Medical Uses of Gold Compounds:Past, Present and Future

Simon P Fricker

Johnson Matthey Technology Centre,Blount's Court, SonningCommon,

Reading, Berkshire, RG49NH, UK

Gold, in a variety of forms, has been used in medicine throughout the history of civilisation. In the twentiethcentury gold complexes were introduced for the treatment for rheumatoid arthritis, culminating in theintroduction of the oral drug Auranofin in 1985. The clinical use and mechanism of action of gold drugs isreviewed here, including recent discoveries on the effect of gold drugs on gene expression. The search for newmedical uses of gold is described, focusing on the anticancer and antimicrobial properties of gold compounds.

MEDICAL USES OF GOLDCOMPOUNDS: PAST, PRESENT ANDFUTURE

Gold has been exploited for its putative medicalproperties throughout the history of civilisation (1, 2).The earliest medical use of gold can be traced back tothe Chinese in 2500 Be. In medieval Europealchemists had numerous recipes for an elixir known asaurum potabile, many of which contained little gold!A gold cordial could be found in the newpharmacopoeias of the 17th century and wasadvocated by Nicholas Culpepper for the treatment ofailments caused by a decrease in the vital spirits, suchas melancholy, fainting, fevers, and falling sickness.Later in the 19th century a mixture of gold chlorideand sodium chloride, 'muriate of gold and soda,'Na[AuCI4] was used to treat syphilis.

The use of gold compounds in modern, twentiethcentury medicine began with the discovery in 1890 bythe German bacteriologist Robert Koch that goldcyanide K[Au(CN}z] was bacteriostatic towards thetubercle bacillus. Gold therapy for tuberculosis wassubsequently introduced in the 1920s. The suggestionthat the tubercle bacillus was a causative agent forrheumatoid arthritis led to the use of gold therapy forthis disease. Gold therapy soon proved to be ineffectivefor tuberculosis but, after a thirty year debate a clinical

($i9' GoldBulletin 1996, 29(2)

study sponsored by the Empire Rheumatism Councilconfirmed the effectiveness of gold compounds againstrheumatoid arthritis. Since that time gold drugs havealso been used to treat a variety of other rheumaticdiseases including psoriatic arthritis, a form of arthritisassociated with psoriasis, juvenile arthritis, palindromicrheumatism and discoid lupus erythematosus (3).Encouraging results have also been obtained with goldtherapy as a treatment for various inflammatory skindisorders such as pemphigus, urticaria and psoriasis(4). Chrysotherapy, treatment with gold based drugs(from the Greek word for gold, chrysos) is now anaccepted part of modern medicine.

These are the major clinical uses for goldcompounds to date and there have been no majorchanges in this field since the introduction ofauranofin for the treatment of rheumatoid arthritis in1985. The use of antiarthritic gold compounds willtherefore be discussed only briefly, and the reader isreferred to the many excellent reviews on this subject(2-7). Some of the most interesting advances in thepharmacology of gold drugs have emerged from studieson their mechanism of action; and these findings, andtheir relationship to the biological chemistry of thegold drugs, is discussed. The future for the medicinalchemistry of gold may be in therapeutic areas otherthan rheumatoid arthritis and new research into theanticancer and antimicrobial activity of goldcompounds will therefore be reviewed.

53

CHRYSOTHERAPY FORRHEUMATOID ARTHRITIS

Rheumatoid arthritis is an inflammatory diseasecharacterized by a progressive erosion of the jointsresulting in deformities, immobility and a great deal ofpain. It is an autoimmune disease in which the body'simmune system mounts a response against itself. Thisresults in a malign growth of the. synovial cells (thecells lining the joint) called a pannus, and infiltrationof the joint space by cells of the immune system,primarily macrophages, and associated production ofimmunoglobulin p.roteins. called rheumatoid factors.Phagocytic cells release degradative enzymes such ascollagenase, and generate reactive oxygen species OH'and 02-,all of which contribute to the resulting tissuedamage. This progressive inflammatory response ispromoted by raised levels of chemical mediators suchas prostaglandins, leukotrienes and cytokines.

