Reviewing Gold(III) complexes as effective biological operators

Abstract

Cancer treatment using platinum has vastly been associated with numerous side effects and resistance generation. As a result, current medicinal chemistry is now emphasized on the development of novel metal based drugs bearing diverse pharmacological profile. There has been an increasing interest in the drafting of Au(III) complexes as new metal based drugs. Au(III) complexes have been observed to be especially steady under different physicochemical situations. Dithiocarbamato-Au(III) complexes show antiproliferative property against specific human tumor cells because of their inhibiting effect towards the tumor cell augmentation. The review focuses on the results obtained in the field of anticancer and antimicrobial efficacy of Au(III) complexes. The represented Au(III) complexes as anticancer agents have been classified as (a) complexes containing Au-N bonds, (b) complexes containing Au-S bonds and (c) complexes containing Au-O bonds. Au(III) complexes as antimicrobial agents have been subdivided as (a) antibacterial and antifungal (b) antimalarial and (c) antitrypanosomial Au(III) complexes. The results obtained from the analysis of anticancer and antimicrobial Au(III) complexes could possibly lead to the design and development of novel potent Au(III) complexes exhibiting enhanced activities.

Keywords

Gold(III) complexes anticancer antimicrobial cytotoxicity

1 Introduction

Gold was discovered as a shining yellow piece of metal produced through mining and extraction. The symbol “Au” derived from the Latin word aurum is related to the Goddess of Dawn, Aurora [1]. Gold (Au) is a transition metal having atomic number and atomic mass as 79 and 196.96657 a.u. respectively. It is one of the least reactive elements [2]. It is generally slightly reddish yellow in color and is ductile (can be stretched into a wire), malleable (pounded into other shapes) and sectility (can be cut into slices) in its purest form. It shows dual oxidation states as Au(I) and Au(III). The electronic configuration of Au (I) is ([Xe]4f ¹⁴5d¹⁰) whereas that of Au(III) ion is ([Xe]4f ¹⁴5d⁸). The less ionic radius of the Au(III) as compared to that of Au(I) accounts for the less polarisability of Au(III) ion [3].

Medical and therapeutic value of gold has been recognized for thousands of years [4 –7]. However, “Chrysotherapy,” (derived from the Greek word chrysos), treatment with gold based drug is now commonly accepted in present-day medicinal science [8 –18]. Egyptians used gold in the form of liquid in order to restore their youth and prevent diseases and evil spirits [19]. The biological utilisation of gold(I) can be resolved way back 2500 B.C. however, it was Robert Koch in 1890, who discovered growth inhibitory impacts of gold cyanide against Tuberculosis bacilli that represented the onset of systematic gold pharmacology and attempts to design gold based drugs [20]. In the beginning of twentieth century, Robert Koch was given the Nobel Prize for utilizing gold(I) thiolate complexes for rheumatoid arthritis treatment. He also found that K[Au(CN)₂] can inhibit tuberculosis causing bacteria. Severe side effects associated with K[Au(CN)₂] forced the use of lesser toxic Au(I) thiolate complexes for pulmonary tuberculosis treatment [21, 22]. French physician J. Forestier exploited these complexes for rheumatoid arthritis treatment [23]. Although Au(I) thiolate complexes were envisaged as a good alternative for rheumatoid arthritis treatments but their serious side effects provoked the search for novel and less toxic gold complexes [24]. During the past few decades, gold has been successfully tested and used to be a perfect metal for fighting cancer [25]. Au(III) complexes usually show intriguing cytotoxic and antitumor activities but poor stability under physiological conditions restricted their development [26].

