9.18 Metal Complexes as Drugs and …cdn.elsevier.com/promis_misc/622954sc9.pdfMetal Complexes as Drugs and Chemotherapeutic ... nases likewise represents a case study in design of

9.18Metal Complexes as Drugs andChemotherapeutic Agents

N. FARRELL

Virginia Commonwealth University, Richmond, VA, USA

9.18.1 INTRODUCTION 8099.18.1.1 Biological Assays 810

9.18.2 PLATINUM COMPLEXES AS THERAPEUTIC AGENTS 8129.18.2.1 Clinically Used Anticancer Agents. Cis-platinum Compounds 8129.18.2.2 Platinum Compounds in Clinical Trials 8179.18.2.2.1 AMD473 (ZDO-473) 8179.18.2.2.2 JM-216 (Satraplatin) 8189.18.2.2.3 Poly (di and tri)-nuclear platinum complexes 8199.18.2.2.4 Transplatinum compounds 823

9.18.3 NONPLATINUM ANTICANCER AGENTS 8259.18.3.1 Ruthenium Complexes 8259.18.3.2 Arsenic Trioxide 8269.18.3.3 The Mitochondrion as Target. Gold–phosphane Complexes 8279.18.3.4 Manganese-based Superoxide Dismutase Mimics 8279.18.3.5 Titanium Compounds 8299.18.3.6 Gallium Nitrate 830

9.18.4 ANTIBACTERIAL AGENTS 8309.18.4.1 Silver and Mercury Salts 8309.18.4.2 Bismuth-containing Antiulcer Drugs 8319.18.4.3 Metal-containing Drugs as Antiparasitic Agents 831

9.18.5 PHARMACODYNAMIC USES OF METAL COMPLEX DRUGS 8329.18.5.1 Lithium Carbonate 8329.18.5.2 Vanadium Complexes in Diabetes 8339.18.5.3 Gold Compounds as Antiarthritic Agents 8339.18.5.4 Nitric Oxide in Physiology and Medicine 8349.18.5.5 Lanthanum Carbonate 834

9.18.6 REFERENCES 834

9.18.1 INTRODUCTION

The medicinal uses and applications of metals and metal complexes are of increasing clinical andcommercial importance. Monographs and major reviews, as well as dedicated volumes, testify tothe growing importance of the discipline.1–11 Relevant reviews are to be found throughout annualseries, 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; andsecondly, metal-based drugs and imaging agents where the central metal ion is usually the keyfeature of the mechanism of action.14 This latter class may also be conveniently expanded toinclude those radionuclides used in radioimmunoimaging and radioimmunotherapy (Chapter 9.20).A reasonable estimate of the commercial importance is approaching US$5 billion annually

809

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 treatmentof Wilson’s 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 metalloprotei-nases likewise represents a case study in design of small organic ligands as drugs to inactivate ametalloenzyme.18,19 Overexpression of these zinc-containing enzymes is associated with severaldiseases including arthritis and cancer, so inhibition of the zinc active site is a reasonable drugdevelopment strategy. Indeed, enzymatic zinc is an attractive target because of the diversity of itsstructural and catalytic roles in enzymes.20,21 This chapter is restricted to the uses of well-definedinorganic compounds as drugs and chemotherapeutic agents. Current uses and prospective uses, aswell as those of essentially historical relevance, are covered. An important distinction to be made isbetween drugs as chemotherapeutic agents, whose function is to kill cells, and drugs acting by apharmacodynamic mechanism—whose 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. Forprospective anticancer drugs, for example, in vitro data obtained by proliferation or colony formationassays give useful initial information on the cytotoxicity of the agents. The preponderance of humantumor tissues now available with well-defined genetic makeup and detailed information of up- ordownregulation of critical genes now means that the relevance of murine (mouse-derived) tumormodels such as P388 and L1210 leukemias is somewhat diminished, although useful for preliminarydata and also for historical and comparative purposes. In vivo assays also rely initially on the murinemodels 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 realsituation. 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 tumorgrowing subcutaneously (sc/iv). The term ‘‘antitumor activity’’ should be reserved for data obtainedon 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 beachieved with a relatively small number of patients. phase II clinical trials usually assess single-agentefficacy in defined diseases, i.e., ovarian cancer or relapsed ovarian cancer etc.; they generally involvemany 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 istreated in this manner. An overview of the drug development and approval process is availablethrough web sites of agencies such as the US Food and Drug Administration23 and the NationalCancer Institute Developmental Therapeutics program.24

The application of inorganic compounds to medicine requires detailed examination of thefundamental aqueous chemistry of the proposed drug, including its pharmacokinetics, the meta-bolic 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 alterthe 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 tominimize such side effects—the 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’’ proteininteractions. Human serum albumin is of fundamental importance in the transport of drugs, meta-bolites, endogenous ligands, and metal ions.25 The crystal structure, combined with physical andbiophysical 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 asmetallothionein27 represent detoxifying but also deactivating pathways for inorganic drugs. A furthersource of metal ion/protein interactions is provided by transferrin, whose natural iron-binding site isaccessible to many metal ions of similar radius and charge including Ru2þ, Ga3þ, and Al3þ.28

The nature of the target to be attacked by any drug obviously depends on the specificapplication. Many cytotoxic metal complexes target DNA because of its importance in replicationand cell viability. Coordination compounds offer many binding modes to polynucleotides, includ-ing outer-sphere noncovalent binding, metal coordination to nucleobase and phosphate backbone

810 Metal Complexes as Drugs and Chemotherapeutic Agents

sites, as well as strand cleavage induced by oxidation using redox-active metal centers. The purineand pyrimidine mononucleotide building blocks are depicted in Figure 1b. The later transitionmetals 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

O

–O

HN

NH

O–

O

O

OHS

NH3+

Glutathione

O

OHH2N

HS

O

OHH2N

S

Cysteine Methionine

(a)

N

NN

N

NH2

O

H

OP–O

O–

O

O

H

N

N

NH2

O

OP

O

O–

–O

NH

N

N

O

NH2N

O

H

OP–O

O

O–O

H

HN

N

O

O

OP–O

O

O–

HOH OH

H

OHH

OHH

2'-Deoxyadenosine-5'-Monophosphate 2'-Deoxycytidine-5'-Monophosphate

2'-Deoxyguanosine-5'-Monophosphate 2'-Deoxythymidine-5'-Monophosphate

(b)

Figure 1 (a) Structures of common sulfur-based amino acids and tripeptides. (b) Structures of nucleic acidmonophosphates capable of metal binding.

Metal Complexes as Drugs and Chemotherapeutic Agents 811

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 inthis respect is the anticancer antibiotic bleomycin, whose mode of action on target DNA is strandscission mediated by Fe binding to the drug.29,30

Cytotoxic agents reduce the proliferation of a tumor but lack of selectivity between normal andmalignant tissue may render many agents of little clinical utility. Drug discovery in general hasbeen transformed by rapid advances in the understanding of the cell’s molecular biology coupledwith information sciences.31 Cancer treatment strategies especially have evolved in favor of agentstargeted toward specific pathways, notably those involved in cell signaling.32 A challenge for themedicinal 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 drugswith emphasis on the most recent literature. The major clinical application and promisingpreclinical areas are summarized in Table 1.

