to be control mechanisms for DNA binding proteins like transcription factors.140 The biological function of Z-DNA is still not clearly defined;141 but Z-DNA is known to form in the wake of RNA polymerase as DNA is transcribed.143 The conformational locking into either A- or Z-form by polynuclear platinum compounds is likely to have profound effects on DNA function. Antibodies raised to cisplatin-DNA adducts do not recognize DNA adducts of dinuclear or trinuclear compounds. An interesting and potentially important finding is that BBR3464 is preferentially bound to single-stranded rather than double-stranded DNA.143 Comparison of single-stranded DNA, RNA, and duplex DNA indicated that the reaction of BBR3464 with single-stranded DNA and RNA was faster than with duplex DNA, and produced more drugDNA and drugRNA adducts. BBR3464 binding to different nucleic acid conformations raises the possibility that the adducts of single-stranded DNA and RNA may play a role in the different antitumor efficacies as compared with cisplatin. Single-stranded DNA is present during transcription, replication, recombination, and repair and is recognized by various single-stranded DNA binding proteins. The kinetics of the reaction of the self-complementary 12-mer duplex d(50 -A1T2ATGTA7CATAT-30 )2 with 15N labeled [{trans-PtCl(NH3)2}2"-(H2N(CH2)6NH2)]4 and BBR3464 indicated the formation of 1,4-interstrand cross-links.144,145 Initial preassociation or electrostatic binding to DNA is observed in both cases, as deduced by chemical shift changes in presence of DNA immediately upon mixing. The time scale of the NMR experiment makes the weak preassociation of cisplatin difficult to observe, although it may be observed with techniques such as quartz crystal microbalance and mass spectrometry. The former system permits direct, real time detection of interactions between platinum complexes and surface immobilized oligonucleotides (in this case 50 -GGGAAGGATGGCGCACGCTG-30 ).146 The closure rates to form bifunctional adducts are significantly faster than the rate of closure to form a 1,2 GG intrastrand cross-link by cis[Pt(H2O)2(NH3)2]2. For the dinuclear compound, consideration of the 1H {Guanine H(8)} and 15 N shifts of the interstrand cross-link showed that an initially formed conformer converts into another nonreversible final product conformer.

Metal Complexes as Drugs and Chemotherapeutic Agents

823

The 1,4-interstrand cross-link of BBR3464 with the self-complementary 50 -(ATGTACAT)2-30 has been characterized and analyzed by MS and CD, UV and NMR spectroscopy.147 The alternating purinepyrimidine sequence mimics the structural requirements for Z-DNA. NMR analysis of the adduct shows the strong H8/H10 intraresidue cross-peaks for the platinated guanine residues, consistent with a syn conformation of the nucleoside. More interestingly, a strong H8/H10 intraresidue cross-peak for the A7 resonance is also consistent with a syn conformation for this base which is usually not observed for adenine residues and bases not directly involved in the cross-link in oligonucleotides. Within the sequence covered by the cross-link, the bases appear to be a mixture of syn and anti and Watson-Crick hydrogen bonding is maintained. The central platinum unit resides in the minor groove. The observation of an altered conformation (Adenine N7 syn) outside the binding site is unique and suggests the possibility of delocalized lesions beyond the binding site. In contrast, long-range interstrand cross-linking agents such as CC-1065 and Bizelesin do not show conformational changes beyond the environment of the binding sequence.148150 These unusual cooperative effects are unique to this class of anticancer drug and are the first demonstration of cooperative effects in solution for an anticancer drug.

(v) Site-specific intrastrand and interstrand cross-links of BBR3464. Bending, protein recognition and nucleotide excision repair Oligonucleotide duplexes containing various site-specific intra- and interstrand cross-links formed by both dinuclear [{trans-PtCl(NH3)2}2m-(H2N(CH2)nNH2)]2 and trinuclear compounds have been prepared. The 1,2-intrastrand cross-link with one Pt unit each attached to two adjacent guanines is formally the structural analog of the most prominent adduct formed by cisplatin. The dinuclear intrastrand adducts distorted the DNA conformation in a way different from those seen for adducts of cisplatin151153 Bending induced in DNA by dinuclear interstrand cross-links is not directed, and at approximately 1012 is much less than that of cisplatin, as was duplex unwinding (9 vs. 13 , respectively). As a result, gel retardation assays revealed only very weak recognition of DNA adducts by HMG1 protein.154 For BBR3464 intrastrand site-specific adducts were also prepared which create a local conformational distortion but without a stable curvature.155 Again, no recognition by HMG1domA and HMG1domB proteins was evident and it is clear that the intrastrand DNA adducts of BBR3464 may present a block to DNA or RNA polymerases but are not a substrate for recognition by HMG-domain proteins. In general, DNA interstrand cross-links could be even more effective lesions than intrastrand adducts in terminating DNA or RNA synthesis in tumor cells and thus could be even more likely candidates for the genotoxic lesion relevant to antitumor effects of BBR3464.156 In addition, the interstrand cross-links pose a special challenge to repair enzymes because they involve both strands of DNA and cannot be repaired using the information in the complementary strand for resynthesis.157 Unlike the intrastrand adduct, the interstrand cross-link is a poor substrate for nucleotide excision repair. These results validate the finding that overexpressing the human nucleotide excision repair complex (ERCC1) was not detrimental to the cellular sensitivity of BBR3464 in two ovarian cancer cell lines.158 These findings in sum suggest that these structurally distinct compounds produce a profile of DNA damage that is quite distinct from that of cisplatin. Lack of recognition by proteins which bind avidly to cisplatin-damaged DNA suggest that the mediation of antitumor properties of polynuclear platinum compounds by cisplatin-like processes is unlikely. Thus, the structural paradigm for antitumor activity based on the cisplatin structure is no longer validclinically useful compounds may arise from study of new structures. Following this work, new dinuclear compounds based on heterocycle azole and 4,40 -dipyrazolylmethane bridges have also been described ((18)(20), Figure 11).159161 These agents again give a different spectrum of activity to the dinuclear complexes with flexible diamine linkers.

9.18.2.2.4

Transplatinum compounds

The earliest structureactivity relationships indicated that the transplatinum geometry is inactive significantly higher doses must be given before any therapeutic effect is seen. In 1991, it was reported that alteration of amine structure and the introduction of sterically hindered amines produced cytotoxicity similar to that of cisplatin.162 The first examples used planar amines and a variety of trans-[PtCl2(L)(L0 )] compounds have been synthesized and evaluated ((21)(26), Figure 12).163

824

Metal Complexes as Drugs and Chemotherapeutic Agents

Cl Pt H3N

NH3 N HN (18 )

H3N Pt N NH

Cl NH3

2+

2+

H3N Pt H3N

N N Pt O H (19)

NH3 NH3

N NH3 H3 N N N Pt Pt H3N NH3 O H (20)

2+

Figure 11 Dinuclear platinum compounds based on heterocycle bridges.

In general, the cytotoxicity of these compounds was equivalent to cisplatin, and they maintained their activity in cisplatin-resistant cells. In many cases the activity of a trans complex was actually comparable to that of the cis isomer.164 Later these general observations were confirmed for a range of complexes in the trans geometry; examples of carrier ligands now include cha, iminoethers, piperazine, and piperidine, as well as sterically hindered primary amines such as isopropylamine.165169 While their in vitro cytotoxicity is clearly comparable with cisplatin, no exceptionally active compounds in vivo have been prepared. This fact may reflect some pharmacokinetic problems still associated with the trans geometry. While most emphasis on the differences between cis- and trans-platin has centered on the structures of their DNA adducts, the different chemistry of the complexes themselves may also be important. This point is emphasized by the enhanced antitumor activity of the PtIV compound (27) over its cytotoxic but antitumor inactive PtII analog, trans-[PtCl2(NH3)(cha)].170 Solubility is still a major issue in the trans complexes; the use of N,O-chelates in complexes such as [PtCl(NH3)(N,O-pyridine-2-acetate)] (compound (28), in which the two N atoms are mutually trans) may solve this problem.171 Nevertheless, formally one may consider that trans-platinum complexes do indeed show in vivo antitumor activity. In the case of complexes such as (21) and (23) which have an extended planar ligand, a significantly higher proportion of interstrand cross-links in DNA is formed in comparison to either cis- or trans-platin.172 The steric effects of these planar ligands result in the formation of structurally unique 1,2-interstrand cross-links like those formed by cisplatin, a unique example of how steric effects may alter a nonactive lesion into an active one (Figure 13).173,174 Model studies predicted this outcome by preparation of the monofunctional models trans-[PtCl(9-ethylguanine) (NH3)(quinoline)] and comparison of substitution rates of the PtCl bond by G or C mononucleotides.175,176 Interestingly, the iminoether compound (25) appears to form predominantly monofunctional adducts with DNA.177 The DNA binding of trans-platinum complexes is thus quite rich and varied. The cellular effects of such adduct formation also appear to be significantly different from those of cisplatin.

Metal Complexes as Drugs and Chemotherapeutic Agents

825

H3N Pt Cl

Cl N S ( 21) Cl Pt N Cl (22) N

Cl Pt N

NH3 Cl

( 23)

Me Cl NH2 H OMe (24) OH Cl Pt N Cl H2 OH ( 27)


Figure 12

OMe N Cl H N Pt NH Cl Cl (26) O

Cl Pt N

Pt NH Cl

Cl Me (25) H2N +

NH3 O Pt H3N Cl ( 28) N

Trans-platinum compounds as potential anticancer compounds.

1,1-Interstrand cross-link L = NH3 (trans-platin)

1,2-Interstrand cross-link L = L'py, tz or L = NH3 or dmso and l' = quin, tz

1,2-Interstrand cross-link L = NH3 (cis-platin)

Figure 13 Interstrand cross-links formed by sterically hindered trans-platinum compounds.

Optimization of the pharmacokinetic profile of trans-platinum compounds may eventually produce a clinically effective agent.