Structural similarity of Au(III) complexes with Pt(II) compounds prompted their extensive study as prospective anticancer agents. Also, Au(III) being isoelectronic with Pt(II) forms square planar complexes. Unlike Pt(II), Au(III) is quickly hydrolyzed under physiological conditions and gets reduced to Au(I) [27]. Thus, in order to attain gold based drugs possessing medicinal activities, relevant ligands are needed for high stabilization of Au(III) center. Au(I) complexes exhibit robust tendency to disproportionate to Au(III) in aqueous solution but in non aqueous aprotic solvents, they are highly stable. Au(III) ion generally prefer ligands bearing hard lewis base donor sites such as nitrogen and oxygen. For example - 2,6-bis(2-pyridyl)-pyridine (terpy), 1,10-phenanthroline (phen), 2,20-bipyridine (bipy) and ethylenediamine(en) containing chelating nitrogen donors [28] and complexes with salicylate ion containing oxygen as donor site. Au(III) center can be stabilized by the introduction of direct Au-C bond [29]. One of the best example is [AuIII(dmamp)Cl₂] where dmamp is 2-(dimethylaminomethyl) phenyl which is a cyclometallated Au(III) complex and exhibits potential anticancer activities against human carcinoma xenografts [30]. The square planar coordination geometry is most commonly observed among Au(III) complexes, although trigonal bipyramidal [31] as well as octahedral arrangements are also found. Trigonal bipyramidal and octahedral arrangements possess axial bond lengths which are elongated and perpendicular to the square plane [32].

Complexes of Au(III) with bidentate ligands present numerous potential applications in chemotherapy [3 –37], catalysis [38] and surface chemistry [39, 40]. Numerous Au(III) complexes with aminoacids are used in fertilizers [41] and food technology [42, 43] whereas its complexes with dithiocarbamates and dithiophosphates have found applications in numerous biological [44, 45] and agricultural fields [46]. Mixed ligand complexes play an important role in biological activities against pathogenic microorganism [47]. This review is aimed to present a comprehensive document encompassing the outcomes achieved in the field of Au(III) complexes as prospective anticancer and antimicrobial agents.

2 Mode of action of gold(III) based drugs

Gold complexes have been considered as an essential part from centuries and their usage can be followed way back over thousands of years [8 –50]. Till today, the side effects of rheumatoid joint pain are cured using different gold complexes including aurothiopropanol sulfonate (allocrysin), aurothiomalate (myocrisin), aurothiosulfate (sanocrysin), aurothioglucose (solganol) and triethylphosphinegold(I)tetraacetylthioglucose (auranofin) (Fig. 1). Current treatment methodologies primarily centralize on reducing the evidences and keeping the dynamic catastrophic procedures. The pharmacological treatment utilizes analgesics thus called disease modifying antirheumatic drugs (DMARDs). Unlike other gold salts, auranofin can be taken orally. Thus, it appeared to be of high interest among hitherto mentioned gold salts [51, 52]. Numerous in vitro and in vivo studies have disclosed the promising cell inhibition effects of auranofin. Thus, it demonstrates an extended life expectancy corresponding to the managed dosage in mice vaccinated with P388 leukemia cells [53].

Fig.1

Representative metallodrugs- Auranofin.

TrxR(Thioredoxin reductase) being homodimeric protein that belongs to the group of pyridine nucleotide-disulfide reductase like compounds help in enhancing the NADPH mediated thioredoxin (Trx) disulfide reduction and numerous other oxidizable cellular components. TrxR is recognized in various species, for example, intestinal sickness parasite Plasmodium falciparum, Drosophila melanogaster. The protein is included in several metabolic paths (e.g. nucleotide blend, antioxidative system) and physiopathological conditions (e.g. tumors, irresistible maladies, rheumatoid joint inflammation) and demonstrates comprehensive substrate meticulosity [54]. Auranofin restrained TrxR with high intensity and 1000-fold selectivity in contrast to glutathione reductase and glutathione peroxidase [55]. Selenocysteine (Sec) having Gly-Cys-Sec-Gly motif being biologically active site of TrxR is engrossed in the catalytic mode of action of the enzyme. In enzyme catalysis, substrate NADPH transfers the reducing counterparts to Trx through FAD prosthetic group [56]. The gold atom, on interaction with the enzyme, loses its former ligands followed by coordination with the cysteine groups [57].

A remarkable method of activity is not likely to exist on account of different structures of ligands of numerous gold complexes but extensive studies on these complexes have emphasized their importance with huge TrxR inhibitory properties in the pharmacology of gold based metallodrugs. The hindrance of TrxR has been accounted for various Au(I) complexes as well as for different Au(III) complexes [58]. Thus, direct DNA damage, mitochondrial deterioration including thioredoxin reductase (TrxR) inhibition, cell cycle modification, proteasome inhibition, specific kinases modulation and other cellular processes affected by gold complexes which eventually prompt apoptosis can be assumed to play an essential part in the course of action of gold(III) complexes [2].