9.18.2 PLATINUM COMPLEXES AS THERAPEUTIC AGENTS

9.18.2.1 Clinically Used Anticancer Agents. Cis-platinum Compounds

Cisplatin, (cis-[PtCl2(NH3)2], also known as cis-DDP) ((1), Figure 2) is perhaps the best knownexample of a small molecule metal-containing drug. The clinically used platinum complexes areshown in Figure 2. The history of the discovery and development of cisplatin remains a remark-able scientific story.33 Its use and effectiveness in cancer chemotherapy since the entry into theclinic in the late 1970s has been thoroughly documented.34–36 Cisplatin is cited for treatment of

Table 1 Medical and prospective medical uses of inorganic compounds.a

Element Compound Uses Trade names/comments

Approved agents (mostly US or worldwide):

Li Li2CO3 Manic depression Camcolit; Cibalith-S; Lithane (of many)Fe [Fe(NO)(CN)5]

2� Vasodilation Nipride. For acute shock. NO releaseGa Ga(NO3)3 Hypercalcemia of

malignancyGanite. Possible anticancer agent. In clinicaltrials for use in lymphomas

As As2O3 Anticancer agent Trisenox. Use in acute promyelocytic leukemiaAg AgNO3 Disinfectant Neonatal conjunctivitis

Ag(sulfadiazene) Antibacterial Flamazine; Silvadene; treatment of burns.1% cream

Sb SbIII(tartarate) Antiparasitic,leishmaniasis

Tartar Emetic Stibophen; Astiban

Pt cis-[Pt(amine)2X2] Anticancer agents Platinol; Paraplatin; EloxatineTesticular, ovarian, colon cancers

Au Au(PEt3)(acetyl-thioglucose)

Rheumatoidarthritis

Ridaura. Orally active

Bi Bi(sugar)polymers

Antiulcer; antacid Pepto-Bismol; Ranitidine Bismutrex; De-Nol

Hg Hg-organiccompounds

Antibacterial Thiomersal; mercurochrome (amongst many)

Antifungal Slow release of Hg2þ

Agents in clinical trials:

Pt PolynuclearPtIV species

Anticancer agents BBR3464, Satraplatin, AMD-473

Expands spectrum of activity of cisplatin;overcomes resistance; oral activity?

Mn Mn chelates Anticancer agents SOD mimicsRu trans-[RuCl4

(Me2SO)(Im)]�Anticancer agent NAMI-A; antiangiogenic?

V VO(maltate)2 Type II diabetes BMOV; insulin mimeticLn Ln(CO3)3 Hyperphosphatemia Fosrenol; phosphate binder

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


germ-cell cancers, gestational trophoblastic tumors, epithelial ovarian cancer, and small cell lungcancer as well as for palliation of bladder, cervical, nasopharyngeal, esophageal, and head andneck cancers.37–39 The use of cisplatin (usually as a principal component of combination regi-mens) has rendered at least one cancer, testicular cancer, curable and is significant in treatment ofovarian and bladder cancers. Typical doses range from 20mg/m2 to 100mg/m2, usually for up tofive consecutive days. Despite this success, there is still a limited range of tumors sensitive tocisplatin intervention—some cancers are inherently resistant.40,41 A further disadvantage is theonset of clinical (acquired) resistance after treatment with the drug. The side effects of cisplatintreatment are severe and include the dose-limiting nephrotoxicity, neurotoxicity, ototoxicity, andemetogenesis. The ‘‘second-generation’’ compounds based on the cisplatin structure were devel-oped 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 thetoxic side effects of the parent drug. Despite this lower toxicity, carboplatin is essentially active inthe same set of tumors as cisplatin and a broader spectrum of activity is not indicated.42 For sometumors, 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 compar-able.43 The choice of the most appropriate analog is a function of the cancer being treated, treatmentintention (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 beenimprovement of toxicity profile, circumvention of resistance, and expansion of the tumors sensitiveto treatment by cisplatin. The importance of circumventing resistance was recognized very early onand reports of the activity of complexes containing 1,2-diaminocyclohexane (dach) in murine L1210resistant 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 incombination with 5-fluorouracil (5-FU).45,46 Little information is available on nedaplatin (4) andlobaplatin (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 under-standing has developed from a detailed structural understanding of the cisplatin–DNA interactionto the biological consequences of these adducts. In this respect, the field has also kept pace with theunderstanding of cellular cancer biology over the same period. Thus, it is not the DNA adduct per sebut the downstream effects of protein recognition and cell signaling events that are the ultimatecauses 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 thedamage, or (ii) or initiate the pathway to apoptosis (programmed cell death). The factors that affectcisplatin cytotoxicity, whether in sensitive or resistant cells, are summarized in Figure 3. DNAdamage by chemotherapeutic agents is in many cases mediated through the p53 pathway.47 Cispla-tin damage to DNA stimulates apoptosis via a p53-dependent pathway, although in some cell linesor 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 ofdecreased cellular accumulation of cisplatin, increased efflux of platinum from the cell,

PtH3N

H3N

Cl

Cl

PtH3N

H3N O

O

O

O

PtNH2

H2N O

O

O

O

PtH3N

H3N O

O

OPt

N

N O

O

O

1 2 3

4 5

H2

H2

( ) ( ) ( )

( )( )

Figure 2 Structures of the clinically used platinum anticancer agents.


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 cisplatinis a much more complicated process than previously thought—both active and passive diffusionpathways are now thought to exist.52 The establishment of resistant cell lines with characterizedand calibrated mechanisms of action has aided greatly in advancing a molecular approach toovercoming resistance.53,54 Coupled with this understanding has been the necessity to under-stand the fate or metabolism of cisplatin in the biological milieu and explain the pharmaco-kinetic profile of the drug. For the purposes of this review, the major outlines of the biologicalunderstanding will be reviewed with reference to key understandings and most recent compre-hensive reviews.

The rate-limiting step in DNA binding is aquation of the Pt�Cl bonds. The major products ofthe aquation of cisplatin are the mono- and bisaqua species cis-[Pt(NH3)2(H2O)Cl]þ andcis-[Pt(NH3)2(H2O)2]

2þ, 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 coordinatedwater molecules coupled with equilibrium constants for both aquation and deprotonation reac-tions allows calculation of speciation in biological medium.55,56 The compound, and its directstructural analogs, form adducts between neighboring guanine residues on DNA, formingd(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 cross-links formed between an adenine and a guanine in a d(AG) adduct as well as a 1,3-intrastrand cross-link where two platinated guanines are separated by one base pair—d(GNG).

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

PtL

L'

Cl

Cl

PtL

L'

OH2

Cl

PtL

L'

Cl

OH2

PtL

L'

OH2

OH2

k1a

k1b

k2a

k2b

1+

1+

2+

Figure 4 Hydrolysis scheme for cisplatin-based anticancer agents. Where L¼L0 ¼NH3 cisplatin is indicated.When L¼NH3 and L0 ¼ 2-picoline or cha the rates of aquation of the trans-chloride ligands are different.


The application of {1H,15N}HSQC NMR techniques has proven to be very informative inelucidating detailed kinetic parameters for both aquation and DNA-binding processes. PlatinatedDNA may be observed at low (mM) concentrations because only 1H and 15N resonancesderived from platinum am(m)ine species are seen and the 15N shifts are strongly influenced bythe trans ligand.57,58 The monoaquated species is the most likely reactant with DNA, althoughevidence has also been put forward for the importance of the cis-[Pt(NH3)2(H2O)2]

2þ species inthis regard.59 The hydrolysis of carboplatin involves the displacement of the chelating cyclo-butane-1,1-dicarboxylate from the coordination sphere and is unsurprisingly very slow. In thepresence of acid, the process resembles the successive displacement of two monodentate carbox-ylates.60 In keeping with the kinetic inertness of carboplatin, significantly higher doses arerequired for both equivalent levels of DNA platination compared to cisplatin and also to generateequitoxic and equivalent antitumor effects—clinical doses are 800–900mg/m2.36 The benefit, ofcourse, 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 withGSH, metallothionein, and human serum albumin.61,62 Interestingly, direct substitution of thePt—Cl bonds by sulfur donors such as cysteine and GSH, without the necessity for prioraquation, is indicated from kinetic studies.63,64 Eventually, binding of the thiolate also results indisplacement of the ammonia ligands by chelation of the tripeptide moiety.65 Novel bindingmodes involving N-ligation from deprotonated amide bonds as well as sulfur have been deducedfrom the reaction of [PtCl2(en)] (where en¼ ethylene 1,2 diamine) and GSH.66 Platinum-thiolatespecies [Pt-RS�] display a great tendency to form dinuclear bridging structures {Pt-�(RS)-Pt} asthe bound thiolate is even more nucleophilic than free ligand.67 The crystal structure of [Pt2(�-N-acetylcysteine)2(2,2