The early gold compounds used for the treatmentof rheumatoid arthritis were gold(I) thiolates (AuSR)such as sodium aurothiomalate (MyocrisinTM) (1) andaurothioglucose (SolganoI™) (2) (Figure 1), SR beingthiomalate and thioglucose respectively (3).Myocrisin" is still to be found in the British NationalFormulary for use in the treatment of arthritis. Both ofthese compounds are oligomers, either forming rings

or chains, with a typical formula of [Au8(STM)9]- forMyocrisinTM, the 'extra' -SR ligand being required tocap the 'bare' gold atom at the end ofthe chain.

Both drugs are water soluble and have to beadministered by deep intramuscular injection at weeklyintervals. An initial dose of 10 mg is given, followed byincreasing doses of up to 50 mg until the onset ofremission when the dosing can be reduced (6). Afterrapid absorption the gold is rapidly cleared from thebloodstream and distributed to various tissuesincluding the kidneys where it accumulates and givesrise to nephrotoxicity, a major side effect. Otheradverse reactions include mouth ulcers, skin reactions,blood disorders and occasional liver toxicity (5). Thegold compounds are also slow acting, requiringtreatment for up to 4 to 6 months before a beneficialeffect is seen.

In spite of these problems there were clearindications that gold therapy was effective in arthritis.This led to the search for a drug with an improvedpharmacokinetic profile and reduced toxicity. In 1985a new compound, auranofin, [tetra-Ovaceryl-f-D>(glucopyranosylrthio] (rriethylphosphinejgoldtlj],Ridaura" (3) (Figure 1), was introduced as an orallybioavailable gold drug for arthritis (8). Auranofin is amonomeric thiolate with the general formulaR3PAuSR, the phosphine ligand making thecompound lipophilic (5). Auranofin has several

CHOAc

H)-O S-Au·

blAcO r-l H

H OAc

(3)

INaG C)"LNaO C S-Au

(1)n

Structures of Gale! Drugs

PEt.

CHOH

~~O S-Au

UHO r-l H

H OH

(2)

Figu~ 1 Thr strut:tU't'lj ufgoldd't':U.gs for lilt twiltm~", ofr/,nJm4toirJ Ilrthn'tis; (1) MHiium flurotbionlillau (Myotrisin rM), (2)lJuioth;agluc(l~ (Solpnol roW), (3) (1U.1'd.tldfin (HitidlJ.'t'4 7:'.1).

54 @ GoldBulletin 1996,29(2)

advantages over previous gold drugs, not least that itcan be taken orally. Serum gold levels are reduced andmaintained for longer, and there is less retention ofgold in the tissues and hence renal toxicity issignificantly reduced. These advantages are, however,offset by a reduction in efficacy compared with theoligomeric gold(I) thiolates.

The mechanism of action of the antiarthritic goldcompounds is unclear, in part due to the lack ofunderstanding of rheumatoid arthritis. An appreciationof the chemical interaction of gold complexes withnaturally occurring ligands in a biologicalenvironment is helpful in our understanding of thepharmacological activity of the gold drugs.

BIOWGICAL CHEMISTRY OFGOLD

There are several excellent reviews on the biologicalchemistry of gold (9-11) so it is appropriate to givehere only a brief overview of selected aspects pertinentto the pharmacology of gold drugs. Gold can exist in anumber of oxidation states: -I, 0, I, II, III, rv and V,but only gold 0, I, and III are stable in aqueous, andtherefore, biological environments. Both gold(I) andgold(III) are unstable with respect to gold(O) and arereadily reduced by mild reducing agents. Gold(I) isthermodynamically more stable than gold(III). Manygold(III) complexes are strong oxidising agents, beingreduced to Au(I) , and this means that they aregenerally toxic. This reduction can be driven bybiologically occurring reductanrs such as thiols.Gold(I) generally forms two coordinate, linearcomplexes such as the gold thiolate antiarthriticcompounds which can undergo associative ligandexchange reactions with biological ligands. Gold(I) hasa preference for 'soft' ligands and will reactpreferentially with S-donors rather than 0- or N­donors. The gold thiolate drugs will undergo ligandexchange with cysteine-rich peptides and proteins suchas glutathione, metallothionein, and albumin (12),particularly where the pK~ of the SH group is low, e.g.the cys-34 of albumin. Gold(I) can be stabilized bycyanide or thiolate ligands, including naturallyoccurring thiols such as the amino acid cysteine, andgold is primarily transported in the bloodstream as analbumin adduct.