9.18.3 9.18.3.1

NONPLATINUM ANTICANCER AGENTS Ruthenium Complexes

In the early development of analogs of the platinum compounds, complexes with windows of reactivity similar to the platinum complexes were examined extensively. Whereas direct Ni and Pd analogs of Pt complexes are too kinetically reactive to be of use as drugs, Ir and Os ammine

826

Metal Complexes as Drugs and Chemotherapeutic Agents

compounds are in general too inert. Ruthenium and rhodium have produced compounds with the greatest promise, although no direct analogs have yet advanced to the clinic. In ruthenium ammine complexes of the general series [RuCln(NH3)6n]z (where n 3, 4, or 5), fac[RuCl3(NH3)3] showed good activity but was not sufficiently water soluble for extensive testing.178,179 Ruthenium-ammine compounds have a rich DNA chemistry which has been described by Clarke. The guanine N7 site is the preferred binding site for the aqua species [Ru(H2O)(NH3)5]2, but metal migration may occur to other nucleobases.180 GSH modulates DNA binding of Ru-ammine complexes: GSH reduction of the RuIII compound [ClRu(NH3)5]2 to the RuII state enhances its DNA binding, but at [GSH]/[Ru] ratios >1 DNA binding is inhibited through eventual formation of [(GS)(NH3)5RuIII]. Covalent binding of trans-[(H2O)(py)Ru(NH3)4]2 to DNA occurs specifically at guanine N7.181 The pyridine ligand further stabilizes the RuII oxidation state, which may lead to disproportionation of the generated RuIII species to RuII and RuIV species.182 Oxidative damage to DNA through base-catalyzed air oxidation of guanine occurs in the presence of {RuIII(NH3)5}-bound DNA. These and other aspects have been reviewed thoroughly. A wide variety of Ru-based complexes, including carboxylate-bridged di- and trinuclear complexes, exhibit antitumor activity in animal models. The imidazole complexes trans-[RuCl4(L)2] (where L imidazole, indazole) have good antitumor activity.183,184 Transferrin and serum albumin may act as transporters of the metal complexes in blood, and DNA is considered the ultimate target.185 Modification of the structural motif of the DMSO complexes cis/trans-[RuCl2(DMSO)4] with imidazole ligands has led to an interesting clinical candidate, NAMI-A ((29), Figure 14).186 The mechanism of action of this compound is not related to DNA binding; rather, it is an antimetastatic agent.187 Metastasis (the process whereby tumor growth occurs distant from the original or primary tumor site) is intimately linked with angiogenesis, the dynamic process that involves new blood vessel formation. Inhibition of angiogenesis is an attractive approach to antitumor (antimetastatic) therapy.188 NAMI-A is active against lung metastasis in vivo and tumor cell invasion in vitro.189191 The molecular details by which NAMI-A exerts antimetastatic effects in vivo have not been definitely determined, and may occur by multiple mechanisms. The solution chemistry of NAMI-A involves both loss of Cl and DMSO. Interestingly, the antimetastatic activity is retained under a wide variety of experimental conditions producing solvolyzed intermediates.192 The exact nature of the active species may be difficult to resolve. A noteworthy addition to Ru-DNA chemistry is the inhibition of topoisomerase II by the areneRu complex [RuCl2(DMSO)(6-C6H6)].193 Further variations on the arene theme produce cytotoxic compounds of formula [(arene)Ru(en)Cl].194,195 The crystal structure of the 9-ethylguanine adduct [(arene)Ru(en)(9-EtG)]2 shows interesting stacking between the arene and guanine rings.

9.18.3.2

Arsenic Trioxide

Platinum complexes are cytotoxic agents yet the paradigm in cancer chemotherapy has moved to a more targeted approach, with special emphasis on signaling pathways. In this respect a remarkable story is that of arsenic trioxide, As2O3 (Trisenox, Cell Therapeutics Inc, Seattle, USA) which was approved by the FDA in September 2000 for treatment of acute promomyelocytic leukemia (APL) in patients who have relapsed or are refractory to retinoid and anthracycline chemotherapy. An estimated 1,500 new cases of APL are diagnosed yearly in the US, of which an

NH N Cl Ru Cl O S Cl CH3 CH3 (29)


Figure 14 Structure of a potential ruthenium-based antimetastatic agent, NAMI-A.

NH Cl N+ H

Metal Complexes as Drugs and Chemotherapeutic Agents

827

estimated 400 patients will not respond to, or will relapse from, first-line therapy. The approval of arsenic trioxide as a chemotherapeutic agent invokes the pioneering work of Ehrlich and the development of Salvarsan for use in syphilisthe foundation stone for the science of chemotherapy. The use of chelating agents in medicine may even be traced to a collaboration between Werner (the father of coordination chemistry) and Ehrlich (the father of chemotherapy) to find less toxic arsenic compounds for the treatment of syphilis.15 Arsenic has been used therapeutically for more than 2,000 years and was used in the 1930s for treatment of chronic myelogenous leukemia until supplanted by newer chemotherapies.196,197 The past, present, and future of medicinal arsenic has been described as a story of use, dishonor, and redemption. Recent interest in arsenic trioxide initially arose through Chinese reports of its efficacy and use.198 The recommended dose is 0.15 mg kg1 d1 until remission.199 Side effects are cardiotoxicity, skin rashes, and hyperglycemia.200 Arsenic trioxide apparently affects numerous intracellular signal transduction pathways and causes many alterations in cellular function. Thus, the mechanisms of cell death induced by arsenic trioxide are multiple: induction of apoptosis, inhibition of proliferation, and even inhibition of angiogenesis have all been reported.201 In cellular studies, arsenic trioxide inhibits glutathione peroxidase, possibly through generation of arsenicGSH conjugates, and increases cellular hydrogen peroxide content.202 Consistent with a general role in redox processes, ascorbic acid enhances arsenic trioxide-induced apoptosis of lymphoma cells but not of normal bone marrow cells, by increasing cellular H2O2 content.203 Arsenic trioxide sensitivity is associated with low levels of GSH in cancer cells.204 Apoptosis is apparent when cells are treated with low concentrations of the drug; this effect is associated with the collapse of mitochondrial transmembrane potentials in a thiol-dependent manner.205 The combined effects have led to the suggestion that arsenic trioxide may be situated as a novel mitochondriotoxic anticancer agent.206 Membrane potential decreases and membrane permeability increases as a result of arsenic treatment, resulting in the release of messenger molecules for the degradation phase of apoptosis.

9.18.3.3

The Mitochondrion as Target. Goldphosphane Complexes

Apoptosis is important in tissue homeostasis; inhibition of apoptosis may contribute to transformation of cells and/or chemotherapy resistance. The apoptosis factors leading to cell death are mitochondrion-regulated. Mitochondria contribute to the regulation of energy production, metabolism, and redox status as well as apoptosis.207 The integral role of the mitochondrion in programmed cell death is by now well recognized and means that the mitochondrion is a suitable target for drug intervention.208 Mitochondrial DNA is also an attractive target because it is significantly more sensitive to covalent damage than nuclear DNA, because of the lack of protective histones and a limited capacity for repair. The pioneering work of Chen showed that enhanced mitochondrial membrane potential is a prevalent cancer cell phenotype;209 lipophilic cations accumulate inside mitochondria as a consequence of the higher membrane potentials.207 Treatment strategies directed at novel cellular targets but which are differentiated between normal and tumor cells are attractive approaches to selective tumor cell killing. The goldphosphane complexes (30)(33) (Figure 15) are examples of lipophilic cations which may also have a role in mitochondrial toxicity.210,211 Whereas the role of gold salts in antiarthritis therapy is intimately related to thiol binding, the tetrahedral diphosphane compounds are much less reactive toward thiols.212,213 The lipophilic cation [Au(dppe)2] (where dppe 2-bis(diphenylphosphino)ethane) showed potent in vitro cytotoxicity with evidence of antimitochondrial function214 but hepatotoxicity attributed to alterations in mitochondrial function curtailed clinical trials. The solution chemistry of golddiphosphane compounds is rich and the interchange between mononuclear and dinuclear phosphane-bridged species has been extensively examined.57 Substitution of the phenyl groups by 2-pyridyl groups provides an opportunity to investigate systematically the relationship of drug activity to lipophilicity.215,216 Compounds that are highly active in vitro may be obtained. Alteration of the lipophilicity greatly affected cellular uptake and binding to plasma proteins. Alterations in lipophilicity also affect host toxicity, allowing the opportunity for optimization of pharmacokinetic properties.

9.18.3.4

Manganese-based Superoxide Dismutase Mimics

A significant amount of the O2 metabolized by the human organism is converted to the highly reactive superoxide radical anion O2. Endogenous overproduction of O2 may cause considerable

828

Metal Complexes as Drugs and Chemotherapeutic Agents

+ R2P Au X ( 30) PR'2 Au X R 2P Au R 2P ( 31) PR'2 PR'2 R2P Au R2P (32) PR'2 Au PR'2

2+

R2 R2 P P Au P P R2 R 2 (33)

R2 P Au P R2

R2 P P R2

2+

Figure 15 Structures of Auphosphane compounds as potential mitochondrial poisons.

damage to biological systems. Superoxide has been shown to be a mediator of reperfusion diseases, such as those occurring after a stroke, and has been shown to be associated with development of inflammatory processes and also in the initiation of neurological disorders such as Parkinsons disease.217 The enzyme superoxide dismutase (SOD), either as the manganesecontaining MnSOD (present in the mitochondrion) or the dinuclear Cu/Zn-SOD (present in the cytosol and extracellular space), performs the role of superoxide detoxification in normal cells and tissue:218
O2 Mn 2H ! H2 O2 Mn1 O2 M
n1

1 2

! O2 M

Overall:
2O2 2H ! H2 O2 O2 3

Attempts to use the enzyme itself as a therapeutic agent have been partially successful in animals, but not in humans.219 Pharmacokinetic problems, including delivery problems and the short half-life in the blood, are major obstacles to use of the enzyme in humans. Cu/ZnSOD preparations (trade names Palosein, Orotein) are used to treat inflammatory diseases in dogs and horses. Small molecule mimics of natural enzymes such as SOD (dubbed synzymes for synthetic enzymes) may effect similar chemistry and thus be useful in treating disease states brought on by an imbalance in superoxide. The considerations for successful application of this strategy are many: a compound must possess high chemical stability, SOD-like activity, specificity under biological conditions, low toxicity, and favorable biodistribution. Manganese chelate compounds such as (34) and (35), especially those based on cyclam (1,4,8,11-tetraazacyclotetradecane) and N,N0 -bis(salicylaldehydo) ethylenediamine (salen), have shown considerable promise in this regard (Figure 16).220222 Rational design has produced an optimal structure M40403 (35) which is a leading clinical candidate.223,224 This pyridine-based macrocycle has been used as a cancer co-therapy with interleukin-2 (IL-2), an immune-stimulating cytokine drug that is approved for use in metastatic melanoma and renal cell carcinoma. As usual, the utility of IL-2 is limited by side effects, notably hypotension, and hospitalization is necessary for many patients. Preclinical studies have shown that M40403 enhances the efficacy of IL-2. A phase I, double-blind, placebo-controlled clinical trial of M40403 administered intravenously to 36 normal, healthy human subjects showed no dose-limiting side effects. A phase II clinical trial is planned to assess the effectiveness of M40403 as co-therapy with IL-2 in patients with advanced skin and end-stage kidney cancers (http://www.metaphore.com). Interestingly,