0-bipyridine)2] confirms the bridging propensity of thiolate.68 Methioninemetabolites such as [Pt(Met-S,N)2] have been identified from the urine of cisplatin-treatedpatients, emphasizing the importance of this amino acid in the biotransformation of the drug.69

The mechanism of formation has been studied—the metabolite exists predominantly as the cis isomer(cis:trans¼ 87:13).70 Methionine interactions with carboplatin and the formation of a stable ring-opened 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 filtrationchromatography identified the dominant binding site on Human Serum Albumin (HSA) as involvingmethionine rather than the expectedCys-34.62The propensity of platinumbinding to sulfur has also ledto use of sulfur compounds as rescue agents in cisplatin toxicity.63 In these cases, a balance must befound 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 removedfrom DNA by strong nucleophiles such as CN�. NMR methods have also provided new insight into

1,2-Intrastrand cross-link 1,3-Intrastrand cross-link Interstrand cross-link

Interstrand cross-link Interstrand cross-link

Bifunctional cisplatinum DNA adducts

Bifunctional transplatinum DNA adducts

Figure 5 Schematic depiction of cross-links formed by both cis- and trans-platin.


the kinetics and mechanism of DNA binding by cisplatin and other mononuclear analogs.The sequence dependence on the rate constants for monofunctional and bifunctional adductformation have been cataloged.72 The structural consequences of bifunctional binding for themajor 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 intrastrandadduct, whilst maintaining the square-planar geometry of PtII, places considerable steric restraints onthe final structure. Molecular and biological studies have confirmed that the principal effect ofbifunctional 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 ofapproximately 30–35� is often quoted from gel electrophoresis studies.72 The high resolution X-raycrystal structure of the 1,2-intrastrand adduct in the sequence d(CCTCTG*G*TCTCC)_d(GGA-GACCAGAGG) shows the helix bending of approximately 50� toward the major groove.75 TheDNA is a mixture of conformations—B-form on the 30-side of the adduct and the more condensedA-form on the 50-side. In agreement with the possibility that the A-form is induced by crystal packingforces or the concentrations of cations in the crystallization procedure, the DNA remains in theB-form in solution.76 The d(ApG) adduct appears to be similarly kinked.77 Spectroscopic (especiallyNMR) studies on the sequence dependence of the adduct have been reviewed.72,78,79 Carboplatin, asmight be expected, gives the same adducts on DNA as cisplatin since loss of the dicarboxylateproduces the same cis-{Pt(NH3)2}

2þ moiety. Interestingly, the crystal structure of the oxaliplatinadduct of the same dodecanucleotide shows the overall geometry to be very similar to the cisplatincase, 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 theO-6 atom of the 3-guanine, emphasizing the importance of chirality in mediating biological proper-ties.80 These results confirm the findings that the oxaliplatin-induced damage of cellular DNA and itsconsequences 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 adductshow that platinum is located in the minor groove and the cytosines of the d(GC) base pairinvolved in interstrand cross-link formation are ‘‘flipped out’’ of the helix stack and a localized‘‘Z-form’’ DNA is observed.83–85 This is a highly unusual structure and very distorting—implica-tions for differential repair of the two adducts have been addressed. Alternatively, the interstrandcross-link of the antitumor inactive trans-DDP is formed between a guanine (G) and its com-plementary cytosine (C) on the same base pair.86,87trans-DDP is sterically incapable of producing1,2-intrastrand adducts and this feature has been cited as a dominant structural reason for its lackof antitumor efficacy. It is clear that the structural distortions induced on the DNA are verydifferent 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 classesof protein may be identified—those that specifically recognize the platinated sites as a first step intheir repair, and those that bind to such sites because of structural similarity to the protein’snatural binding sites. DNA repair occurs primarily through the nucleotide excision repair path-way and proteins of the first class include the human excision repair complex, mismatch repairproteins, XPA, and RPA (single stranded binding proteins involved in DNA replication andrepair) 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.


so-called high mobility group (HMG) domain motif. The exact function of these nuclear butextrachromosomal DNA binding proteins is still a matter of debate but they bind strongly tounusual noncanonical DNA structures, such as cruciform DNA.91 A common feature of allHMG domain proteins is their ability to bend DNA. Several HMG domain proteins recognizecisplatin-DNA adducts but not those of the clinically ineffective adducts of trans-DDP or themonofunctional [PtCl(dien)]þ (where dien¼ diethylenetriamine). This preferential recognition hasled to the suggestion that proteins with high binding affinity for cisplatin-damaged DNA mayshield the polynucleotide from cellular repair. The structural characterization of the recognitionmotifs of HMG protein and cisplatin-adducted DNA give insight into the molecular details of proteinrecognition.92 Domain A of the structure-specific HMG-domain protein, HMG1, binds to thewidened minor groove of a 16-base pair DNA duplex containing a site-specific 1,2-GG intrastrandcross-link. The DNA in the protein complex is bent significantly further than in the Pt-DNA adductalone, and a phenylalanine moiety intercalates into a hydrophobic notch created at the platinatedd(GpG)-binding site. The importance of an intercalating protein residue such as phenylalanine informing the bend and in contributing to the affinity toward platinated DNA was confirmed by site-directed 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 cureor induce remissions in common tumors such as breast, lung, colon, or prostate cancer. Newcytotoxic agents building on our experience and knowledge of the current armamentariumcontinue to play an important role in the clinical management of cancer. Approximately 28 directstructural analogs of cisplatin entered clinical trials but most have been abandoned through acombination of unacceptable toxicity profile and/or lack of improved or expanded anticancerefficacy.38 For new, direct structural analogs of cisplatin to find clinical use exceptional propertieswould need to be found.38 Currently, there are three principal drugs ((6)–(8); Figure 7) in clinicaltrials—the approaches to their development represent examples of steric control of reactivity,control of oxidation state and ligand lipophilicity aimed at producing orally active agents, andmanipulation 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 rationallydesigned platinum derivatives have been synthesized. One approach has been to insert steric

PtNH2

H3N Cl

Cl

O

O

PtN

H3N Cl

Cl

CH3

Pt

H3N

Cl

NH2(CH2)6H2N

NH3

Pt

H3N

NH3

NH2(CH2)6H2N

Pt

NH3

H3N Cl

O

O

4+

6 (JM-216)7

8 (BBR3464)

( ) ( )

( )

Figure 7 Platinum-based drugs in clinical trials.


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 drugresistance by sterically hindering its reaction with GSH while retaining the ability to formcytotoxic adducts with DNA.96 GSH competes for platinum binding and may diminish DNAplatination, thus reducing cytotoxicity. The rate of aquation of AMD473 is 2–3 times slower thanthat of cisplatin,97 and interstrand cross-link formation is much slower. The DNA binding issimilar to cisplatin, and the complex forms a highly stereoselective adduct on DNA, but not forreactions with mono- and dinucleotides.98 In cell lines with previously determined mechanisms ofcell resistance, AMD473 showed little cross-resistance compared with cisplatin or carboplatin.This partial or complete circumvention of acquired platinum drug resistance makes this a promis-ing compound for clinical development. It is currently undergoing phase II trials where it hasshown 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-dependentthrombocytopenia. 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 propertiesthrough oxidation number. Indeed, the early Rosenberg studies recognized the PtIV complexcis-[PtCl4(NH3)2] as an active anticancer agent.33 A number of PtIV compounds have sinceundergone clinical trials—including cis-[PtCl4(1,2-dach)], known as tetraplatin, and cis,cis,cis-[PtCl2(OH)2(Pr

iNH2)2], known as CHIP or Iproplatin. These compounds have been abandonedbecause of either undesirable side effects or lack of a significantly enhanced therapeutic rangecompared to cisplatin.38 Potential oral activity of JM-216 (6) is achieved by carboxylation of thePt-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 givemore 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 suitablemodification of pharmacokinetic parameters.101 Biological reducing agents, however, such asGSH, 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) followedby conversion to the dichloride greatly facilitates synthesis.