There have been suggestions that auranofin has adifferent mechanism of action to the simple gold(I)thiolates (13). Auranofin is extensively metabolised in

<B9' GoldBulletin 1996,29(2)

vitro so that the final active species is probably similarto that of the oligomeric gold complexes. There is alsoevidence to suggest that auranofin inhibits theproduction of reactive oxygen species, such assuperoxide and the hydroxyl radical, produced duringthe oxidative burst of activated polymorphonuclearcells (a phagocytic cell of the immune system). In thiscase the active metabolite may be aurocyanide. Onesuggestion is that gold complexes may react with thecyanide released during phagocytosis formingaurocyanide. This can readily enter cells, and has beenshown to inhibit the oxidative burst (3).

GOLD-PROTEIN INTERACTIONS

The ability of gold thiol compounds to undergo ligandexchange reactions with biological ligands such as theamino acid cysteine may contribute to theirpharmacological activity. One proposal is that golddrugs inhibit the interaction of the degradativeenzymes by reacting with thiol groups inmetalloproteinases such as collagenase (7).

Gold(I) also undergoes ligand exchange with otherbiological proteins including albumin, andmetallothioneins forming aurothioneins (12). Theprecise pharmacological significance of these inter­actions is unclear but may well provide a focus for thedevelopment of third generation antiarthritic drugs.

GOLD COMPOUNDS AND GENEEXPRESSION

Gold compounds exert a number of effects on theimmune response, one of these being a reduction incytokine levels. Recent data indicates that this may bea result of the interaction of gold with thiol groups onthe proteins responsible for regulating the transcriptionof the genes controlling cytokine expression. Transcrip­tion is the copying of the DNA sequence encodinggenes into the RNA messenger molecule. This is thensubsequently translated into the protein productencoded by the gene. This process is controlled anddirected by a number of ancillary proteins calledtranscription factors which bind to specific DNAsequences and initiate gene transcription. Regulationof gene transcription plays an important part in anumber of diseases including oncogene expression incancer and cytokine production in inflammatorydiseasesuch as rheumatoid arthritis.

55

Many transcription factors contain cysteine, suchas the Bzip transcription factors jun and los oncogenes.The cysteine residues in the transcription factorsencoded by the oncogenes jun and los are flanked bythe basic amino acids lysine and arginine. This resultsin the lowering of the pKa·of the cysteine -SH thusfavouring ligand exchange with gold(I) thiolates, Thesetranscription factors are known to control thetranscription of a gene known as AP-l which in turn isinvolved in the expression of genes for collagenase andthe eytokine IL-2. It has been shown thataurothiomalate .can inhibit AP-l transcription viainteraction with jun and los (14). This has importantimplications for rheumatoid arthritis as anothertranscription factor NF-KB, which controlstranscription of other inflammatory mediatorsincluding Tumour Necrosis Factor (TNF) , alsocontains a cysteine flanked by lysine and arginine. It istherefore possible that one molecular mechanism forthe gold antiarthritic drugs is inhibition of transcrip­tion of crucial mediators of the inflammatory process.

ANTICANCER ACTNITY OF GOLDCOMPOUNDS

The discovery of the antitumour activity of cisplatin,cis-[PtCI2(NH 3)zJ , in 1969 prompted the search forother metal-containing antitumour drugs (15, 16).Gold has been included in this search; and there hasbeen intensive effort to identify a gold antitumourdrug. There were early indications that auranofin hadlimited antitumour activity in in vitro systems and inthe P388 leukaemia in vivo, however, it was inactiveagainst solid tumours. Severalother gold(I) phosphineswith thiosugar ligands were investigated with similarresults.

More promising indications were achieved with aseries of digold phosphine complexes. The leadcompound was [dppe(AuCI}z] (4) (Figure 2). Thedppe ligand itself exhibits anti tumour activity, and ithas been suggested that the gold serves to protect theligand from oxidation and aids in the delivery of theactive species. This is an oversimplification, however,and there is substantial evidence to support a directrole for the gold in the anticancer activity of thiscomplex (15). The digold phosphine complex wasshown to rearrange to give the tetrahedral complex[Au(dppe)zJ+ (5) (Figure 2) (17). The tetrahedralcomplex is more stable as the chelate effect stabilisesthe compound, and the phosphine ligand is more inert