Metal Complexes as Drugs and Chemotherapeutic Agents

829

Cl N Mn O A O NH Cl (34)
Figure 16

N NH

N Mn HN HN

(35)
Manganese compounds as SOD mimics.

there is some indication that the salen-based compounds may involve catalase rather than SOD activity (Equation 4):
H2 O2 2H ! 2H2 O 4

9.18.3.5

Titanium Compounds

Two titanium compounds have had clinical trials in Germany. The titanocene compound [TiCl2Cp2] ((36); known as MTK4) and budotitane (37), a -diketonate derivative, are structurally quite different compounds (Figure 17). Little information is available on the mode of action of budotitane which is formulated in a mixture of glycols and water because of a lack of aqueous solubility.225 Budotitane exists as a mixture of three cis isomers (37ac) in thermal equilibrium, so that no isomerically pure species have been isolated.226 Hydrolysis of the ethoxy groups is rapid the formulation slows this down and prevents formation of oligomeric oxo-bridged complexes. The MTD of budotitane was 230 mg m2 and the dose-limiting toxicity was cardiac arrhythmia.227 The poorly defined aqueous properties and lack of details on the mechanism of action do not bode well for this drug. The phase I clinical trial of [TiCl2Cp2] indicated a MTD of 315 mg m2 for a single intravenous infusion, and 185 mg m2 weekly.228 The dose-limiting toxicity was nephrotoxicity.229 A phase II trial in renal cell cancer concluded that no advantage was gained by use of [TiCl2Cp2].230 Modifications on the basic [TiCl2Cp2] structure have included metal modification, Cp and leaving group (Cl) substitution, as well as use of ionic metallocenes for improving aqueous solubility.231

R1 R2 Cl Ti Cl R4 O O O O R3 (36) (37) a: R1 = R3 = Me; R2 = R4 = Ph b: R1 = R3 = Ph; R2 = R4 = Me c: R1 = R4 = Me; R2 = R3 = Ph


Figure 17 Titanium anticancer agents that have undergone clinical trials.

Ti

OEt OEt

830

Metal Complexes as Drugs and Chemotherapeutic Agents

DNA is purportedly the target of [TiCl2Cp2]. The somewhat na ve early assertion that it could act in a manner similar to cisplatin because of the similarity in ClCl distances has never been upheld experimentally.232,233 Instead the aqueous chemistry of [TiCl2Cp2] is dominated by loss of the Cp ring as well as hydrolysis of the TiCl bonds. DNA interactions at pH 7 are very weak and the adducts when formed do not suppress DNA-processing enzymes so there is doubt as to whether DNA is the locus of action for these drugs. TiDNA interactions are dominated by interaction with the phosphodiester backbone. Other biological effects observed for [TiCl2Cp2] include inhibition of protein kinase C and DNA topoisomerase II activity, as well as inhibition of collagenase type IV activity, suggesting some antimetastatic behavior. Titanium may also replace iron in transferrin, allowing a possible uptake mechanism into tumor cells.234

9.18.3.6

Gallium Nitrate

The principal, approved use of Ga(NO3)3 (Ganite, gallium nitrate) is in treating hypercalcemia of malignancy, by reducing the elevated Ca2 in blood.235 This disorder is often associated with bone cancers and is an acute-care condition in which rapid bone loss leads to life-threatening levels of blood calcium. Gallium reduces the rate of bone loss by inhibition of the action of osteoclasts, which produce acid onto the bone surface dissolving mineral and protein components. Inhibition of this proton pump is thus a well-defined mechanism of action for gallium. Relatively low levels (200 mg m2 day1) are effective. At therapeutic doses, it has few side effects and is well tolerated. Most recent attention has focused on the activity of gallium nitrate against malignancies, especially non-Hodgkins lymphoma, non-squamous cell carcinoma of the cervix, and bladder cancer. Clinical trials under the auspices of Genta (http://www.genta.com) will evaluate its efficacy on patients with low- or intermediate-grade non-Hodgkins lymphoma who have failed prior chemotherapy. The results of phase II trials in non-small-cell lung cancer and prostate cancer have also been reported.236,237 Gallium compounds may be designed to deliver the Ga3 cation more effectively or selectively. Combination with bisphosphonates has been suggested to improve oral availability of gallium. Chelating agents such as 8-hydroxyquinoline,238 thiosemicarbazones239 and pyridoxal isonicotinoyl hydrazone (Ga-PIH)240 give well-defined GaIII complexes.

9.18.4 9.18.4.1

ANTIBACTERIAL AGENTS Silver and Mercury Salts

Silver and mercury salts have a long history of use as antibacterial agents.241243 The use of mercurochrome ((40), Figure 18) as a topical disinfectant is now discouraged. Silver sulfadiazene (38) finds use for treatment of severe burns; the polymeric material slowly releases the antibacterial Ag ion. Silver nitrate is still used in many countries to prevent ophthalmic disease in newborn children.244 The mechanism of action of Ag and Hg is through slow release of the active metal ioninhibition of thiol function in bacterial cell walls gives a rationale for the specificity of bacteriocidal action.

Ag+ N N O N S O (38) COONa NH2 SHgEt (39) NaO O HgOH (40) Br

COONa Br

Figure 18 Silver- and mercury-based antibacterial agents.

Metal Complexes as Drugs and Chemotherapeutic Agents 9.18.4.2 Bismuth-containing Antiulcer Drugs

831

Bismuth compounds have been used for their antacid and astringent properties in a variety of gastrointestinal disorders.245,246 The effectiveness of bismuth is due to its bacteriocidal action against the Gram-negative bacterium, Helicobacter pylori. Usually the bismuth preparations are obtained by mixing an inorganic salt with a sugar-like carrier (see Figure 19). Commonly used agents are colloidal bismuth subcitrate (CBS), and bismuth subsalicylate (BSS). The mechanism of action is complex and includes inhibition of protein and cell wall synthesis, membrane function, and ATP synthesis. The most notable salts are tripotassiumdicitratobismuth, bismuth salicylate, Pepto-Bismol (BSS), and De-Nol (CBS; (41)). The sub designation most likely arose from stoichiometry of oxygen to bismuth. The combination of ranitidine (a histamine H2-receptor antagonist) and bismuth citrate is marketed as Ranitidine Bismutrex for the management of peptic ulcer and ulcers associated with H. pylori.247 Much progress has been made on the coordination chemistry of these preparations. Detailed molecular characterization is obviously of primary importance in understanding chemical and biochemical function. BiIII is highly acidic in aqueous medium and the oxygen-rich nature of the sugar carrier ligands leads to formation of di- and polynuclear-bridged complexes, based on the typical dinuclear unit (41) shown in Figure 19.248251 The nature of the ranitidine/bismuth citrate adduct has been examined and second coordination sphere effects were noted for the organic amine.252 Methylthiosalicylate has also been used instead of salicylate, and discrete complexes (e.g., (42)) have been comprehensively characterized.253,254 Bismuth (III) remarkably forms stable complexes with GSH255 and transferrin.256 The latter observation may be correlated with the high acidity of the BiIII ion.

9.18.4.3

Metal-containing Drugs as Antiparasitic Agents

There remains an urgent need for new effective antiparasitic agents, an area of drug development that has languished because of poor economic return. The spread of resistance to chloroquine (an antimalaria treatment) is one reason for attention to be paid to this area, as well as the sheer numbers of people affected. Antimony compounds (43) and (44) (Figure 20) are used to treat

O O OH OH H2sal HO

OH HO OH

OH HO OH HO OH O

OH

O OH H4cit

OH H4gal

H4tar

O O O O Bi O O O O O O Bi O O O

O MeO O S O MeO (42) S Bi O S OMe

( 41) (basic skeleton only shown for clarity)


Figure 19

Bismuth antiulcer drugsthe sugars used to produce the usually polymeric structures are shown in the top panel.

832

Metal Complexes as Drugs and Chemotherapeutic Agents

O O Sb O O

H C O O C H

H C O Sb O O O

C H (43)

SO3 O Sb

SO3 O SO3

O3S

O (44 )

Figure 20 Antimony-based antiparasitic agents.

leishmaniasis (H. Sun, personal communication). Another approach is to complex metal ions to known antiparasitic agents in attempts to gain selective uptake or selective action of the metal drug conjugate. Gold and ruthenium complexes of chloroquine and clotrimazole have been described ((45) and (46), Figure 21).257260 In favorable cases, some of these compounds show good activitythe chloroquine complexes being useful even in chloroquine-resistant cases.

9.18.5 9.18.5.1

PHARMACODYNAMIC USES OF METAL COMPLEX DRUGS Lithium Carbonate

The clinical value of lithium has been recognized since 1949. Lithium carbonate is used in manic depressive psychoses for the treatment of recurrent mood changes.261,262 Mood stability may only occur after months rather than weeks. The drug is administered orally in doses up to 2 g day1 (30 mmol day1). The serum Li concentration should be in the range of 0.40.8 mmol l1.

+ HN N(CH2CH3)2

Et2N Cl Cl

NH

Ru N Cl Cl N Cl Cl

Cl

N Au PPh3 (45) HN (46) Ru

NEt2

Figure 21 Gold and ruthenium complexes of antiparasitic agents.

Metal Complexes as Drugs and Chemotherapeutic Agents

833

The development of lithium-specific electrodes has assisted greatly in monitoring patient compliance. The toxicity profile of lithium carbonate is now well established and the drug is safely administered and well tolerated. It is of limited use in other psychiatric disorders such as pathological aggression, although additional benefit may also include a reduction in actual or attempted suicide. Newer uses have appeared in the treatment of viral diseases including AIDS, alteration of the immune response, and cancer. The lithium salt of -linolenic acid (LiGLA) has a significant anticancer effect against certain cancers. The neurochemical basis for lithium action is difficult to define. Lithium carbonate induces a wide range of intra- and extracellular changesmost emphasis has been naturally on the similarities with Na/K/Ca/Mg ions. Lithium selectively interferes with the inositol lipid cycle, representing a unified hypothesis of action. The biochemistry, distribution, and cellular localization of lithium has been extensively documented.