PtH3N

Cl

Cl

Cl

PtH3N

cha

Cl

Cl

H2O2

Ptcha

H3N Cl

Cl

OH

OH

R O R

O O

–

cha

(JM-216)

Ptcha

H3N Cl

Cl

O

O

O

O

( )6Figure 8 Preparation of JM-216.


Despite the reputed inertness of PtIV compounds, JM-216 undergoes rapid biotransformationin 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 thegeneral similarity of the cis-dichlorodiam(m)ineplatinum structure.107 An interesting differencebetween the cha and pyridine groups is that in the former case stereoisomers are seen in the 1,2-intrastrand adduct—the cha group may reside either on the 30 or 50 end of the duplex. Thecytotoxicity of both the PtII and PtIV compounds has been examined extensively. The compoundwas 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 DNAand it is, therefore, not surprising that they induce similar biological consequences. This latterconsideration led to the hypothesis that development of platinum compounds structurally dissim-ilar to cisplatin may, by virtue of formation of different types of Pt-DNA adducts, lead tocompounds with a spectrum of clinical activity genuinely complementary to the parent drug.110–113

In terms of cellular biology, the cell signals (structure and conformation of Pt-DNA adducts asoutlined in Figure 3) must be altered to produce different cell signaling and protein recognitionand induction effects downstream of the platination event, which may be eventually reflected in analtered pattern of antitumor activity. Polynuclear (dinuclear and trinuclear) bifunctional DNA-binding agents are amongst the best studied of these nonclassical structures. The class as a wholerepresents a second, distinctly new structural group of platinum-based anticancer agents. The firstexample 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 compoundsdiffering in functionality (bifunctional to tetrafunctional DNA-binding), geometry (leaving chloridegroups cis or trans to diamine bridge), as exemplified in Figure 9.114 Further systematic variationson nonleaving groups in the Pt coordination spheres (NH3 or a planar group such as pyridine orquinoline) and linker (flexible, variable chain length) are also possible.115

The patterns of DNA modification induced by the various structural motifs have been exam-ined and further related to cytotoxicity and antitumor activity.116,117 The necessity to concentrateon a limited number of compounds identified the 1,1/t,t series (see Figure 9 for explanation of thisnomenclature) as having the most promising pattern of antitumor activity and DNA-binding.Linker modifications have produced most success in terms of enhanced cytotoxicity. The presenceof charge and hydrogen bonding capacity within the central linker (either in the form ofa 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 theoverall 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 notbased 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 presenceof the central Pt, which contributes to DNA affinity only through electrostatic and hydrogenbonding interactions. The 4þ charge, the presence of at least two Pt coordination units capable ofbinding to DNA, and the consequences of such DNA binding are remarkable departures from thecisplatin structural paradigm.

In tissue culture, BBR3464 is cytotoxic at 10–100-fold lower molar concentrations than cisplatinand displays activity in cisplatin-resistant cell lines.119 The profile of antitumor efficacy mirrors itsunique structure and is characterized by activity in human tumor (e.g., ovarian) xenografts resistant tocisplatin and alkylating agents.120 Importantly, BBR3464 also consistently displays high antitumoractivity in human tumor xenografts characterized as mutant p53.121 These tumors are historicallyinsensitive to drug intervention. This important feature suggests that the new agent may find utility inthe over 60% of cancer cases where mutant p53 status is indicated. Consistently, cytotoxicitydisplayed 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


Pt

Cl

Cl

NH3

NH2(CH2)6H2N

Pt

H3N Cl

Cl

Pt

H3N

H3N

Cl

NH2(CH2)6H2N

Pt

Cl NH3

NH3

Pt

Cl

H3N

NH3

NH2(CH2)6H2N

Pt

H3N Cl

NH3

Pt

H3N

H3N

Cl

NH2(CH2)6H2N

Pt

H3N Cl

Cl

Pt

Cl

H3N

NH3

NH2(CH2)6H2N

Pt

H3N Cl

Cl

2+ 2+

1+ 1+

9 (2,2/c,c )

10 (1,1/c,c ) 11 (1,1/t,t)

12 (1,2/c,c ) 13 (1,2/t,c )

( )

( ) ( )

( ) ( )

Pt

NH3

Cl

NH3

Y Pt

NH3

Cl

NH3

H2N NH2

H2NNH2

Pt

NH3

NH3

H2N

NH2

H2NH2N

NH2

NH2

H2NH2N

NH2

2+

4+

4+

3+

14 Y =

15 Y =(BBR3464)

16 Y =

17 Y =

( )

( )

( )

( )

Figure 9 (a) Variation of structures of dinuclear platinum complexes depending on the coordination sphere ofthe platinum. The structural notation describes the number of chloride ligands at each platinum center, followedby 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.


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 carryingmutant 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 forsolid 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 istreatable with loperamide. Signs of biological activity were seen. Notably one patient withmetastatic pancreatic cancer showed a partial response (for 4 months) and two further patients,one with metastatic melanoma and one with bronchoalveolar carcinoma, also showed partialresponses. In a phase I trial in combination with 5-FU, a partial response in breast cancer wasobserved.125 Furthermore, a reduction in tumor marker levels was observed in two patients, onewith ovarian cancer, and one with colon cancer. Phase II studies have shown partial responses incisplatin-resistant ovarian and nonsmall-cell lung cancer.126,127 The indications are that the profileof clinical activity is different and complementary to the mononuclear platinum agents.

Cellular pharmacology studies showed enhanced cellular uptake of the charged polynuclearplatinum compounds in comparison to cisplatin.128,129 This in itself is very surprising given thatthe ‘‘classical’’ structure–activity paradigms for platinum agents require complex neutrality. Theenhanced 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 timeand very slow removal suggests that they are not good substrates for DNA repair. The cellularresponse of HCT116 (human colon tumor) mismatch repair-deficient cells was consistent with alack 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 complexesbecause the predominant DNA lesions are long-range inter- and intrastrand cross-links where thesites of platination may be separated by up to four base pairs. The consequent structural andconformational 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] coordinationspheres (e.g., mononuclear complexes such as [PtCl(dien)]þ or [PtCl(NH3)3]

þ and the 1,1/t,t and1,1/c,c dinuclear compounds of (Figure 9) differs from that of cisplatin.130 The aquationrate constant is comparable, but the reverse chloride anation rate constant is much higher sothat the equilibrium favors the chloro form.131 For the dinuclear diaqua complex [{trans-Pt(H2O)(NH3)}2�-(H2N(CH2)6NH2)]

4þ the pKa of the aqua ligands (pKa 5.62) is much lowerthan in cis-[PtCl(H2O)(NH3)2]

þ (pKa 6.41). For the trinuclear compound BBR3464 the aquationrate constant is comparable to the dinuclear analog, but the chloride anation rate constant islower so that there is a significantly greater percentage of aquated species (�30%) present atequilibrium. The pKa of 5.62 for the aqua ligands is identical to the dinuclear case. Based on thecalculated equilibrium and dissociation constants, and assuming physiological pH (7.2), themaximum tolerated dose (MTD) of BBR3464 in patients corresponds to 1.8� 10�8 M and atan intracellular chloride concentration of 22.7mM the drug will be 98.7% in the dichloro form atequilibrium. In blood plasma, at a [Cl�] of 103mM 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 DNA–DNA interstrand cross-links, unwinding of supercoiled plasmid DNAtypical 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 modelingsuggested 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).