56

(5)

Figure 2 Thestructures ofanticancer gold(!) phosphinecompounds; (4) [dppe(AuCl)), (5) [Au(dppe))+ .

to substitution by the types of thiolate ligands thatcould be encountered in a biological environment. Theproposed mechanism of action for [Au(dppe}zJCI wasthe formation of DNA-protein crosslinks, the lack ofaffinity for Au(I) for 0- and N- containing ligandsresulting in poor reactivity with the bases of DNA(18). Though this compound had marked activityagainst peritoneal cancer cells, [Au(dppe}zJCI was stillonly slightly active against solid tumour models. Thiscompound was not entered for clinical trials, however,due to problems with cardiotoxicity highlighted duringpre-clinical toxicology studies (19).

One avenue of investigation has been to synthesizegold complexes containing ligands with knownantitumour activity (16). Examples of this are a seriesof Ph3PAu(I)-nucleotide complexes containing ligandssuch as 5-fluorouracil and 6-mercaptopurine;phosphinogold(I) ferrocene complexes such as [p-I,1­bisbis(diphenylphosphino) ferroceneJbis(chloro­goldflj), and more recently a series of novel nitrogencontaining phosphinogold(I) ferrocenes (20); and agold(III) complex of streptonigrin, a substituted 7­amino-quinoline-S.R-dione (16).

Gold(III) complexes have not been as thoroughlyinvestigated as gold(I) complexes, primarily because oftheir reactivity. Gold(III) is isoelectronic (d8) withplatinum(II) and likewise forms square planarcomplexes. It is therefore tempting to speculate thatsuch complexes would have similar antitumour activityto cisplatin. One approach has been to synthesize

~ GoldBulletin 1996, 29(2)

---------------------

Figure 4 T/,~ 1fr:roIIA"CI/dPmp)} on thegrolOlh ofthrZR475-1 breast tumour xmografi. Tbe compoundwas administ~,'(;"don Uys 0.,7, 14 llnd 21. 1umtmrgror;.lth ii ~p1Wf:dM "Iiltive mmeur volume, HITR7V = 100 ~ (mean volume 0fwmo"r (If assessmemtimt)l(mM:n tumour Ito/ume 41 start},

14

Days

7

r -.- ControlsI - 0- 6.25mglkfj

l- .a.- 12,5rng/\\g-0- 25rnglkg

o

2500

300D.,-;:====::::=-::====~-----.n

>l­ll:

2000

compounds can be further evaluated in an in vivosetting. Initial in vitro studies indicated that the breastcarcinoma cell line ZR-75-1 was sensitive to[AuCI2(damp)] (6) (Table 1). This compound was thenfurther tested in vivo against a xenograft of the sametumour cells where it demonstrated modestantitumour activity, seen as a reduction in tumourgrowth compared with controls, and comparable to

cisplatin activity against the same tumour in vivo(Figure 4). Further analogues of [AuCI2(damp)] havebeen evaluated in this way (21). Biochemical studies

Figure 3 The structures ofgold(III) compounds withantitumour and antibacterial activity inexperimental models; (6) [AuClldamp)}, (7)[Au(OAc)ldamp)).

(6)

of the amine group and the carbon of the aryl ringbond to the metal. The monodentare ligands arereadily hydrolysed and are available for substitution.

These gold(IlI) complexes have been evaluatedagainst an in vitro panel of human tumour cell linescomprising cells of different tissue types and differentresponses to cisplatin (21). Differential toxicity, asopposed to non-selective toxicity, across the cell linepanel is used as an indicator of potential antitumouractivity (22). Most of the cell lines used in this panelcan also be grown as solid tumour xenografts inimmune-deprived, nude, mice and this means the

complexes with a single mono negative bidentateligand, damp, (2-[(dimethylamino)methyl]phenyl),and two monodenrate anionic ligands e.g. CI oracetate (OAc) (Figure 3). The damp ligand forms partof a five-membered chelate ring in which the nitrogen

IC SD (lJg/rnl)

[AuC I,(damp)]

[PtC ',(NH,)J

SW620(colon)

50

120

SWII16(colon)

48

135

SW403(colon)

56

200

ZR-75-1(breast)

II

15

HT29/219(rectum)

22

30

HTI376(bladder)

12

15

SK-OV-3(ovary)

18

14

Table 1 Cytotoxicity ofgold (III) complex againsta panel ofhuman tumour celllines. Cisplatin is includedfOr comparison. TheIe50 is the concentration ofcompoundgiving50% inhibition ofcellgrowth.