3 Gold(III) complexes as anticancer agents

The discovery of anticancer activities of cisplatin generated rapid interest towards the evolution of metal-based antitumor agents [59]. Numerous reports on anticancer properties of cisplatin have revealed that the other metal-based complexes can possibly be utilized as anticancer drugs [60, 61].

Complexes of Au(III) tetraarylporphyrins series (1–5) (Fig. 2) are invariable in presence of glutathione and have very high potential in inhibiting human tumor cells as compared to cisplatin. Laser confocal microscopy and flow cytometric studies revealed that gold-induced cytotoxicity proceeds via apoptotic pathway [51].

Fig.2

Au(III) tetraarylporphyrin complex.

Inhibition to the rapid increase in number of tumor cells by Au(I) complexes in vitro [51] prompted the researchers to focus more and more towards in vivo activity. Au(III) complexes being isostructural to Pt(II) compound (cisplatin) exhibit fascinating cytotoxic and antitumor properties and are prospective anticancer agents [62]. Unlike many platinum-based anti-cancer drugs primarily targeting DNA [3 –65], Au(I) and/or Au(III) complexes exhibit variety of actions, including thioredoxin reductase inhibition, direct DNA damage, alteration of cell cycles and proteasome inhibitions [63 , 6–79]. These intricate modes of action are crucial for the gold complexes to exhibit potential cytotoxic properties against cancer cells, particularly multidrug-resistant cell lines [63 , 74]. Generally, Au(III) is unstable and gets reduced to Au(I) and Au(0) under reducing mammalian environment which heavily hamper their development as therapeutic drug [80]. The efficacy of metal complex is dependent upon the type of metal and its oxidation states, types of ligands and geometry of the coordinated complex. Thus, highly stable Au(III) complexes can be synthesized using suitable ligands containing nitrogen atoms as donor groups that can sustain the reducing environment.

Gold(III) complexes having pyridine ligands 6 and 7 exhibit excellent cytotoxicity in lymphoblastic and ovarian cell lines of humans which are comparable to that of NaAuCl₄ (Fig. 3 for structures). Mode of action of these complexes is through binding with DNA [67]. Complexes 6 and 7 undergo hydrolysis in aqueous buffer medium which limits their practical application whereas in organic solvents, they are comparatively stable [81]. The bipyridine complexes 8 and 9 being stable in physiological buffer at 37°C show cytotoxicity [67]. Inspite of having weak interaction with DNA, Au(III) complexes comprising multidentate ligands like polyamines, cyclam, terpyridine and phenathroline are preferentially used in order to increase the stability of the Au(III) centre [28]. Some gold complexes with these multidentate ligands, namely 10, 11, 12, 13 and 14, also show reasonable stability in physiologically same environment and act as potential cytotoxic agents [67]. These complexes are also effective in inhibiting the cancer cell growth including those which are resistant to cisplatin. Reducing agents like ascorbic acid decrease the stability of these complexes which further lead to the oxidation of enzymes by targeting thiol group as potential anticancer targets [62, 82]. For example, TrxR [83] the copper chaperone Atox [84] and aquaporin [85, 86] are potential targets for such mode of action. Also, the relatively stable [Au(cyclam)](ClO₄)₂Cl (cyclam = 1,4,8,11-tetraazacyclotetradecane) found to be non-toxic to cancer cells even at 100 mM. The relative order of cytoxicity for these complexes is: Au(terpy) > >Au(phen) >Au(dien) > >Au(cyclam). Their cytotoxic nature is equivalent or even greater than cisplatin [24]. The anticancer activity of these complexes is shown in Table 1. Gold(III) corrole complex 15 exhibits high cytotoxic activity towards cisplatin-resistant cancer cells [87]. Mass spectrometric and Emission quenching studies have revealed the weak binding of gold(III) corrole complex to BSA(bovine serum albumin). This weak binding with BSA is responsible for the high cytotoxicity as compared to the Ga-corrole variant. Three or four nitrogen atoms in the donor sites lead to strong stabilization of the Au(III) complex and decrease in the reduction potential, thus preventing reduction as well as hydrolysis of Au(III) complex [88].

Fig.3

Au(III) complexes comprising Au-N bonds.