Due to the charged nature of polynuclear platinum complexes, ranging from 2þ to 4þ, it is notsurprising that binding to DNA occurs significantly more rapidly than for cisplatin. The bindingof polyamine-bridged dinuclear compounds is even faster than BBR3464, suggesting strongpreassociation or electrostatic binding prior to covalent attachment. Conformational changescharacteristic 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.135–138 Ethidiumbromide binding favors the B-form of DNA, and intercalation into Z-DNA induced by NaCl or[Co(NH3)6]

3þ results in reversal to the B-form.139 In contrast, intercalation into A- and Z-formDNA induced by dinuclear or trinuclear platinum compounds is inhibited indicating that theconformational changes are essentially irreversible. The ability to maintain unusual DNA con-formations in solution is a unique characteristic of polynuclear platinum compounds. InducedA-like conformations in vivo are theorized to be control mechanisms for DNA binding proteinslike transcription factors.140 The biological function of Z-DNA is still not clearly defined;141 butZ-DNA is known to form in the wake of RNA polymerase as DNA is transcribed.143 Theconformational ‘‘locking’’ into either A- or Z-form by polynuclear platinum compounds is likelyto have profound effects on DNA function. Antibodies raised to cisplatin-DNA adducts do notrecognize DNA adducts of dinuclear or trinuclear compounds.

An interesting and potentially important finding is that BBR3464 is preferentially bound tosingle-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 DNAand RNA was faster than with duplex DNA, and produced more drug–DNA and drug–RNAadducts. BBR3464 binding to different nucleic acid conformations raises the possibility that theadducts of single-stranded DNA and RNA may play a role in the different antitumorefficacies as compared with cisplatin. Single-stranded DNA is present during transcription,replication, recombination, and repair and is recognized by various single-stranded DNAbinding proteins.

The kinetics of the reaction of the self-complementary 12-mer duplex d(50-A1T2ATGTA7CA-TAT-30)2 with

15N labeled [{trans-PtCl(NH3)2}2�-(H2N(CH2)6NH2)]4þ and BBR3464 indicated the

formation of 1,4-interstrand cross-links.144,145 Initial preassociation or electrostatic binding toDNA is observed in both cases, as deduced by chemical shift changes in presence of DNAimmediately upon mixing. The time scale of the NMR experiment makes the weak preassociationof cisplatin difficult to observe, although it may be observed with techniques such as quartzcrystal microbalance and mass spectrometry. The former system permits direct, real time detec-tion of interactions between platinum complexes and surface immobilized oligonucleotides (in thiscase 50-GGGAAGGATGGCGCACGCTG-30).146 The closure rates to form bifunctional adductsare significantly faster than the rate of closure to form a 1,2 GG intrastrand cross-link by cis-[Pt(H2O)2(NH3)2]

2þ. For the dinuclear compound, consideration of the 1H {Guanine H(8)} and15N shifts of the interstrand cross-link showed that an initially formed conformer converts intoanother nonreversible final product conformer.

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.


The 1,4-interstrand cross-link of BBR3464 with the self-complementary 50-(ATGTACAT)2-30

has been characterized and analyzed byMS and CD, UV and NMR spectroscopy.147 The alternatingpurine–pyrimidine sequence mimics the structural requirements for Z-DNA. NMR analysis of theadduct 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 thisbase which is usually not observed for adenine residues and bases not directly involved in thecross-link in oligonucleotides. Within the sequence covered by the cross-link, the bases appear tobe a mixture of syn and anti and Watson-Crick hydrogen bonding is maintained. The centralplatinum unit resides in the minor groove. The observation of an altered conformation (AdenineN7 syn) outside the binding site is unique and suggests the possibility of delocalized lesions beyondthe binding site. In contrast, long-range interstrand cross-linking agents such as CC-1065 andBizelesin do not show conformational changes beyond the environment of the binding sequence.148–150

These unusual cooperative effects are unique to this class of anticancer drug and are the firstdemonstration of cooperative effects in solution for an anticancer drug.

(v) Site-specific intrastrand and interstrand cross-links of BBR3464. Bending, proteinrecognition and nucleotide excision repair

Oligonucleotide duplexes containing various site-specific intra- and interstrand cross-links formedby both dinuclear [{trans-PtCl(NH3)2}2m-(H2N(CH2)nNH2)]

2þ and trinuclear compounds havebeen prepared. The 1,2-intrastrand cross-link with one Pt unit each attached to two adjacentguanines 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 seenfor adducts of cisplatin151–153 Bending induced in DNA by dinuclear interstrand cross-links is notdirected, and at approximately 10–12� 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 recognitionof DNA adducts by HMG1 protein.154 For BBR3464 intrastrand site-specific adducts werealso 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 thatthe intrastrand DNA adducts of BBR3464 may present a block to DNA or RNA polymerases butare not a substrate for recognition by HMG-domain proteins.

In general, DNA interstrand cross-links could be even more effective lesions than intrastrand adductsin terminating DNA or RNA synthesis in tumor cells and thus could be even more likely candidates forthe genotoxic lesion relevant to antitumor effects of BBR3464.156 In addition, the interstrand cross-linkspose a special challenge to repair enzymes because they involve both strands of DNA and cannot berepaired using the information in the complementary strand for resynthesis.157 Unlike the intrastrandadduct, the interstrand cross-link is a poor substrate for nucleotide excision repair. These results validatethe finding that overexpressing the human nucleotide excision repair complex (ERCC1) was notdetrimental 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 ofDNA damage that is quite distinct from that of cisplatin. Lack of recognition by proteins whichbind avidly to cisplatin-damaged DNA suggest that the mediation of antitumor properties ofpolynuclear platinum compounds by cisplatin-like processes is unlikely. Thus, the structuralparadigm for antitumor activity based on the cisplatin structure is no longer valid—clinicallyuseful compounds may arise from study of new structures. Following this work, new dinuclearcompounds based on heterocycle azole and 4,40-dipyrazolylmethane bridges have also beendescribed ((18)–(20), Figure 11).159–161 These agents again give a different spectrum of activityto the dinuclear complexes with flexible diamine linkers.

9.18.2.2.4 Transplatinum compounds

The earliest ‘‘structure–activity’’ relationships indicated that the transplatinum geometry is inactive—significantly higher doses must be given before any therapeutic effect is seen. In 1991, it was reportedthat alteration of amine structure and the introduction of sterically hindered amines producedcytotoxicity similar to that of cisplatin.162 The first examples used planar amines and a variety oftrans-[PtCl2(L)(L

0)] compounds have been synthesized and evaluated ((21)–(26), Figure 12).163


In general, the cytotoxicity of these compounds was equivalent to cisplatin, and they main-tained their activity in cisplatin-resistant cells. In many cases the activity of a trans complex wasactually comparable to that of the cis isomer.164 Later these general observations were confirmedfor 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 asisopropylamine.165–169 While their in vitro cytotoxicity is clearly comparable with cisplatin, noexceptionally active compounds in vivo have been prepared. This fact may reflect some pharma-cokinetic problems still associated with the trans geometry. While most emphasis on the differ-ences between cis- and trans-platin has centered on the structures of their DNA adducts, thedifferent chemistry of the complexes themselves may also be important. This point is emphasizedby the enhanced antitumor activity of the PtIV compound (27) over its cytotoxic but antitumorinactive PtII analog, trans-[PtCl2(NH3)(cha)].

170 Solubility is still a major issue in the transcomplexes; 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 vivoantitumor activity.