@ GoldBulletin 1996, 29(2) 57

(23) indicate that these compounds have a mechanismof action significantly different to that of cisplatinsuggesting that this is a potentially important novelclassof metal-containing anti tumour agents.

ANTIMICROBIAL ACTIVITY OFGOLD COMPOUNDS

The implication of microbial infection as a causativeagent in arthritis was the stimulus for the investigationof the antimicrobial properties of gold complexes. Theearly work by Robert Koch demonstrated that goldcompounds were active against the tubercle bacillus.Subsequent extensive work in the 1930's and 1940'sdemonstrated that a variety of gold compounds wereactive against a broad spectrum of microorganisms(24). Activity in in.uitro test systems was demonstratedagainst both gram negative and gram positive bacteria,a number of strains of mycoplasma, and the protozoanLeishmania. Gold complexes were also able to modifythe course of a number of in vivo infections in a varietyof animal hosts. Many of these early studies wereflawed, however, and the lack of evidence for the roleof an infectious agent in rheumatoid arthritis meantthat this work was not pursued. Since then there hasbeen little novel work on the antimicrobial activity ofgold complexes. There are indications that theantiarthritic gold complexes may suppress H pyloriinfections in the gastric mucosa (25), a causative agentfor peptic ulcers, and that gold phosphine complexesin vitro are cytocidal towards Pseudomonas putida (26).

There is a growing clinical need for newantimicrobial agents.. The therapeutic efficacy of drugscurrently available for the treatment of a class ofbacteria known as the 'problem Gram positive cocci' islimited by the emergence of multiply-resistant strainssuch as methicillin-resistant Staphylococus aureus

(MRSA) and enterococci e.g. Enterococcus faecalis (27).Vancomycin is the drug of choice for these organismsbut it too has limitations as it must be administered byintravenous infusion, and has problems with resistance,particularly against the enterococci.

In recent studies a number of different metalcomplexes have been tested for antimicrobial activity(28). The compounds were tested against a number ofbacterial strains including clinical isolates ofmethicillin-resistant S. aureus (MRSA), methicillin­sensitive S. aureus, enterococci, coagulase-negativestaphylococci, and streptococci. A gold(I) thiocyanatecomplex [Au(SCN)(PMe3) ] demonstrated activityagainst Gram positive bacteria including MRSA.Comparative toxicity against mammalian cells wasestimated in vitro against the CHO rodent cell line.The complex [Au(SCN)(PMe 3) ] demonstrated goodselectivity for bacteria over mammalian cells with anMICso, minimum concentration inhibiting 50%bacterial growth, of 0.33 against Staphylococcusaureus and 0.77 against Enterococcus faecalis, and withtoxicity against the CHO cells at concentrations atleast lOx greater than the MIC. This compound wasalso active in an in vivo murine model of topical, skinsurface, infection achieving a 2-3 log reduction for alltest organisms, including Staphylococcus aureus andEnterococcus faecalis, compared with controls (29).

Further investigation of gold complexes has led tothe identification of a series of gold(I) phosphoniumdithiocarboxylate complexes which also have activityagainst Gram positive bacteria, including the 'problemGram positive cocci' (28). The antimicrobial activity ofthe gold(III) compounds [AuClz(damp)] (6) and[Au(OAc}z(damp)] (7) (Figure 3) has been investigated(29). Both exhibit broad spectrum activity against arange of organisms, with a small degree of specificityagainst the Gram positive organisms S. aureus and E.faecaliswith the more water soluble ci:.1Ll-j on> (:l'-~i\-;lf iVl-

MIC (~g/ml)

S.aureus E. faecalis E.coli P. aeruginosa

[AuC12(damp)] 1.0- 2.5 1.0 - 2.5 10 - 25 10 - 25

[A\J(OAc)2(damp)] 0.25 - 1.0 0.25 - 1.0 2.5 - 10 50 - 100

Table 2 Antibacterial activityofgold(III) complexes against a range ofbacteria.MIC is the range between the highest concentration allowinggrowth and the lowest inhibitinggrowth.