Table 1

Anticancer activity of Au(III) complexes against different tumor cells [88]

Complexes	A2780/S	A2780/R	CCRF-CEM/R	SK-OV-3	MCF7	HT29	A549
8	8.8±3.9	24.1±8.7	58.6±0.9	34.4±4.7	–	–	–
9	3.3±1.4	8.2±1.5	51.2±5.6	13.3±1.6	35.3±8.8	24.60	>50
10	3.8±1.1	3.49±0.91	6	–	–	–	–
11	0.2	0.37±0.032	–	–	–	–	–
12	8.2±0.93	18.7±2.16	32.7±6.6	–	–	–	–
13	8.36±0.77	17±4.24	–	–	–	–	–
14	99.0	>120.0	–	–	–	–	–

Fregona and coworkers synthesized and characterised Au(III) dithiocarbamate complexes [89] containing N,N-dimethyl dithiocarbamate and ethylsarcosine dithiocarbamate ligands. These complexes (Fig. 4) exhibit superior cytotoxicity in comparison to cisplatin, induced apoptosis and also active in resistant cells [89, 90] and showed good stability under physiological conditions. Au(III) dithiocarbamate complexes (16–23) readily binds with DNA and thus inhibit replication and transcription. Hemolytic properties could contribute incomparably to the bioactivity of these complexes [88] Au(III) dithiocarbamate complexes preferably act through a novel mechanism for metal based anticancer drugs [88], through inhibition of the cancer cell proteasome [91]. These complexes stimulate cancer cell death through apoptotic and non-apoptotic pathways, affect the functioning of mitochondria, generate free radicals, help in enhancing ERK1/2 phosphorylation and TrxR inhibition [92, 93].

Fig.4

Dithiocarbamato Au(III) complexes showing cytotoxic nature.

A series of 2-phenylpyridine Au(III) complexes (Fig. 5) having general formula [Au(ppy)X] comprising different thiolate ligands ([Au(ppy)(SCN)(NCS)] displayed good cytotoxicity in comparison to cisplatin [94]. Labile ligands get hydrolysed in gold–carbon complexes (24–26) whereas the oxidation state remains unchanged [67]. Among these complexes, 25 and 26 are the most active and exhibit high cytotoxic activity against A2780/S [95]. IC₅₀ values of these complexes are equivalent to those of cisplatin both in A2780/S and A2780/R cell lines [96]. These complexes foster anti-apoptotic effects [67] accompanied by adequate agitation of the cell cycle [30, 95]. Radioactive isotopes of gold, ¹⁹⁸Au and ¹⁹⁹Au are generally suitable for cancer treatment. Thus, gold(III) complexes can also act as prospective radiotherapeutic agents. Numerous Schiff bases and thiosemicarbazonato complexes have been synthesized using radioactive isotope, ¹⁹⁸Au at macroscopic as well as radiotracer levels. These complexes have been assessed in vitro for stability at the tracer level and complex 27 (Fig. 6) has been chosen for in vivo study in mice. In vivo distribution of complexes has shown that low serum stability and rapid reduction to colloidal gold does not occur immediately [97].

Fig.5

Au(III) complexes with Au-C bonds.

Fig.6

¹⁹⁸Au thiosemicarbazonato complex.

4 Gold (III) complexes as antimicrobial agents

Robert Koch’s observation in 1890 resulted in the beginning of gold pharmacology [6]. Antitumor properties of gold complexes have been much identified and exploited due to which their antimicrobial activities gathered less attention. However, the gold complexes not only exhibit antitumour property but also antimicrobial activity. Thereafter, numerous Au(I) and Au(III) complexes have displayed efficacy towards wide range of microorganisms and thus can be used as antimicrobial drugs [32]. Therefore, there is a plenty of scope related to exploration of antimicrobial activity of Au(III) complexes.

4.1 Antibacterial and antifungal Au(III) complexes

Bacteria are microscopic single-celled organisms that can exist either as independent organisms or as parasites. Fungus is a single celled microorganism that lives by absorbing and decomposing the organic material in which they grow. These include mushrooms, moulds, smuts and yeasts etc. Antibacterial and antifungal activity refers to the selective inhibition of bacterial and fungal pathogens from a host with minimal toxicity to the host.