In the case of complexes such as (21) and (23) which have an extended planar ligand, asignificantly higher proportion of interstrand cross-links in DNA is formed in comparison toeither cis- or trans-platin.172 The steric effects of these planar ligands result in the formation ofstructurally unique 1,2-interstrand cross-links like those formed by cisplatin, a unique example ofhow steric effects may alter a nonactive lesion into an active one (Figure 13).173,174 Model studiespredicted this outcome by preparation of the monofunctional models trans-[PtCl(9-ethylguanine)(NH3)(quinoline)] and comparison of substitution rates of the Pt—Cl bond by G or C mono-nucleotides.175,176 Interestingly, the iminoether compound (25) appears to form predominantlymonofunctional adducts with DNA.177

The DNA binding of trans-platinum complexes is thus quite rich and varied. The cellulareffects of such adduct formation also appear to be significantly different from those of cisplatin.

PtCl

H3N

NH3

N

HN NH

NPt

H3N Cl

NH3

PtH3N

H3N

NPt

NH3

NH3

N

OH

2+

PtH3N

H3N

NPt

NH3

NH3

NN

OH

2+

2 +

18

19

20

( )

( )

( )

Figure 11 Dinuclear platinum compounds based on heterocycle bridges.


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

9.18.3 NONPLATINUM ANTICANCER AGENTS

9.18.3.1 Ruthenium Complexes

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

PtH3N

Cl

Cl

NS

PtCl

N

N

Cl

PtCl

N

NH3

Cl

PtCl NH2

Cl

PtN

Cl N

ClPt

Cl

NH

N

Cl

PtNH2

Cl NH3

Cl

OH

OH

NH

H

OMeMe

H

MeOMe H2N+

NO

O

PtH3N Cl

21 22 23

24 25 26

27 28

Cl–

( ) ( ) ( )

( )( )

( )

( )

( )

Figure 12 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.


compounds are in general too inert. Ruthenium and rhodium have produced compounds with thegreatest promise, although no direct analogs have yet advanced to the clinic. In rutheniumammine complexes of the general series [RuCln(NH3)6�n]

zþ (where n¼ 3, 4, or 5), fac[RuCl3(NH3)3]showed good activity but was not sufficiently water soluble for extensive testing.178,179 Ruthe-nium-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]

2þ, but metalmigration may occur to other nucleobases.180 GSH modulates DNA binding of Ru-amminecomplexes: GSH reduction of the RuIII compound [ClRu(NH3)5]

2þ to the RuII state enhances itsDNA binding, but at [GSH]/[Ru] ratios >1 DNA binding is inhibited through eventual formationof [(GS)(NH3)5RuIII]. Covalent binding of trans-[(H2O)(py)Ru(NH3)4]

2þ to DNA occurs specifi-cally at guanine N7.181 The pyridine ligand further stabilizes the RuII oxidation state, which maylead to disproportionation of the generated RuIII species to RuII and RuIV species.182 Oxidativedamage 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 com-plexes, exhibit antitumor activity in animal models. The imidazole complexes trans-[RuCl4(L)2]

�

(where L¼ imidazole, indazole) have good antitumor activity.183,184 Transferrin and serum albuminmay act as transporters of the metal complexes in blood, and DNA is considered the ultimatetarget.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 Themechanism of action of this compound is not related to DNA binding; rather, it is an antimetastaticagent.187 Metastasis (the process whereby tumor growth occurs distant from the original or primarytumor site) is intimately linked with angiogenesis, the dynamic process that involves new bloodvessel 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.189–191

The molecular details by which NAMI-A exerts antimetastatic effects in vivo have not beendefinitely determined, and may occur by multiple mechanisms. The solution chemistry of NAMI-Ainvolves both loss of Cl and DMSO. Interestingly, the antimetastatic activity is retained under awide variety of experimental conditions producing solvolyzed intermediates.192 The exact natureof the active species may be difficult to resolve.

A noteworthy addition to Ru-DNA chemistry is the inhibition of topoisomerase II by the arene-Ru complex [RuCl2(DMSO)(�6-C6H6)].

193 Further variations on the arene theme produce cytotoxiccompounds of formula [(arene)Ru(en)Cl]þ.194,195 The crystal structure of the 9-ethylguanine adduct[(arene)Ru(en)(9-EtG)]2þ 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 toa more targeted approach, with special emphasis on signaling pathways. In this respect aremarkable 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 promomyelo-cytic leukemia (APL) in patients who have relapsed or are refractory to retinoid and anthracyclinechemotherapy. An estimated 1,500 new cases of APL are diagnosed yearly in the US, of which an

RuCl

Cl Cl

Cl

N

S

NH

OCH3

CH3

NH

NH

–

+

29( )

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


estimated 400 patients will not respond to, or will relapse from, first-line therapy. The approval ofarsenic trioxide as a chemotherapeutic agent invokes the pioneering work of Ehrlich and thedevelopment of Salvarsan for use in syphilis—the foundation stone for the science of chemotherapy.The use of chelating agents in medicine may even be traced to a collaboration between Werner (thefather of coordination chemistry) and Ehrlich (the father of chemotherapy) to find less toxic arseniccompounds for the treatment of syphilis.15 Arsenic has been used therapeutically for more than 2,000years and was used in the 1930s for treatment of chronic myelogenous leukemia until supplanted bynewer chemotherapies.196,197 The past, present, and future of medicinal arsenic has been describedas a story of ‘‘use, dishonor, and redemption’’. Recent interest in arsenic trioxide initially arosethrough Chinese reports of its efficacy and use.198 The recommended dose is 0.15mg kg�1 d�1

until remission.199 Side effects are cardiotoxicity, skin rashes, and hyperglycemia.200

Arsenic trioxide apparently affects numerous intracellular signal transduction pathways andcauses many alterations in cellular function. Thus, the mechanisms of cell death induced byarsenic trioxide are multiple: induction of apoptosis, inhibition of proliferation, and even inhibi-tion of angiogenesis have all been reported.201 In cellular studies, arsenic trioxide inhibitsglutathione peroxidase, possibly through generation of arsenic–GSH conjugates, and increasescellular hydrogen peroxide content.202 Consistent with a general role in redox processes, ascorbicacid enhances arsenic trioxide-induced apoptosis of lymphoma cells but not of normal bonemarrow cells, by increasing cellular H2O2 content.203 Arsenic trioxide sensitivity is associatedwith low levels of GSH in cancer cells.204 Apoptosis is apparent when cells are treated with lowconcentrations of the drug; this effect is associated with the collapse of mitochondrial transmem-brane potentials in a thiol-dependent manner.205 The combined effects have led to the suggestionthat arsenic trioxide may be situated as a novel mitochondriotoxic anticancer agent.206 Membranepotential decreases and membrane permeability increases as a result of arsenic treatment, result-ing in the release of messenger molecules for the degradation phase of apoptosis.

9.18.3.3 The Mitochondrion as Target. Gold–phosphane Complexes

Apoptosis is important in tissue homeostasis; inhibition of apoptosis may contribute to transfor-mation of cells and/or chemotherapy resistance. The apoptosis factors leading to cell death aremitochondrion-regulated. Mitochondria contribute to the regulation of energy production, meta-bolism, and redox status as well as apoptosis.207 The integral role of the mitochondrion inprogrammed cell death is by now well recognized and means that the mitochondrion is a suitabletarget for drug intervention.208 Mitochondrial DNA is also an attractive target because it issignificantly more sensitive to covalent damage than nuclear DNA, because of the lack ofprotective histones and a limited capacity for repair. The pioneering work of Chen showed thatenhanced mitochondrial membrane potential is a prevalent cancer cell phenotype;209 lipophiliccations accumulate inside mitochondria as a consequence of the higher membrane potentials.207

Treatment strategies directed at novel cellular targets but which are differentiated between normaland tumor cells are attractive approaches to selective tumor cell killing.