58 @ GoldBulletin 1996, 2L~: ~I

REFERENCES

CONCLUSIONS

ABOUT THE AUTHOR

being the most potent (Table 2). Both are similarlytoxic against the mammalian CH0 cells indicatingthat the diacetato complex is the more selective of thetwo complexes for bacteria over mammalian cells.

10 e.P. Shaw III, Inorg. Persp, Biol. Med., 1979, 2,278

1 D.H. Brown and WE. Smith, Chem. Soc. Rev.,1980,9,217

12 c.s Shaw III, Comments Inorg. Chem., 1989, 8,233

13 D.T. Walz, M.J. Dimartino and D.E. Griswold,J Rbeumatol, 1982,9, Supple 8, 54

14 M.L. Handel, e.K.W Watts, A deFazio, R.O.Day and R.L. Sutherland, Proc. Natl. Acad. Sci.USA, 1995, 92,4497

15 O.M. Ni Dhubhghaill and P.J. Sadler, in 'MetalComplexes in Cancer Chemotherapy', ed. B.K.Keppler,VCH, Weinheim, 1993, p. 221.

16 e.P. Shaw III, in 'Metal Compounds in CancerTherapy', ed. S.P. Fricker, Chapman and Hall,London, 1994,p.46

17 c.x Mirabelli, R.K. Johnson, S.T. Crooke, M.R.Mattern, S.M. Mong, e.M. Sung, G. Rush, S.J.Berners-Price, P.S. Jarrett and P.J. Sadler, in '5thInternational Symposium on Platinum and OtherMetal Coordination Compounds in CancerChemotherapy', ed. M. Nicolini and G. Bandoli,Cleup, Padua, Italy, 1987, p. 319

18 S.]. Berners-Price, P.S. Jarrett and P.]. Sadler,Inorg. Cbem., 1987,26,3074

19 G.D. Hoke, R.A Macia, zc. Meunier, P.J.Bugelski, e.K. Mirabelli, G.P. Rush and WD.Matthews, Toxicol. Appl. Pbarmacol., 1989, 100,293

20 M. Viotte, B. Gautheron, M.M. Kubicki, I.E.Nifant'ev and S.P. Fricker, Metal Based Drugs,1995,2,311

21 R.Y: Parish, B.P. Howe, J.P. Wright, J. Mack,R.G. Pritchard, R.G. Buckley, A.M. Elsome andS.P. Fricker, Inorg. Cbem., 1996,35, 1659

22 S.P. Fricker, in 'Metal Ions in Biology andMedicine', ed. Ph. Collery, L.A Poirier, M.Manfait and j-C, Etienne John Libby Eurotext,Paris, 1990, p. 452

23 AM. Elsome, PhD Thesis, King's College,London, 1995

24 J.H. Liebarth and R.H. Persellin, Agents andActions, 1981,11,458

25 L. Girgis, P.G. Conaghan and P. Brooks,Curr. Opin. Rheumatol., 1994, 6, 252

26 M.D. Rhodes, P.]. Sadler, M.D. Scawen and S.Silver,] Inorg. Biochem., 1992,46, 129

27 W Brumfitt, J.M.T. Hamilton-Miller, DrugsExpt!. Clin. Res., 1990,16,205

28 AM. Elsome, W Brumfitt, J.M.T. Hamilton­Miller, P.D. Savage, R.O. King and S.P. Fricker,

G;]. Higby, GoldBull, 1982,15, 130RV Parish, Interdisc. Sci. Rev., 1992, 17,221G.D. Champion, G.G. Graham and J.B. Ziegler,Ballieres Clin. Rbeumatol.,1990, 4, 491R.E. Thomas and R.A Papandrea, Med. J Aust.,1993,158,720R.Y: Parish and S.M.. Cottrill, Gold Bull, 1987,20,3N.L. Gottlieb, J Rheumatol., 1982, 9 (Suppl.8),99R.M. Snyder, e.K. Mirabelli and S.T. Crooke,Semin. Arthritis Rheum.,1987, 17, 71T.G. Davis (ed), Scand. J Rheumatol., Supplement63, 1986P.J. Sadler, Struct. Bonding, 1976, 29, 1719

8

'7

6

4

3

Dr Simon Fricker is a Principal Scientist in theBiomedical Technology Department at the JohnsonMatthey Technology Centre, where he has beenresponsible for pharmacology and toxicology for 12years, on the research and development of novelinorganic pharmaceuticals.