Tripodal bis(imidazole) thioether 28 (Fig. 7) derived gold(III) complexes were screened for antifungal and antibacterial activity against gram-positive and gram-negative bacteria. Gold(III) complexes, being more toxic than gold(I) complexes exhibited selective antibacterial and antifungal activity against Bacillus cereus and Staphyloccocus aureus, while the free ligand was totally inactive [98].

Fig.7

Au(III) tripodal bis(imidazole) thioether complex.

Au(III) complexes (29–35) having general formula [AuX₂(Y)], where Y is a bifunctional ligand forms Au-C sigma bond and coordinate Au-N bond [99]. These form square planar complexes with Au(III) at the centre and the remaining two position occupied either by one bidentate ligand or two monodentate leading to the development of neutral complex. Different biological tests were carried out by Parish et al. to evaluate the antimicrobial activity of [AuCl₂(damp)] where damp is 2-((dimethylamino)methyl) phenyl (complex 27) and [AuCl₂(ppy)] where ppy is 2-pyridylphenyl (complex 28) (Fig. 8) [100, 101]. The antimicrobial activity of Au(III) complexes is presented in Table 2.

Fig.8

Organometallic Au(III)complexes.

Table 2

Range showing the concentration for the growth and inhibition of antibacterial and antifungal activity [100, 102]

Minimum inhibitory concentration (μg/ mL)
	Antibacterial activity
Complexes	E. Faecalis	E. Coli	K. pneumoniae	P. Aeruginosa	S. aureus
[AuCl₂(damp)] 29	1.0–2.5	0–25	0–25	0–25	1.0–2.5
[AuCl₂(ppy)] 30	2.5–10	5–100	5–100	5–100	1.0–2.5
[Au(CH₃COO)₂(damp)] 31	0.5–1.0	2.5–10		50–100	0.5–1.0
Ciprofloxacin	1.0–2.5	<0.25	<0.25	<0.25	<0.25
	Antifungal activity
	A. fumigates	A. niger	Ca. albicans	Ca. albicans NCFC 3153	Cr. Neoformans
[AuCl₂(damp)] 29	2.5–10	0–25	5–100	0–25	5–100
[AuCl₂(ppy)] 30	5–100	5–100	5–100	5–100	1.0–2.5
Amphotericin B	0.5–1.0	0.5–1.0	<0.25	<0.25	<0.25
damp = 2-((dimethylamino) methyl) phenyl; ppy = 2-pyridylphenyl

When evaluated for selected bacterial and fungal strains, complex 30 found to be more active than complex 29 and neither of two was sufficiently active as ciprofloxacin amphotericin B. Minimal selectivity of complex 29 made it unsuitable as an antimicrobial chemotherapeutic agent. Chloride ligands were replaced with the acetate ligands in order to enhance the efficacy of complex 29, leading to the formation of a water-soluble complex 31 (Fig. 8) [101, 102]. Au(III) complexes containing chelating thiosalicylate and salicylate ligands 33 and 34 respectively showed extremely higher activity for the investigated microorganisms [103]. Replacing thiosalicylate ligand in complex 32 with N,N’-diaacetylureate ligand resulted in the formation of complex 35 (Fig. 8), thus enhancing its activity against bacterial and fungicidal strains [104]. Au(III) dithiocarbamato complexes of amino acids like L-leucine, D,L-valine, D,L-alanine and L-valine displayed high antimicrobial activity towards Streptococcus pneumoniae than the reference agents [105]. Dinuclear gold(III) complexes of bis(imidazolium) salts (36–50) (Fig. 9) were evaluated against the chloroquine resistant Plasmodium falciparum strain FcM29-Cameroon (IC₅₀ of chloroquine ¼ 445 nM) for doses varying from 0.5–50 mg/mL. Their antifungal activity is shown in Table 3. The complexes (40–43) showed excellent antifungal activities towards both Candida strains with minimum inhibitory concentration (MIC) varying from 0.8–2 mM whereas the other complexes showed no activity against Candida albicans and Candida glabrata (MIC greater than 50 mg/ml corresponds to the values varying from >27 to 107 mM). Higher-valent gold(III) complexes 49, 50 exhibited much higher activity in comparison to their gold(I) counterparts [106]. This increase in activity can be attributed to the change in oxidation state from gold(I) to gold (III).