9.18.5.2

Vanadium Complexes in Diabetes

The role of vanadium in biological systems in general is of increasing interest.263 The discovery of the insulin-like properties of vanadate ions spurred research into the clinical use of vanadium compounds as insulin mimics.264 Inadequate glucose metabolism, either through absence of endogenously secreted insulin or insulin resistance, leads to diabetes mellitus. The potential of insulin-mimetic compounds as drugs lies in their oral administrationinsulin, as a small protein, is not orally active. The vanadate (V) ion is effective upon oral administration, and an obvious strategy to enhance the pharmacokinetic characteristics and the efficacy of the insulin-mimetic response is complexation of vanadate with suitable biologically compatible ligands.265,266 Insulin binding to the extracellular side of cell membranes initiates the insulin cascade, a series of phosphorylation/dephosphorylation steps. A postulated mechanism for vanadium is substitution of vanadate for phosphate in the transition state structure of protein tyrosine phosphatases (PTP).267,268 In normal physiological conditions, the attainable oxidation states of vanadium are VIII, VIV and VV. Relevant species in solution are vanadate, (a mixture of HVO42/ H2VO4) and vanadyl VO2. Vanadyl is not a strong inhibitor of PTPs, suggesting other potential mechanisms for insulin mimesis for this cation. Both VIV and VV coordination compounds have been tested as insulin mimics. The preponderance of VIV compounds contain the VO(L-L)2 motif (e.g., (47) and (48), Figure 22) and complexes containing a variety of O,O; N,O; N,S; and S,S bidentate ligands LL have been synthesized and tested. Control of lability and ligand displacement are important criteria for drug design in terms of delivery of the biologically active vanadate. Clinical trials have focused to date on sodium orthovanadate and the bis(maltolato)oxovanadium(IV) compound (BMOV) (47). The speciation and aqueous chemistry of BMOV have been described.266

9.18.5.3

Gold Compounds as Antiarthritic Agents

Gold salts have had a long history of use in rheumatoid arthritis.269,270 The development of orally active auranofin (also known as Ridaura; (50), Figure 23) was a major improvement over the early injectable gold preparations which were polymeric (e.g., (51)(53)). However, use has declined with the popularity of nonsteroidal antiinflammatory drugs (NSAIDS) such as indomethacin; a recent estimate of the commercial value for auranofin was $6 million. The mechanism

CH3 O O O O V O O O CH3 (47) C8H17 N H O H2 O H 2 N N V S S (48 )


Figure 22 Vanadium compounds in treatment of diabetes.

O N H C8H17

834

Metal Complexes as Drugs and Chemotherapeutic Agents

SO3 S O3S (49) Au S

3 AcO

CH2OAc O OAc ( 50) OAc

Au(PEt3)

Polymeric [AuRS]n compounds: ( 51) RS = CO2 CH S CH2 CO2


Figure 23 Au antiarthritis compounds.

(52) RS =

( 53) RS = S HO

CH2OH O OH S

O3S

OH

of action is postulated to occur through thiolate exchange reactions.271 The structures of the polymeric gold compounds have been described in detail. An interesting feature of gold metabolism is the production of [Au(CN)2]269 as a metabolite of the gold-thiol compounds.

9.18.5.4

Nitric Oxide in Physiology and Medicine

An intriguing aspect of the role of metal complexes in medicine is the role of NO.272,273 The nitroprusside ion, [Fe(NO)(CN)5]2 is a vasodilator used in emergency situations to treat hypertensive patients in operating theaters.274,275 The complex is 30100 times more potent than simple nitrites. The mechanism is considered to be release of NO, an understanding prompted by the emergence of NO as a prominent cell signaling molecule.273 Related to the biology of NO is production of peroxynitrite ONOO through reaction of NO with O2. In this regard, production of peroxynitrite may play a role in many pathological conditions.276,277 Water-soluble porphyrins and texaphyrins may catalytically react with ONOO and may have clinical utility in peroxynitrite scavenging.

9.18.5.5

Lanthanum Carbonate

Patients with end-stage renal disease hyperphosphatemia ineffectively filter excess phosphate that enters the body in the normal diet.278 Elevated phosphate produces the bone disorder renal osteodystrophy. Skeletal deformity may occur, possibly associated with cardiovascular disease. Calcium deposits may further build up around the body and in blood vessels creating further health risks. The use of lanthanum carbonate is being promoted as an alternative to aluminumbased therapies.279,280 Systemic absorption, and cost have produced a clinical candidate, Fosrenol (AnorMED), an intriguing use of a lanthanide compound in therapy.

9.18.6

REFERENCES

1. Farrell, N. P. Transition Metal Complexes as Drugs and Chemotherapeutic Agents; James, B. R.; Ugo, R., Ed.; ReidelKluwer Academic Press: Dordrecht, 1989; Vol. 11. 2. Farrell, N. P. The Uses of Inorganic Chemistry in Medicine; The Royal Society of Chemistry: Cambridge, 1999. 3. Orvig, C.; Abrams, M. J. Chem. Rev. 1999, 99, 22012204. 4. Guo, Z.; Sadler, P. J. Angew Chem., Int. Ed. Engl. 1999, 38, 15121531.

Metal Complexes as Drugs and Chemotherapeutic Agents


5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.

835

32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59.

Keppler, B. Metal Complexes in Cancer Chemotherapy; VCH: Basel, 1993. Clarke, M. J. Progress in Clinical Biochemistry and Medicine, 1989; Vol. 10. Fricker, S. P., Ed.; Metal Complexes in Cancer Therapy. Chapman and Hall: London, 1994; Vol. 1, p 215. Berthon, G. Handbook of Metalligand Interactions in Biological Fluids; Marcel-Dekker Inc.: New York, 1995; Vol. 1 and 2. Clarke, M. J.; Sadler, P. J., Eds.; Metallopharmaceuticals I: DNA Interactions; Springer-Verlag: Berlin 1999; Vol. 1, p 199. Sadler, P. J. Adv. Inorg. Chem. 1999, 49, 183306. Roat, R. M. Bioinorganic Chemistry: A Short Course, Wiley Interscience, Hoboken, New Jersey, 2002. Sigel, H.; Sigel, A., Eds., Metal Ions in Biological Systems; Marcel Dekker: New York 1995; Vol. 31. Lever, A. B. P. Ed., Coord. Chem. Rev. 2003, Vol. 232 Aspects of Biomedical Inorganic Chemistry. Elsevier Press. Reynolds, J. E. F. Ed., Martindale The Extra Pharmacopoeia, 31sted.; The Royal Pharmaceutical Society; London, 1996. Martindales Pharmacopeia. Andersen, O. Chem. Rev. 1999, 99, 26832710. Liu, Z. D.; Hider, R.C. Coord. Chem. Rev. 2002, 232, 151172. Sarkar, B. Chem. Rev. 1999, 99, 25352544. Whittaker, M.; Floyd, C. D.; Brown, P.; Gearing, A. J. Chem. Rev. 1999, 99, 27352776. Parks, W. C.; Mecham, R.; Mecham, R. P. Matrix Metalloproteinases; Academic Press, 1998. Vallee, B. L.; Auld, D. S.; Acc. Chem. Res. 1993, 26, 543551. Jolles, P.; Jornvall, H., Eds.; Verlag: Basel, 1995, p 259. Rein, A.; Henderson, L. E.; Levin, J. G. Trends Biochem. Sci. 1998, 23, 297301. Albert, A. Selective Toxicity, 6th ed.; Wiley: New York, 1979. Food and Drug Administration: http://www.fda.gov United States Food and Drug Administration; Vol. 2002. National Cancer Institute: http://nci.nih.gov/dtp.cfm NCI-DTP; Vol. 2002. Bertucci, C.; Domenici, E. Curr. Med. Chem. 2002, 9, 14631481. He, X. M.; Carter, D. C. Nature 1992, 358, 209215. Chan, J.; Huang, Z.; Merrifield, M. E.; Salgado, M. T.; Stillman, M. J. Studies of metal binding reactions in metallothioneins by spectroscopic, molecular biology, and molecular modeling techniques. Coord. Chem. Rev. 2002, 233, 319339. Sun, H.; Li, H.; Sadler, P. J. Chem. Rev. 1999, 99, 28172842. Petering, D.; Xiao, J.; Nyayapati, S.; Fulmer, P.; Antholine, W. Oxidation Damage by Bleomycin, Adriamycin and Other Cytotoxic Agents that Require Iron or Copper; Farrell, N., Ed.; The Royal Society of Chemistry: Cambridge, 1999, pp 135157. Claussen, C. A.; Long, E. C. Chem. Rev. 1999, 99, 27972816. Weinstein, J. N.; Myers, T. G.; OConnor, P. M.; Friend, S. H.; Fornace, A. J., Jr.; Kohn, K. W.; Fojo, T.; Bates, S. E.; Rubinstein, L. V.; Anderson, N. L.; Buolamwini, J. K.; van Osdol, W. W.; Monks, A. P.; Scudiero, D. A.; Sausville, E. A.; Zaharevitz, D. W.; Bunow, B.; Viswanadhan, V. N.; Johnson, G. S.; Wittes, R. E.; Paull, K. D. Science 1997, 275, 343349. Boyle, F. T.; Costello, G. F. Chem. Soc. Rev. 1998, 27, 251261. Rosenberg, B. Platinum Complexes for the Treatment of Cancer. Why the Search goes on. In Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug; Lippert, B., Ed.; Wiley-VCH: New York, 1999 pp 330. Lippert, B., Ed. Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug; Wiley-VCH: New York, 1999. Kelland, L. R.; Farrell, N. P. Platinum-based Drugs in Cancer Therapy; Humana Press, Totawa, New Jersey. 2000. Wong, E.; Giandomenico, C. M. Chem. Rev. 1999, 99, 24512466. Weiss, R. B.; Christian, M. C. Drugs 1993, 46, 360377. Lebwohl, D.; Canetta, R. Eur. J. Cancer 1998, 34, 15221534. ODwyer, P. J.; Johnson, S. W.; Hamilton, T. C. Cisplatin and Its Analogues. In Cancer Principles and Practice of Oncology 5th ed.; DeVita, V. T., Hellman, S.; Rosenberg, S. A., Eds.; Lippincott-Raven: Philadelphia, 1997; Vol. 2, pp 418431. ODwyer, P. J.; Stevenson, J. P.; Johnson, S. W. Clinical Status of Cisplatin, Carboplatin, and Other Platinum-based Antitumor Drugs. In Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug; Lippert, B., Ed.; WileyVCH: New York 1999, pp 3172. Highley, M. S.; Calvert, A. H. Clinical Experience with Cisplatin and Carboplatin; Kelland, L. R.; Farrell, N. P., Eds.; Humana Press: Totowa NJ, 2000, pp 89113. Christian, M. C. Semin. Oncol. 1992, 19, 720. Lokich, J.; Anderson, N. Ann. Oncol. 1998, 9, 1321. Burcheranal, J. H.; Kalaher, K.; Dew, K. Biochemie 1978, 60, 961. Macdonald, J. S.; Astrow, A. B. Semin. Oncol. 2001, 28, 3040. Pelley, R. J. Curr. Oncol. Rep. 2001, 3, 147155. Ruley, H. E. Important Adv. Oncol. 1996, 10, 3756. Eastman, A. The Mechanism of Action of Cisplatin: From Adducts to Apoptosis. In Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug; Lippert, B., Ed.; Wiley-VCH: Weinheim, 1999, pp , 111134. Gonzalez, V. M.; Fuertes, M. A.; Alonso, C.; Perez, J. M. Mol. Pharmacol. 2001, 59, 657663. Kartalou, M.; Essigmann, J. M. Mutat. Res. 2001, 478, 2343. Perez, R. P. Eur. J. Cancer 1998, 34, 15351542. Kartalou, M.; Essigmann, J. M. Mutat. Res. 2001, 478, 121. Harrap, K. R.; Jones, M.; Siracky, J.; Pollard, L. A.; Kelland, L. R. Ann. Oncol. 1990, 1, 6576. Loh, S. Y.; Mistry, P.; Kelland, L. R.; Abel, G.; Harrap, K. R. Br. J. Cancer 1992, 66, 11091115. Berners-Price, S. J.; Appleton, T. G. The Chemistry of Cisplatin in Aqueous Solution; In Platinum-Based Drugs in Cancer Therapy. Kelland, L. R.; Farrell, N., Eds.; Humana Press: Totowa, NJ, 2000. Miller, S. E.; House, D. A. Inorg. Chim. Acta 1991, 187, 125132. Berners-Price, S. J.; Sadler, P. J. Coord. Chem. Rev. 1996, 151, 140. Appleton, T. G.; Hall, J. R.; Ralph, S. F. Inorg. Chem. 1985, 24, 46854693. Kozelka, J.; Legendre, F.; Reeder, F.; Chottard, J. Coord. Chem. Rev. 1999, 190192, 6182.