Gold therapy has been a component of the physiciansstock in trade since the earliestdaysofcivilisation. In thetwentieth century chrysotherapy has become establishedas an important part of the treatment regimen forrheumatoid arthritis. In terms of drug discovery nomajor advances have been made for the last decade,despite the considerable effort to find new therapeuticuses for gold compounds, particularly for anticancertherapy. However, our understanding of the mechanismof these drugs continues to improve, particularly withthe exciting observations of the effect of gold drugs ongene expression. After sixty years of chrysotherapy it ispossible that an improved understanding of themolecular and biochemical mechanism of goldcompounds will provide the impetus for new advancesin the medical use of gold drugs.

(fiS' GoldBulletin 1996, 29(2) 59

in 'Program and Abstracts of the 31st InterscienceConference on Anti-Microbial Agents andChemotherapy, Chicago', American Society forMicrobiology, Washlllgton, DC, 1991, Abstract387, p.163

29 A.M. Elsome, J.MT. Hamilton-Miller, W

Brumfitt and W.e. Noble, J. Anttmzcrob.Chemothe~, 1996,37,911

30 R.Y: Parish, J. Mack, L. Hargreaves, J.P. Wright,R.G. Buckley, A.M. Elsome, S.P. Fricker andB.R.e. Theobald, J Chem. Soc., Dalton Trans.,1996,69

Studies on Activation Mechanism for Au/Zn

CO-Sensing Systems

60

A recent paper describes the use of FourierTransform Infrared Spectroscopy (FTIR) andquadruple mass spectroscopy to assist inunderstanding the processes of adsorption andoxidation of CO on an Au/ZnO sample (1).160 2 and 180 2 were used to demonstrate thatCO adsorbed on gold sites at the perimeterinterface with ZnO reacts with surface latticeoxygens to form carbonate-like intermediates. Itis claimed that this reaction and thedecomposition of the intermediates is theprincipal reason for the conductivity changes inthe semiconducting metal oxide when in contactwith CO in air.

The oxygen adsorbed from the air onto goldvicinal sites facilitates nucleophilic attack bysurface oxygen on the CO. It had beenpreviously shown that highly dispersed goldappreciably enhances the sensitivity and selectivityto CO detection (2). The samples for the recentstudy were prepared by co-precipitation fromHAuC14 and Zn(N03h solutions, followed bycalcination in air at 400°e. TEM micrographsshowed that the gold particles' werehomogeneously dispersed on ZnO, with particlediameters smaller than 5 nm (1, '3). The infraredspectra were run at room temperature in aninfrared cell designed to examine samples in situ,under controlled atmospheres.

The results showed that:• CO is activated by gold in three molecular

forms: a linear carbonyl species bonded at Auterrace, step and kink sites, a carbonyl speciesbonded to Au borderline sites, and a carbonylspecies also interacting with Zn cations, viathe rt-orbitals.

• The high CO oxidation activity of Group 11(IB) elements supported on ZnO can berelated to the high basicity of oxygen atomsadsorbed on these metals and/or to aperturbation of the oxide defect equilibria bymetal/oxide junction effects.

• Two independent pathways are possiblefor CO oxidation on the Au/ZnO sample,i.e. molecular oxygen reacts directly withCO at the surface of the gold particles,leading to the formation of molecularCO2, or molecular oxygen activates orenhances the reactivity of CO speciesadsorbed at the border of gold particleswith the surface oxygens.

• The electron-withdrawing effect of theadsorbed oxygen facilitates the nucleophilicattack of surface oxygens on the CO.

The chemistry described in this paper could beused as a basis .. for catalytic gas sensor systemsdesigned for the detection of carbon monoxide.

David Thompson

References1 F. Boccuzzi, A. Clnorino, S. Tsubota and M.

Haruta, Sensors and Actuators, 1995,B24-25,540

2 T. Kobayashi, M. Haruta, H. Sano and M.Nakane, Sensors and Actuators, 1988, 13,339

3 M. Haruta, N. Yamada, T. Kobayashi and S.Iijima,] Catal., 1989, 115,301

~ GoldBulletin 1996, 29(2)