The gold–phosphane complexes (30)–(33) (Figure 15) are examples of lipophilic cations whichmay also have a role in mitochondrial toxicity.210,211 Whereas the role of gold salts in antiarthritistherapy is intimately related to thiol binding, the tetrahedral diphosphane compounds are muchless reactive toward thiols.212,213 The lipophilic cation [Au(dppe)2]

þ (where dppe¼ 2-bis(diphe-nylphosphino)ethane) showed potent in vitro cytotoxicity with evidence of antimitochondrialfunction214 but hepatotoxicity attributed to alterations in mitochondrial function curtailed clinicaltrials. The solution chemistry of gold–diphosphane compounds is rich and the interchangebetween mononuclear and dinuclear phosphane-bridged species has been extensively examined.57

Substitution of the phenyl groups by 2-pyridyl groups provides an opportunity to investigatesystematically the relationship of drug activity to lipophilicity.215,216 Compounds that are highlyactive in vitro may be obtained. Alteration of the lipophilicity greatly affected cellular uptake andbinding to plasma proteins. Alterations in lipophilicity also affect host toxicity, allowing theopportunity 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 highlyreactive superoxide radical anion O2

��. Endogenous overproduction of O2�� may cause considerable


damage to biological systems. Superoxide has been shown to be a mediator of reperfusiondiseases, such as those occurring after a stroke, and has been shown to be associated withdevelopment of inflammatory processes and also in the initiation of neurological disorders suchas Parkinson’s disease.217 The enzyme superoxide dismutase (SOD), either as the manganese-containing MnSOD (present in the mitochondrion) or the dinuclear Cu/Zn-SOD (present in thecytosol and extracellular space), performs the role of superoxide detoxification in normal cells andtissue:218

O2�� þMnþ þ 2Hþ ! H2O2 þMðnþ1Þþ ð1Þ

O2�� þMðnþ1Þþ ! O2 þMnþ ð2Þ

Overall:

2O2�� þ 2Hþ ! H2O2 þ O2 ð3Þ

Attempts to use the enzyme itself as a therapeutic agent have been partially successful inanimals, but not in humans.219 Pharmacokinetic problems, including delivery problems andthe short half-life in the blood, are major obstacles to use of the enzyme in humans. Cu/Zn-SOD preparations (trade names Palosein, Orotein) are used to treat inflammatory diseases indogs and horses. Small molecule mimics of natural enzymes such as SOD (dubbed synzymesfor synthetic enzymes) may effect similar chemistry and thus be useful in treating diseasestates brought on by an imbalance in superoxide. The considerations for successful applica-tion of this strategy are many: a compound must possess high chemical stability, SOD-likeactivity, 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), haveshown considerable promise in this regard (Figure 16).220–222 Rational design has produced anoptimal structure M40403 (35) which is a leading clinical candidate.223,224 This pyridine-basedmacrocycle has been used as a cancer co-therapy with interleukin-2 (IL-2), an immune-stimulatingcytokine drug that is approved for use in metastatic melanoma and renal cell carcinoma. Asusual, the utility of IL-2 is limited by side effects, notably hypotension, and hospitalization isnecessary for many patients. Preclinical studies have shown that M40403 enhances the efficacy ofIL-2. A phase I, double-blind, placebo-controlled clinical trial of M40403 administered intrave-nously to 36 normal, healthy human subjects showed no dose-limiting side effects. A phase IIclinical trial is planned to assess the effectiveness of M40403 as co-therapy with IL-2 in patientswith advanced skin and end-stage kidney cancers (http://www.metaphore.com). Interestingly,

PR'2R2P

AuAu

X X

AuR2P

R2P

PR'2

PR'2

PR'2R2P

AuAu

R2P PR'2

+ 2+

P PAu

P

R2P

PR2

AuPR2

R2P

P

2+

30 31 32

33

R2R2

R2R2

( ) ( ) ( )

( )

Figure 15 Structures of Au–phosphane compounds as potential mitochondrial poisons.


there is some indication that the salen-based compounds may involve catalase rather than SODactivity (Equation 4):

H2O2 þ 2Hþ ! 2H2O ð4Þ

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 structu-rally quite different compounds (Figure 17). Little information is available on the mode of actionof budotitane which is formulated in a mixture of glycols and water because of a lack of aqueoussolubility.225 Budotitane exists as a mixture of three cis isomers (37a–c) in thermal equilibrium, sothat 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 230mgm�2 and the dose-limiting toxicity was cardiac arrhyth-mia.227 The poorly defined aqueous properties and lack of details on the mechanism of action donot bode well for this drug.

The phase I clinical trial of [TiCl2Cp2] indicated a MTD of 315mgm�2 for a single intravenousinfusion, and 185mgm�2 weekly.228 The dose-limiting toxicity was nephrotoxicity.229 A phase IItrial 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 andleaving group (Cl) substitution, as well as use of ionic metallocenes for improving aqueoussolubility.231

O

N

O

NMn

A

N

HNNH

NH HN

Mn

Cl

Cl34 35( ) ( )

Figure 16 Manganese compounds as SOD mimics.

Ti

Cl

ClTi

O

O OEt

OEt

O

O

R1

R2

R3

R4

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.


DNA is purportedly the target of [TiCl2Cp2]. The somewhat naı̈ve early assertion that it couldact in a manner similar to cisplatin because of the similarity in Cl��Cl distances has never beenupheld experimentally.232,233 Instead the aqueous chemistry of [TiCl2Cp2] is dominated by loss ofthe Cp ring as well as hydrolysis of the Ti—Cl bonds. DNA interactions at pH 7 are very weakand the adducts when formed do not suppress DNA-processing enzymes so there is doubt as towhether DNA is the locus of action for these drugs. Ti–DNA interactions are dominated byinteraction 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 ofcollagenase type IV activity, suggesting some antimetastatic behavior. Titanium may also replaceiron 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 ofmalignancy, by reducing the elevated Ca2þ in blood.235 This disorder is often associated withbone cancers and is an acute-care condition in which rapid bone loss leads to life-threateninglevels of blood calcium. Gallium reduces the rate of bone loss by inhibition of the action ofosteoclasts, 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 (200mgm�2 day�1) are effective. At therapeutic doses, it has few side effectsand is well tolerated. Most recent attention has focused on the activity of gallium nitrate againstmalignancies, especially non-Hodgkin’s lymphoma, non-squamous cell carcinoma of the cervix,and bladder cancer. Clinical trials under the auspices of Genta (http://www.genta.com) willevaluate its efficacy on patients with low- or intermediate-grade non-Hodgkin’s lymphoma whohave failed prior chemotherapy. The results of phase II trials in non-small-cell lung cancer andprostate cancer have also been reported.236,237

Gallium compounds may be designed to deliver the Ga3þ 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 isonicotinoylhydrazone (Ga-PIH)240 give well-defined GaIII complexes.

9.18.4 ANTIBACTERIAL AGENTS

9.18.4.1 Silver and Mercury Salts

Silver and mercury salts have a long history of use as antibacterial agents.241–243 The use ofmercurochrome ((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 antibacter-ial Agþ ion. Silver nitrate is still used in many countries to prevent ophthalmic disease in newbornchildren.244 The mechanism of action of Ag and Hg is through slow release of the active metalion—inhibition of thiol function in bacterial cell walls gives a rationale for the specificity ofbacteriocidal action.

COONa

SHgEtO

COONa

Br

NaO

HgOH

Br

ON

N

N SO

ONH2–

38 39 40

Ag+

( ) ( ) ( )Figure 18 Silver- and mercury-based antibacterial agents.