836

Metal Complexes as Drugs and Chemotherapeutic Agents

60. Canovese, L.; Cattalini, L.; Chessa, G.; Tobe, M. L. J. Chem. Soc. Dalton Trans. 1988, 21352140. 61. Esposito, B. P.; Najjar, R. Coord. Chem. Rev. 2002, 232, 137150. 62. Ivanov, A. I.; Christodoulou, J.; Parkinson, J. A.; Barnham, K. J.; Tucker, A.; Woodrow, J.; Sadler, P. J. J. Biol. Chem. 1998, 273, 1472114730. 63. Reedijk, J. Chem. Rev. 1999, 99, 24992510. 64. Djuran, M. I.; Lempers, E. L. M.; Reedijk, J. Inorg. Chem. 1991, 30, 26482652. 65. Appleton, T. G.; Connor, J. W.; Hall, J. R.; Prenzler, P. D. Inorg. Chem. 1989, 28, 20302037. 66. Murdoch, P. d. S.; Kratochwil, N. A.; Parkinson, J. A.; Patriarca, M.; Sadler, P. J. Angew Chem., Int. Ed. Engl. 1999, 38, 19492951. 67. Lempers, E. L. M.; Inagaki, K.; Reedijk, J. Inorg. Chim. Acta 1988, 152, 201207. 68. Mitchell, K. A.; Streveler, K. C.; Jensen, C. M. Inorg. Chem. 1993, 32, 26082609. 69. Alden, W. W.; Repta, A. J. Chem. Biol. Interact. 1984, 48, 121124. 70. Murdoch, P. d. S.; Ranford, J. D.; Sadler, P. J.; Berners-Price, S. J. Inorg. Chem. 1993, 32, 22492255. 71. Barnham, K. J.; Djuran, M. I.; Murdoch, P. d. S.; Ranford, J. D.; Sadler, P. J. Inorg. Chem. 1996, 35, 10651072. 72. Hambley, T. W. J. Chem. Soc., Dalton Trans. 2001, 27112718. 73. Cohen, S. M.; Lippard, S. J. Prog. Nucleic Acid Res. Mol. Biol. 2001, 67, 93130. 74. Brabec, V. DNA Modifications by Antitumor Platinum and Ruthenium Compounds: Their Recognition and Repair; Academic Press: Amsterdam, 2002; Vol. 71 pp 245. 75. Takahara, P. M.; Rosenzweig, A. C.; Frederick, C. A.; Lippard, S. J. Nature 1995, 377, 649652. 76. Gelasco, A.; Lippard, S. J. Biochemistry 1998, 37, 92309239. 77. Schwartz, A.; Marrot, L.; Leng, M. Biochemistry 1989, 28, 79757979. 78. Gelasco, A.; Lippard, S. J. Anticancer Activity of Cisplatin and Related Complexes; In Metallopharmaceuticals l: DNA Interactions. Clarke, M. J.; Sadler, P. J., Eds.; Springer-Verlag: Berlin, 1999; Vol. 1, pp 144. 79. Marzilli, L. G.; Saad, J. S.; Kuklenyik, Z.; Keating, K. A.; Xu, Y. J. Am. Chem. Soc. 2001, 123, 27642770. 80. Spingler, B.; Whittington, D. A.; Lippard, S. J. Inorg. Chem. 2001, 40, 55965602. 81. Mani, S.; Graham, M. A.; Bregman, D. B.; Ivy, P.; Chaney, S. G. Cancer Invest. 2002, 20, 246263. 82. Woynarowski, J. M.; Faivre, S.; Herzig, M. C.; Arnett, B.; Chapman, W. G.; Trevino, A. V.; Raymond, E.; Chaney, S. G.; Vaisman, A.; Varchenko, M.; Juniewicz, P. E. Mol. Pharmacol. 2000, 58, 920927. 83. Coste, F.; Malinge, J. M.; Serre, L.; Shepard, W.; Roth, M.; Leng, M.; Zelwer, C. Nucleic Acids Res. 1999, 27, 18371846. 84. Coste, F.; Shepard, W.; Zelwer, C. Acta Crystallogr. D 2002, 58, 431440. 85. Huang, H.; Zhu, L.; Reid, B. R.; Drobny, G. P.; Hopkins, P. B. Science 1995, 270, 18421845. 86. Paquet, F.; Perez, C.; Leng, M.; Lancelot, G.; Malinge, J. M. J. Biomol. Struct. Dyn. 1996, 14, 6777. 87. Brabec, V.; Leng, M. Proc. Natl. Acad. Sci. USA 1993, 90, 53455349. 88. Chu, G. J. Biol. Chem. 1994, 269, 787790. 89. Zlatanova, J.; Yaneva, J.; Leuba, S. H. Faseb J. 1998, 12, 791799. 90. Patrick, S. M.; Turchi, J. J. Biochemistry 1998, 37, 88088815. 91. Thomas, J. O. Biochem. Soc. Trans. 2001, 29, 395401. 92. Ohndorf, U. M.; Rould, M. A.; He, Q.; Pabo, C. O.; Lippard, S. J. Nature 1999, 399, 708712. 93. He, Q.; Ohndorf, U. M.; Lippard, S. J. Biochemistry 2000, 39, 1442614435. 94. Holford, J.; Sharp, S. Y.; Murrer, B. A.; Abrams, M.; Kelland, L. R. Br. J. Cancer 1998, 77, 366373. 95. Raynaud, F. I.; Boxall, F. E.; Goddard, P. M.; Valenti, M.; Jones, M.; Murrer, B. A.; Abrams, M.; Kelland, L. R. Clin. Cancer Res. 1997, 3, 20632074. 96. Holford, J.; Raynaud, F.; Murrer, B. A.; Grimaldi, K.; Hartley, J. A.; Abrams, M.; Kelland, L. R., Anticancer Drug Des. 1998, 13, 118. 97. Chen, Y.; Guo, Z.; Parsons, S.; Sadler, P. J. Chem. Eur. J. 1998, 4, 672676. 98. Chen, Y.; Parkinson, J. A.; Guo, Z.; Brown, T.; Sadler, P. J. Angew Chem., Int. Ed. 1999, 38, 20602063. 99. Trigo, J. M.; Beale, P.; Judson, I. R.; Raynaud, F.; Rees, C.; Milan, D.; Wolf, L.; Walker, R.; Hanwell, J.; Giandomenico, C. ASCO 1999, 648. 100. Mellish, K. J.; Barnard, C. F.; Murrer, B. A.; Kelland, L. R. Int. J. Cancer 1995, 62, 717723. 101. Hall, M. D.; Hambley, T. W. Coord. Chem. Rev. 2002, 232, 4967. 102. Lemma, K.; Sargeson, A. M.; Elding, L. I. J. Chem. Soc., Dalton Trans. 2000, 11671172. 103. Lemma, K.; Berglund, J.; Farrell, N.; Elding, L. I. J. Biol. Inorg. Chem. 2000, 5, 300306. 104. Giandomenico, C. M.; Abrams, M. J.; Murrer, B. A.; Vollano, J. F.; Rheinheimer, M. I.; Wyer, S. B.; Bossard, G. E.; Higgins, III, J. D. Inorg. Chem. 1998, 34, 10151021. 105. Carr, J. L.; Tingle, M. D.; McKeage, M. J. Cancer Chemother. Pharmacol. 2002, 50, 915. 106. Raynaud, F. I.; Mistry, P.; Donaghue, A.; Poon, G. K.; Kelland, L. R.; Barnard, C. F.; Murrer, B. A.; Harrap, K. R. Cancer Chemother. Pharmacol. 1996, 38, 155162. 107. Hartwig, J. F.; Lippard, S. J. J. Am. Chem. Soc. 1992, 114, 56465654. 108. Kurata, T.; Tamura, T.; Sasaki, Y.; Fujii, H.; Negoro, S.; Fukuoka, M.; Saijo, N. Jpn J. Clin. Oncol. 2000, 30, 377384. 109. Kelland, L. R. Exp. Opin. Invest. Drugs 2000, 9, 13731382. 110. Farrell, N.; Qu, Y.; Hacker, M. P. J. Med. Chem. 1990, 33, 21792184. 111. Farrell, N. Comm. Inorg. Chem. 1995, 16, 373389. 112. Farrell, N. DNA Binding of Dinuclear Platinum Complexes; In Advances in DNA Sequence Specific Agents. Vol. 2 Hurley, L. H.; Chaires, J. B., Eds.; JAI Press, 1996, pp 187216. 113. Farrell, N. Cancer Invest. 1993, 11, 578589. 114. Qu, Y.; Rauter, H.; Soares Fontes, A. P.; Bandarage, R.; Kelland, L. R.; Farrell, N. J. Med. Chem. 2000, 43, 31893192. 115. Farrell, N. P.; Qu, Y.; Bierbach, U.; Valsecchi, M.; Menta, E. Structureactivity Relationships within Di- and Trinuclear Platinum Phase I Clinical Agents; In Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug; Lippert, B., Ed.; Verlag, 1999, pp 479496. 116. Farrell, N.; Spinelli, S. Dinuclear and Trinuclear Platinum Anticancer Agents; In Uses of Inorganic Chemistry in Medicine, Farrell, N., Ed.; The Royal Society of Chemistry: Cambridge, 1999, pp 124134.