9.18.4.2 Bismuth-containing Antiulcer Drugs

Bismuth compounds have been used for their antacid and astringent properties in a variety ofgastrointestinal disorders.245,246 The effectiveness of bismuth is due to its bacteriocidal actionagainst the Gram-negative bacterium, Helicobacter pylori. Usually the bismuth preparations areobtained by mixing an inorganic salt with a sugar-like carrier (see Figure 19). Commonly usedagents are colloidal bismuth subcitrate (CBS), and bismuth subsalicylate (BSS). The mechanismof action is complex and includes inhibition of protein and cell wall synthesis, membranefunction, and ATP synthesis. The most notable salts are tripotassiumdicitratobismuth, bismuthsalicylate, Pepto-Bismol (BSS), and De-Nol (CBS; (41)). The ‘‘sub’’ designation most likely arosefrom stoichiometry of oxygen to bismuth. The combination of ranitidine (a histamine H2-receptorantagonist) and bismuth citrate is marketed as Ranitidine Bismutrex for the management ofpeptic ulcer and ulcers associated with H. pylori.247

Much progress has been made on the coordination chemistry of these preparations. Detailedmolecular characterization is obviously of primary importance in understanding chemical andbiochemical function. BiIII is highly acidic in aqueous medium and the oxygen-rich nature of thesugar carrier ligands leads to formation of di- and polynuclear-bridged complexes, based on thetypical dinuclear unit (41) shown in Figure 19.248–251 The nature of the ranitidine/bismuth citrateadduct has been examined and second coordination sphere effects were noted for the organicamine.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 stablecomplexes with GSH255 and transferrin.256 The latter observation may be correlated with the highacidity 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 developmentthat has languished because of poor economic return. The spread of resistance to chloroquine (anantimalaria treatment) is one reason for attention to be paid to this area, as well as the sheernumbers of people affected. Antimony compounds (43) and (44) (Figure 20) are used to treat

OH

O

OH

OH

HO

OH

OH

O OH

OHO

HOOH

O OH

O

HO

OH

O

O

HO

O Bi

O

O

OOOBi

O

O

O

O

H2sal H4gal H4tar H4cit

O

O

O

O

41 (basic skeleton only shown for clarity)

BiS

O O

S

S

O

OMe

MeO

MeO

42( )( )

Figure 19 Bismuth antiulcer drugs—the sugars used to produce the usually polymeric structures are shownin the top panel.


leishmaniasis (H. Sun, personal communication). Another approach is to complex metal ions toknown 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 beendescribed ((45) and (46), Figure 21).257–260 In favorable cases, some of these compounds showgood activity—the chloroquine complexes being useful even in chloroquine-resistant cases.

9.18.5 PHARMACODYNAMIC USES OF METAL COMPLEX DRUGS

9.18.5.1 Lithium Carbonate

The clinical value of lithium has been recognized since 1949. Lithium carbonate is used in manicdepressive psychoses for the treatment of recurrent mood changes.261,262 Mood stability may onlyoccur after months rather than weeks. The drug is administered orally in doses up to 2 g day�1

(30mmol day�1). The serum Li concentration should be in the range of 0.4–0.8mmol l�1.

CH

CH

HC

HC O

O

O

O OO

OO

O OO OSb Sb

O

O

O

O

Sb

SO3–

–O3S

SO3–

SO3–

5 –

2–

43

44

( )

( )

Figure 20 Antimony-based antiparasitic agents.

RuCl

Cl

Et2N

N

NH

NCl

Ru

NEt2

Cl

Cl

HN

Cl

N

Au

PPh3

Cl

HNN(CH2CH3)2

+

4546

( )( )

Figure 21 Gold and ruthenium complexes of antiparasitic agents.


The development of lithium-specific electrodes has assisted greatly in monitoring patient compli-ance. The toxicity profile of lithium carbonate is now well established and the drug is safelyadministered and well tolerated. It is of limited use in other psychiatric disorders such aspathological aggression, although additional benefit may also include a reduction in actual orattempted suicide.

Newer uses have appeared in the treatment of viral diseases including AIDS, alteration of theimmune response, and cancer. The lithium salt of �-linolenic acid (LiGLA) has a significantanticancer effect against certain cancers. The neurochemical basis for lithium action is difficult todefine. Lithium carbonate induces a wide range of intra- and extracellular changes—mostemphasis has been naturally on the similarities with Na/K/Ca/Mg ions. Lithium selectivelyinterferes with the inositol lipid cycle, representing a unified hypothesis of action. The biochem-istry, 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 ofthe insulin-like properties of vanadate ions spurred research into the clinical use of vanadiumcompounds as insulin mimics.264 Inadequate glucose metabolism, either through absence ofendogenously secreted insulin or insulin resistance, leads to diabetes mellitus. The potential ofinsulin-mimetic compounds as drugs lies in their oral administration—insulin, as a small protein,is not orally active. The vanadate (V) ion is effective upon oral administration, and an obviousstrategy to enhance the pharmacokinetic characteristics and the efficacy of the insulin-mimeticresponse is complexation of vanadate with suitable biologically compatible ligands.265,266

Insulin binding to the extracellular side of cell membranes initiates the ‘‘insulin cascade’’, aseries of phosphorylation/dephosphorylation steps. A postulated mechanism for vanadium issubstitution of vanadate for phosphate in the transition state structure of protein tyrosinephosphatases (PTP).267,268 In normal physiological conditions, the attainable oxidation states ofvanadium are VIII, VIV and VV. Relevant species in solution are vanadate, (a mixture of HVO4

2�/H2VO4

�) and vanadyl VO2þ. Vanadyl is not a strong inhibitor of PTPs, suggesting otherpotential mechanisms for insulin mimesis for this cation.

Both VIV and VV coordination compounds have been tested as insulin mimics. The preponder-ance of VIV compounds contain the V¼O(L-L)2 motif (e.g., (47) and (48), Figure 22) andcomplexes containing a variety of O,O; N,O; N,S; and S,S bidentate ligands L–L have beensynthesized and tested. Control of lability and ligand displacement are important criteria for drugdesign in terms of delivery of the biologically active vanadate. Clinical trials have focused to dateon sodium orthovanadate and the bis(maltolato)oxovanadium(IV) compound (BMOV) (47). Thespeciation 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 orallyactive auranofin (also known as Ridaura; (50), Figure 23) was a major improvement over theearly ‘‘injectable gold’’ preparations which were polymeric (e.g., (51)–(53)). However, use hasdeclined with the popularity of nonsteroidal antiinflammatory drugs (NSAIDS) such as indo-methacin; a recent estimate of the commercial value for auranofin was $6 million. The mechanism

OV

O

O

OO

O

OCH3

CH3S

V

H2N

S

H2N

ONH

NH

OO

C8H17C8H17

47 48( ) ( )

Figure 22 Vanadium compounds in treatment of diabetes.


of action is postulated to occur through thiolate exchange reactions.271 The structures of thepolymeric gold compounds have been described in detail. An interesting feature of gold metabo-lism 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 Thenitroprusside ion, [Fe(NO)(CN)5]

2� is a vasodilator used in emergency situations to treat hyper-tensive patients in operating theaters.274,275 The complex is 30–100 times more potent than simplenitrites. The mechanism is considered to be release of NO, an understanding prompted by theemergence of NO as a prominent cell signaling molecule.273 Related to the biology of NO isproduction of peroxynitrite ONOO� through reaction of NO with O2

�. In this regard, productionof peroxynitrite may play a role in many pathological conditions.276,277 Water-soluble porphyrinsand texaphyrins may catalytically react with ONOO� and may have clinical utility in peroxynitritescavenging.

9.18.5.5 Lanthanum Carbonate

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

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O3S

S Au S

SO3

CH2

CO2–

CH S–

CO2–

3–

Polymeric [AuRS]n compounds:

OCH2OAc

AcO

OAc

SAu(PEt3)

OAc

49 50

51 RS– =

–O3S S–

52 RS– =O

CH2OH

HO

OH

S–

OH

53 RS– =

( )

( )( )( )

( )

Figure 23 Au antiarthritis compounds.


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