Metal Complexes as Drugs and Chemotherapeutic Agents

837

117. Farrell, N. P. Polynuclear Charged Platinum Compounds as a New Class of Anticancer Agents: Toward a New Paradigm; In Platinum-Based Drugs in Cancer Therapy, Kelland, L. R. and Farrell, N. P., Ed.; Humana Press, 2000, pp 321338. 118. Qu, Y.; Appleton, T. G.; Hoeschele, J. D.; Farrell, N. Inorg. Chem. 1993, 32, 2591. 119. Manzotti, C.; Pratesi, G.; Menta, E.; Di Domenico, R.; Cavalletti, E.; Fiebig, H. H.; Kelland, L. R.; Farrell, N.; Polizzi, D.; Supino, R.; Pezzoni, G.; Zunino, F. Clin. Cancer Res. 2000, 6, 26262634. 120. Pratesi, G.; Perego, P.; Polizzi, D.; Righetti, S. C.; Supino, R.; Caserini, C.; Manzotti, C.; Giuliani, F. C.; Pezzoni, G.; Tognella, S.; Spinelli, S.; Farrell, N.; Zunino, F. Br. J. Cancer 1999, 80, 19121919. 121. Perego, P.; Caserini, C.; Gatti, L.; Carenini, N.; Romanelli, S.; Supino, R.; Colangelo, D.; Viano, I.; Leone, R.; Spinelli, S.; Pezzoni, G.; Manzotti, C.; Farrell, N.; Zunino, F. Mol. Pharmacol. 1999, 55, 528534. 122. Orlandi, L.; Colella, G.; Bearzatto, A.; Abolafio, G.; Manzotti, C.; Daidone, M. G.; Zaffaroni, N., Eur. J. Cancer 2001, 37, 649659. 123. Calvert, P. M.; Highley, M. S.; Hughes, A. N.; Plummer, E. R.; Azzabi, A. S. T.; Verrill, M. W.; Camboni, M. G.; Verdi, E.; Bernareggi, A.; Zucchetti, M.; Robinson, A. M.; Carmichael, J.; Calvert, A. H. Clin. Cancer Res. 1999, 5, 3796s. 124. Sessa, C.; Capri, G.; Gianni, L.; Peccatori, F.; Grasselli, G.; Bauer, J.; Zucchetti, M.; Vigano, L.; Gatti, A.; Minoia, C.; Liati, P.; Van den Bosch, S.; Bernareggi, A.; Camboni, G.; Marsoni, S. Ann. Oncol. 2000, 11, 977983. 125. Gourley, C.; Cassidy, J.; Bisset, D.; Camboni, G.; Boyle, D.; Joddrell, D. Proc. AACR 2002, 2760. 126. Calvert, A. H.; Thomas, H.; Colombo, N.; Gore, M.; Earl, H.; Sena, L.; Camboni, G.; Liati, P.; Sessa, C. European Journal of Cancer 2001, 37 (supp6) Poster Discussion 965. Phase II Clinical Study of BBR3464, a Novel, Bifunctional Platinum Analogue, in Patients with Advanced Ovarian Cancer, 2001. 127. Scagliotti, G.; Crino, L.; de Marinis, F.; Tonato, M.; Selvaggi, G.; Massoni, F.; Maestri, A.; Gatti, B.; Camboni, G. European Journal of Cancer 2001, 37 (Supp6) Poster 182. Phase II Trial of BBR3464, a Novel, Bifunctional Platinum Analogue, in Advanced but Favourable Out-come, Non Small Cell Lung Cancer Patients, 2001. 128. Roberts, J. D.; Peroutka, J.; Farrell, N. J. Inorg. Biochem. 1999, 77, 5157. 129. Perego, P.; Gatti, L.; Caserini, C.; Supino, R.; Colangelo, D.; Leone, R.; Spinelli, S.; Farrell, N.; Zunino, F. J. Inorg. Biochem. 1999, 77, 5964. 130. Guo, Z.; Chen, Y.; Zang, E.; Sadler, P. J. J. Chem. Soc., Dalton Trans. 1997, 41074111. 131. Davies, M. S.; Cox, J.; Berners-Price, S.; Barklage, W.; Qu, Y.; Farrell, N. Inorg. Chem. 2000, 39, 17101715. 132. Davies, M. S.; Thomas, D. S.; Hegmans, A.; Berners-Price, S. J.; Farrell, N. Inorg. Chem. 2002, 41, 11011109. 133. McGregor, T. D.; Hegmans, A.; Kasparkova, J.; Neplechova, K.; Novakova, O.; Penazova, H.; Vrana, O.; Brabec, V.; Farrell, N. J. Biol. Inorg. Chem. 2002, 7, 397404. 134. Brabec, V.; Kasparkova, J.; Vrana, O.; Novakova, O.; Cox, J. W.; Qu, Y.; Farrell, N. Biochemistry 1999, 38, 67816790. 135. Johnson, A.; Qu, Y.; Van Houten, B.; Farrell, N. Nucleic Acids Res. 1992, 20, 16971703. 136. Wu, P. K.; Kharatishvili, M.; Qu, Y.; Farrell, N. J. Inorg. Biochem. 1996, 63, 918. 137. McGregor, T. D.; Balcarova, Z.; Qu, Y.; Tran, M. C.; Zaludova, R.; Brabec, V.; Farrell, N. J. Inorg. Biochem. 1999, 77, 4346. 138. McGregor, T. D.; Bousfield, W.; Qu, Y.; Farrell, N. J. Inorg. Biochem. 2002, 91, 212219. 139. Walker, G. T.; Stone, M. P.; Krugh, T. R. Biochemistry 1985, 24, 74627471. 140. Kim, Y.; Geiger, J. H.; Hahn, S.; Sigler, P. B. Nature 1993, 365, 512520. 141. Herbert, A.; Rich, A. J. Biol. Chem. 1996, 271, 1159511598. 142. Gohlke, C.; Murchie, A. I.; Lilley, D. M.; Clegg, R. M. Proc. Natl. Acad. Sci. USA 1994, 91, 1166011664. 143. Kloster, M. B.; Hannis, J. C.; Muddiman, D. C.; Farrell, N. Biochemistry 1999, 38, 1473114737. 144. Cox, J. W.; Berners-Price, S. J.; Davies, M. S.; Qu, Y.; Farrell, N. J. Am. Chem. Soc. 2001, 123, 13161326. 145. Davies, M. S.; Thomas, D. S.; Hegmans, A.; Berners-Price, S. J.; Qu,Y.; Farrell, N. A Comparison of the kinetics of formation of 1,4-interstrand crosslinks by the trinuclear clinical agent BBR3464: Preassociation and evidence of conformational flexibility J. Am. Chem. Soc. submitted for publication. 146. Wang, Y.; Farrell, N.; Burgess, J. D. J. Am. Chem. Soc. 2001, 123, 55765577. 147. Qu, Y.; Scarsdale, N. J.; Tran, M. C.; Farrell, N. Cooperative effects in long-range 1,4 DNA-DNA interstrand crosslinks formed by polynuclear platinum complexes: an unexpected syn-orientation of adenine bases outside the binding sites. J Biol Inorg Chem 2003, 8, 1928. 148. Rajski, S. R.; Williams, R. M. Chem. Rev. 1998, 98, 27232796. 149. Thompson, A. S.; Hurley, L. H. J. Mol. Biol. 1995, 252, 86101. 150. Seaman, F. C.; Chu, J.; Hurley, L. J. Am. Chem. Soc. 1996, 118, 53835395. 151. Qu, Y.; Bloemink, M. J.; Reedijk, J.; Hambley, T. W.; Farrell, N. J. Am. Chem. Soc. 1996, 118, 9307. 152. Kasparkova, J.; Novakova, O.; Vrana, O.; Farrell, N.; Brabec, V. Biochemistry 1999, 38, 1099711005. 153. Kasparkova, J.; Mellish, K. J.; Qu, Y.; Brabec, V.; Farrell, N. Biochemistry 1996, 35, 1670516713. 154. Kasparkova, J.; Farrell, N.; Brabec, V. J. Biol. Chem. 2000, 275, 1578915798. 155. Zehnulova, J.; Kasparkova, J.; Farrell, N.; Brabec, V. J. Biol. Chem. 2001, 276, 2219122199. 156. Kasparkova, J.; Zehnulova, J.; Farrell, N.; Brabec, V. DNA interstrand crosslinks of novel antitumor trinuclear platinum complex BBR. Conformation, recognition by HMG-domain proteins and nucleotide excision repair. J Biol Chem 2002, 277, 4807648086. 157. Sancar, A. Annu. Rev. Biochem. 1996, 65, 4381. 158. Servidei, T.; Ferlini, C.; Riccardi, A.; Meco, D.; Scambia, G.; Segni, G.; Manzotti, C.; Riccardi, R. Eur. J. Cancer 2001, 37, 930938. 159. Wheate, N. J.; Webster, L. K.; Brodie, C. R.; Collins, J. G. Anticancer Drug Des. 2000, 15, 313322. 160. Komeda, S.; Lutz, M.; Spek, A. L.; Chikuma, M.; Reedijk, J. Inorg. Chem. 2000, 39, 42304236. 161. Komeda, S.; Lutz, M.; Spek, A. L.; Yamanaka, Y.; Sato, T.; Chikuma, M.; Reedijk, J. J. Am. Chem. Soc. 2002, 124, 47384746. 162. Farrell, N.; Ha, T. T.; Souchard, J. P.; Wimmer, F. L.; Cros, S.; Johnson, N. P. J. Med. Chem. 1989, 32, 22402241. 163. Van Beusichem, M.; Farrell, N. Inorg. Chem. 1992, 31, 634. 164. Farrell, N.; Kelland, L. R.; Roberts, J. D.; Van Beusichem, M. Cancer Res. 1992, 52, 50655072.

838

Metal Complexes as Drugs and Chemotherapeutic Agents

165. Natile, G.; Coluccia, M. Trans-platinum Compounds in Cancer Therapy: A Largely Unexplored Strategy for Identifying Novel Antitumor Platinum Drugs; In Metallopharmaceuticals l: DNA Interactions, Clarke, M. J.; Sadler, P. J., Eds.; Springer-Verlag: Berlin, 1999; Vol. 1, pp 7398. 166. Natile, G.; Coluccia, M. Coord Chem. Rev. 2001, 216, 383410. 167. Perez, J. M.; Montero, E. I.; Gonzalez, A. M.; Solans, X.; Font-Bardia, M.; Fuertes, M. A.; Alonso, C.; NavarroRanninger, C. J. Med. Chem. 2000, 43, 24112418. 168. Montero, E. I.; Diaz, S.; Gonzalez-Vadillo, A. M.; Perez, J. M.; Alonso, C.; Navarro-Ranninger, C. J. Med. Chem. 1999, 42, 42644268. 169. Khazanov, E.; Barenholz, Y., Gibson, D., Najraeh, Y. Novel apoptosis-including trans-platinum piperidine and piperazine derivatives: Synthesis and biological characterization. J. Med. Chem. 2002, 45, 51895195 . 170. Farrell, N. Met. Ions Biol. Sys. 1996, 32, 603634. 171. Bierbach, U.; Sabat, M.; Farrell, N. Inorg. Chem. 2000, 39, 18821890. 172. Zou, Y.; Van Houten, B.; Farrell, N. Biochemistry 1993, 32, 96329638. 173. Brabec, V.; Neplechova, K.; Kasparkova, J.; Farrell, N. J. Biol. Inorg. Chem. 2000, 5, 364368. 174. Bierbach, U.; Qu, Y.; Hambley, T. W.; Peroutka, J.; Nguyen, H. L.; Doedee, M.; Farrell, N. Inorg. Chem. 1999, 38, 35353542. 175. Bierbach, U.; Farrell, N. Inorg. Chem. 1997, 36, 36573665. 176. Bierbach, U.; Farrell, N. J. Biol. Inorg. Chem. 1998, 3, 570. 177. Zaludova, R.; Zakovska, A.; Kasparkova, J.; Balcarova, Z.; Vrana, O.; Coluccia, M.; Natile, G.; Brabec, V. Mol. Pharmacol. 1997, 52, 354361. 178. Clarke, M. J.; Zhu, F.; Frasca, D. R. Chem. Rev. 1999, 99, 25112534. 179. Clarke, M. J. Ruthenium Chemistry Pertaining to the Design of Anticancer Agents; Progress in Clinical Biochemistry and Medicine; Springer-Verlag: Berlin, 1989; Vol. 10, pp 2540. 180. Frasca, D. R.; Clarke, M. J. J. Am. Chem. Soc. 1999, 121, 85238532. 181. Zhao, M.; Clarke, M. J. J. Biol. Inorg. Chem. 1999, 4, 318324. 182. LaChance-Galang, K.; Zhao, M.; Clarke, M. J. Inorg. Chem. 1996, 35, 60216026. 183. Keppler, B. K.; Friesen, C.; Moritz, H. G.; Vongerichten, H.; Vogel, E. Struct. Bonding 1991, 78, 97127. 184. Pieper, T.; Borsky, K.; Keppler, B. K. Non-platinum Antitumor Compounds; In Metallopharmacecuticals l: DNA Interactions, Clarke, M. J.; Sadler, P. J., Eds.; Springer-Verlag: Berlin, 1999; Vol.1, pp , 171199. 185. Kratz, F.; Hartmann, M.; Keppler, B.; Messori, L. J. Biol. Chem. 1994, 269, 25812588. 186. Sava, G.; Alessio, E.; Bergamo, A.; Mestroni, G. Sulfoxide Ruthenium Complexes: Non Toxic Tools for the Selective Treatment of Solid Tumor Metastases; In Metallopharmaceuticals l: DNA Interactions, Clarke, M. J. and Sadler, P. J., Ed.; Springer-Verlag: Berlin, 1999; Vol.1, pp 143170. 187. Sanna, B.; Debidda, M.; Pintus, G.; Tadolini, B.; Posadino, A. M.; Bennardini, F.; Sava, G.; Ventura, C. Arch. Biochem. Biophys. 2002, 403, 209218. 188. Cherrington, J. M.; Strawn, L. M.; Shawver, L. K. Adv. Cancer Res. 2000, 79, 138. 189. Sava, G.; Clerici, K.; Capozzi, I.; Cocchietto, M.; Gagliardi, R.; Alessio, E.; Mestroni, G.; Perbellini, A. Anticancer Drugs 1999, 10, 129138. 190. Bergamo, A.; Gagliardi, R.; Scarcia, V.; Furlani, A.; Alessio, E.; Mestroni, G.; Sava, G. J. Pharmacol. Exp. Ther. 1999, 289, 559564. 191. Zorzet, S.; Bergamo, A.; Cocchietto, M.; Sorc, A.; Gava, B.; Alessio, E.; Iengo, E.; Sava, G. J. Pharmacol. Exp. Ther. 2000, 295, 927933. 192. Sava, G.; Bergamo, A.; Zorzet, S.; Gava, B.; Casarsa, C.; Cocchietto, M.; Furlani, A.; Scarcia, V.; Serli, B.; Iengo, E.; Alessio, E.; Mestroni, G. Eur. J. Cancer 2002, 38, 427435. 193. Gopal, Y. N.; Jayaraju, D.; Kondapi, A. K. Biochemistry 1999, 38, 43824388. 194. Chen, H.; Parkinson, J. A.; Parsons, S.; Coxall, R. A.; Gould, R. O.; Sadler, P. J. J. Am. Chem. Soc. 2002, 124, 30643082. 195. Morris, R. E.; Aird, R. E.; Murdoch Pdel, S.; Chen, H.; Cummings, J.; Hughes, N. D.; Parsons, S.; Parkin, A.; Boyd, G.; Jodrell, D. I.; Sadler, P. J. J. Med. Chem. 2001, 44, 36163621. 196. Antman, K. H. Oncologist 2001, 6, 12. 197. Waxman, S.; Anderson, K. C. Oncologist 2001, 6, 310. 198. Shen, Z. X.; Chen, G. Q.; Ni, J. H.; Li, X. S.; Xiong, S. M.; Qiu, Q. Y.; Zhu, J.; Tang, W.; Sun, G. L.; Yang, K. Q.; Chen, Y.; Zhou, L.; Fang, Z. W.; Wang, Y. T.; Ma, J.; Zhang, P.; Zhang, T. D.; Chen, S. J.; Chen, Z.; Wang, Z. Y. Blood 1997, 89, 33543360. 199. Novick, S. C.; Warrell, R. P., Jr. Semin. Oncol. 2000, 27, 495501. 200. Rust, D. M.; Soignet, S. L. Oncologist 2001, 6, 2932. 201. Miller, W. H., Jr.; Schipper, H. M.; Lee, J. S.; Singer, J.; Waxman, S. Cancer Res. 2002, 62, 38933903. 202. Jing, Y.; Dai, J.; Chalmers-Redman, R. M.; Tatton, W. G.; Waxman, S. Blood 1999, 94, 21022111. 203. Dai, J.; Weinberg, R. S.; Waxman, S.; Jing, Y. Blood 1999, 93, 268277. 204. Yang, C. H.; Kuo, M. L.; Chen, J. C.; Chen, Y. C. Br. J. Cancer 1999, 81, 796799. 205. Zhang, T. D.; Chen, G. Q.; Wang, Z. G.; Wang, Z. Y.; Chen, S. J.; Chen, Z. Oncogene 2001, 20, 71467153. 206. Kroemer, G.; de The, H. J. Natl. Cancer Inst. 1999, 91, 743745. 207. Preston, T. J.; Abadi, A.; Wilson, L.; Singh, G. Adv. Drug Deliv. Rev. 2001, 49, 4561. 208. Costantini, P.; Jacotot, E.; Decaudin, D.; Kroemer, G. J. Natl. Cancer Inst. 2000, 92, 10421053. 209. Koya, K.; Li, Y.; Wang, H.; Ukai, T.; Tatsuta, N.; Kawakami, M.; Shishido; Chen, L. B. Cancer Res. 1996, 56, 538543. 210. McKeage, M.J.; Maharaj, L.; Berners-Price, S. J. Coord. Chem. Rev. 2002, 232, 127135. 211. Berners-Price, S. J.; Bowen, R. J.; Galettis, P.; Healy, P. C.; McKeage, M. J. Coord. Chem. Rev. 1999, 185186, 823836. 212. Berners-Price, S.; Jarrett, P.; Sadler, P. Inorg. Chem. 1987, 26, 30743077. 213. Shaw, C. F. Chem. Rev. 1999, 99, 25892600. 214. Berners-Price, S. J.; Girard, G. R.; Hill, D. T.; Sutton, B. M.; Jarrett, P. S.; Faucette, L. F.; Johnson, R. K.; Mirabelli, C. K.; Sadler, P. J. J. Med. Chem. 1990, 33, 13861392.

Metal Complexes as Drugs and Chemotherapeutic Agents

839

215. McKeage, M. J.; Berners-Price, S. J.; Galettis, P.; Bowen, R. J.; Brouwer, W.; Ding, L.; Zhuang, L.; Baguley, B. C. Cancer Chemother. Pharmacol. 2000, 46, 343350. 216. Berners-Price, S.; Bowen, R.; Hambley, T.; Healy, P. J. Chem. Soc., Dalton Trans. 1999, 8, 13371346. 217. Riley, D. P. Chem. Rev. 1999, 99, 25732588. 218. McCord, J. M.; Fridovich, I. J. Biol. Chem. 1969, 244, 60496055. 219. Kramer, R. Angew Chem., Int. Ed. 2000, 39, 44694470. 220. Weiss, R.; Riley, D. Therapeutic Aspects of Manganese(II)-based Superoxide Dismutase Mimics; In Uses of Inorganic Chemistry in Medicine, Farrell, N., Ed.; The Royal Society of Chemistry: Cambridge, 1999, pp 7792. 221. Doctrow, S. R.; Huffman, K.; Marcus, C. B.; Musleh, W.; Bruce, A.; Baudry, M.; Malfroy, B. Adv. Pharmacol. 1997, 38, 247269. 222. Melov, S.; Ravenscroft, J.; Malik, S.; Gill, M. S.; Walker, D. W.; Clayton, P. E.; Wallace, D. C.; Malfroy, B.; Doctrow, S. R.; Lithgow, G. J. Science 2000, 289, 15671569. 223. Salvemini, D.; Wang, Z. Q.; Zweier, J. L.; Samouilov, A.; Macarthur, H.; Misko, T. P.; Currie, M. G.; Cuzzocrea, S.; Sikorski, J. A.; Riley, D. P. Science 1999, 286, 304306. 224. Aston, K.; Rath, N.; Naik, A.; Slomczynska, U.; Schall, O. F.; Riley, D. P. Inorg. Chem. 2001, 40, 17791789. 225. Melendez, E. Crit. Rev. Oncol. Hematol. 2002, 42, 309315. 226. Comba, P.; Jakob, H.; Nuber, B.; Keppler, B. K. Inorg. Chem. 1994, 33, 33963400. 227. Schilling, T.; Keppler, K. B.; Heim, M. E.; Niebch, G.; Dietzfelbinger, H.; Rastetter, J.; Hanauske, A. R. Invest. New Drugs 1996, 13, 327332. 228. Christodoulou, C. V.; Ferry, D. R.; Fyfe, D. W.; Young, A.; Doran, J.; Sheehan, T. M.; Eliopoulos, A.; Hale, K.; Baumgart, J.; Sass, G.; Kerr, D. J. J. Clin. Oncol. 1998, 16, 27612769. 229. Korfel, A.; Scheulen, M. E.; Schmoll, H. J.; Grundel, O.; Harstrick, A.; Knoche, M.; Fels, L. M.; Skorzec, M.; Bach, F.; Baumgart, J.; Sass, G.; Seeber, S.; Thiel, E.; Berdel, W. E. Clin. Cancer Res. 1998, 4, 27012708. 230. Lummen, G.; Sperling, H.; Luboldt, H.; Otto, T.; Rubben, H. Cancer Chemother. Pharmacol. 1998, 42, 415417. 231. Harding, M. M.; Mokdsi, G. Curr. Med. Chem. 2000, 7, 12891303. 232. Kuo, L. Y.; Liu, A. H.; Marks, T. J. Met. Ions Biol. Syst. 1996, 33, 5385. 233. Harding, M. M.; Mokdsi, G.; Lucas, W. Inorg. Chem. 1998, 37, 24322437. 234. Sun, H.; Li, H.; Weir, R. A.; Sadler, P. J. Angew Chem., Int. Ed. Engl. 1998, 37, 15771579. 235. Apseloff, G. Am. J. Ther. 1999, 6, 327339. 236. Webster, L. K.; Olver, I. N.; Stokes, K. H.; Sephton, R. G.; Hillcoat, B. L.; Bishop, J. F. Cancer Chemother. Pharmacol. 2000, 45, 5558. 237. Senderowicz, A. M.; Reid, R.; Headlee, D.; Abornathy, T.; Horti, J.; Lush, R. M.; Reed, E.; Figg, W. D.; Sausville, E. A. Urol. Int. 1999, 63, 120125. 238. Collery, P.; Lechenault, F.; Cazabat, A.; Juvin, E.; Khassanova, L.; Evangelou, A.; Keppler, B. Anticancer Res. 2000, 20, 955958. 239. Arion, V. B.; Jakupec, M. A.; Galanski, M.; Unfried, P.; Keppler, B. K. J. Inorg. Biochem. 2002, 91, 298305. 240. Knorr, G. M.; Chitambar, C. R. Anticancer Res. 1998, 18, 17331737. 241. Grier, N. MercurialsInorganic and Organic. In MercurialsInorganic and Organics (Disinfection, Sterilization and Preservation.), Block, S. S., Ed.; Lea and Fabringer, 1983, pp 346374. 242. Grier, N. Silver and Its Compounds. In MercurialsInorganic and Organics (Disinfection, Sterilization and Preservation.), Block, S. S., Ed.; Lea and Fabringer, 1983, pp 375389. 243. Gupta, A.; Matsui, K.; Lo, J. F.; Silver, S. Nat. Med. 1999, 5, 183188. 244. Clement, J. L.; Jarrett, P. S. Met. Based Drugs 1994, 1, 467782. 245. Briand, G. G.; Burford, N. Chem. Rev. 1999, 99, 26012658. 246. Reglinski, J. Chemistry of Arsenic, Antimony, and Bismuth; Blackie Academic & Professional: London 1998. 247. Briand; Burford, N. Adv. Inorg. Chem. 2002, 50, 285357. 248. Asato, E.; Driessen, W. L.; de Graaff, R. A. G.; Hulsbergen, F. B.; Reedijk, J. Inorg. Chem. 1991, 30, 42104218. 249. Asato, E.; Katsura, K.; Mikuriya, M.; Fujii, T.; Reedijk, J. Inorg. Chem. 1993, 32, 53225329. 250. Asato, E.; Katsura, K.; Mikuriya, M.; Turpeinen, U.; Mutikainen, I.; Reedijk, J. Inorg. Chem. 1995, 34, 24472454. 251. Sadler, P. J.; Li, H.; Sun, H. Coord. Chem. Rev. 1999, 185-186, 689709. 252. Sadler, P. J.; Sun, H. J. Chem. Soc., Dalton Trans. 1995, 13951401. 253. Burford, N.; Eelman, M. D.; Cameron, T. S. Chem. Commun. (Camb) 2002, 14021403. 254. Whitmire, K. J. Chem. Soc. Chem. Commun. 2002, 28342835.. 255. Sadler, P. J.; Sun, H. Z.; Li, H. Y. Chem. Eur. J. 1996, 2, 701708. 256. Sun, H.; Li, H.; Mason, A. B.; Woodworth, R. C.; Sadler, P. J. Biochem. J. 1999, 337, 105111. 257. Navarro, M.; Perez, H.; Sanchez-Delgado, R. A. J. Med. Chem. 1997, 40, 19371939. 258. Navarro, M.; Cisneros-Fajardo, E. J.; Lehmann, T.; Sanchez-Delgado, R. A.; Atencio, R.; Silva, P.; Lira, R.; Urbina, J. A. Inorg. Chem. 2001, 40, 68796884. 259. Sanchez-Delgado, R. A.; Lazardi, K.; Rincon, L.; Urbina, J. A. J. Med. Chem. 1993, 36, 20412043. 260. Sanchez-Delgado, R. A.; Navarro, M.; Perez, H.; Urbina, J. A. J. Med. Chem. 1996, 39, 10951099. 261. Birch, N. Biomedical Uses of Lithium; Farrell, N., Ed.; The Royal Society of Chemistry: Cambridge, 1999, pp 1121. 262. Birch, N. J. Chem. Rev. 1999, 99, 26592682. 263. Orvig, C.; Thompson, K. H.; Battell, M.; McNeill, J. H. Metal Ions in Biological Systems: Vanadium and its Role in Life; In Metal Ions in Biological Systems, Sigel, H.; Sigel, A.; Eds.; Marcel Dekker: New York, 1995; Vol. 31, p 575. 264. Blondel, O.; Simon, J.; Chevalier, B.; Portha, B. Am. J. Physiol. 1990, 258, E459E467. 265. Thompson, K. H.; McNeill, J. H.; Orvig, C. Chem. Rev. 1999, 99, 25612572. 266. Orvig, C.; Thompson, K.; Cam, M.; McNeil, J. Vanadium Compounds as Possible Insulin Modifiers; In Uses of Inorganic Chemistry in Medicine, Farrell, N. Ed.; The Royal Society of Chemistry: Cambridge, 1999, pp 93108. 267. Huyer, G.; Liu, S.; Kelly, J.; Moffat, J.; Payette, P.; Kennedy, B.; Tsaprailis, G.; Gresser, M. J.; Ramachandran, C. J. Biol. Chem. 1997, 272, 843851. 268. Elberg, G.; He, Z.; Li, J.; Sekar, N.; Shechter, Y. Diabetes 1997, 46, 16841690. 269. Shaw, C. Gold Complexes with Anti-arthritic, Anti-tumour and Anti-HIV Activity; In Uses of Inorganic Chemistry in Medicine, Farrell, N., Ed.; The Royal Society of Chemistry: Cambridge, 1999, pp 2657.

840

Metal Complexes as Drugs and Chemotherapeutic Agents

270. Snyder, R. M.; Mirabelli, C. K.; Crooke, S. T. Semin. Arthritis Rheum. 1987, 17, 7180. 271. Rudkowski, R.; Graham, G. G.; Champion, G. D.; Ziegler, J. B. Biochem. Pharmacol. 1990, 39, 16871695. 272. Butler, A.; Rhodes, P. Nitric Oxide in Physiology and Medicine; In Uses of Inorganic Chemistry in Medicine, Farrell, N., Ed.; The Royal Society of Chemistry: Cambridge, 1999, pp 5876. 273. Clarke, M. J.; Gaul, J. B. Struct. Bonding 1993, 81, 147181. 274. Butler, A. R.; Williams, D. L. H. Chem. Soc. Rev. 1993, 22, 233241. 275. Groves, J. T. Curr. Opin. Chem. Biol. 1999, 3, 226235. 276. Shimanovich, R.; Groves, J. T. Arch. Biochem. Biophys. 2001, 387, 307317. 277. Shimanovich, R.; Hannah, S.; Lynch, V.; Gerasimchuk, N.; Mody, T. D.; Magda, D.; Sessler, J.; Groves, J. T. J. Am. Chem. Soc. 2001, 123, 36133614. 278. Hergesell, O.; Ritz, E. Kidney Int. 1999, 73, S42S45. 279. Hutchison, A. J. Perit. Dial. Int. 1999, 19, S408S412. 280. Hergesell, O.; Ritz, E., Phosphate binders on iron basis: a new perspective? Kidney Int. Suppl. 1999, 73, S4245.

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Comprehensive Coordination Chemistry II ISBN (set): 0-08-0437486 Volume 9, (ISBN 0-08-0443311); pp 809840

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