Fig.9

(a) Heteroditopic polydentate bis(N-heterocylic carbine) ligand, (b) Dinuclear Ag(I) N-functionalized N-heterocylic carbine complex, (c) Dinuclear Au(I) N-functionalized N-heterocylic carbine complex, and (d) Dinuclear Au(III) N-functionalized N-heterocylic carbine complex.

Table 3

Antifungal activities of dinuclear gold(III) complexes [107]

Antifungal activity MIC(μM)
Complexes	36	37	38	39	40	41	42	43	44	45	46	47	48	49	50
C. albicans	>92	>107	>89	>86	1.6	1.3	2.0	1.4	>39	>39	>34	>33	>32	>28	>27
C. glabrate	>92	>107	>89	>86	1	0.8	1.5	1.5	>39	>39	>34	>33	>32	>28	>27

4.2 Antimalarial Au(III) complexes

Malaria is a contagious microbial disease that is caused by protozoan parasites of Plasmodium type and is one of the prime causes of death in tropical countries [107]. According WHO (World Health Organization) report in 2011 about 3.5 billion people were affected by malaria, African region being most affected with around 80% of malarial cases and 90% death cases [108]. Malaria is usually caused by five species (P. knowlesi, P. ovale, P. vivax, P. falciparum and P. malariae) and of which highly significant of its form is caused by P. falciparum. Quinine, chloroquine, primaquine, amodiaquine, mefloquine and artemisinin are widely used drugs for malaria treatment [109].

Amodiaquine and primaquine with choloroquine are well-known Au(III) complexes used for the malarial treatment and are prepared and evaluated using in vitro microtechnique for their antimalarial activities [110]. Au(III) complexes with chloroquine (CQ), [AuCl(SR)(CQ)(Et₂O)]Cl and [AuCl₂(CQ)₂]Cl appeared to be highly active as compared to chloroquine diphosphate (drug used to cure malaria) against the resistant K1 strain [111]. Bis(N-heterocyclic carbene) ligands containing Au(III) complexes 51 and 52 (Fig. 10) exhibited considerate efficacy towards P. falciparum strain FcM29 having IC₅₀ values as 9 and 13μM, respectively, which were extremely lower than that of chloroquine (IC₅₀ = 0.445μM) against same strain [106].

Fig.10

Au(III) complexes having coordinated bis(N-heterocyclic carbene) ligand.

Coordinated 2,2^′-bipyridine ligand (bipy) bearing mono and dinuclear Au(III) complexes like [Au(bipy)(OH)₂][PF₆] (53), [Au₂(μ-O)₂(6-CH₂CMe₃bipy)₂][PF₆]₂ (54), [Au₂(μ-O)₂(6-(2,6-Me₂C₆H₃)bipy)₂][PF₆]₂ (55) and [Au₂(μ-O)₂(6,6^′-Mebipy)₂][PF₆]₂ (56) (Fig. 11) caused growth inhibition of P. Falciparum strain with IC₅₀ values ranging from 2.3–12.2μM [112] whereas [Au(cyclam)](ClO₄)₂Cl complex 14 (cyclam = 1,4,8,11-tetraazacyclotetradecane) exhibited less noteworthy antimalarial efficacy towards the same strain with IC₅₀ value as 439μM [113].

Fig.11

Antimalarial Au(III) complexes.

The antimalarial activities of cyclometallated gold(III) complex 57 (Fig. 12) and thiosemicarbazones (58–64) (Fig. 13) are shown in Table 4, along with IC₅₀ values for chloroquine (CQ) and artemisinin (ART) [114]. The W2 strain is commonly used for screening potential antimalarials strain which is resistant to a range of antimalarial drugs such as chloroquine (CQ), quinine (QN) and antifolates [115].

Fig.12

Cyclometallated Au(III) complex.

Fig.13

Structures of thiosemicarbazone.

Table 4

In vitro antimalarial activity against P. falciparum strain [114]

Complex	P. falciparum (IC₅₀/mM) W2
57	1.88 (±0.27)
58	>20
59	>20
60	>20
61	4.94 (±0.14)
62	>20
63	>20
64	>20
CQ	0.049 (±0.001)
ART	0.0082 (±0.0003)

4.3 Antitrypanosomial Au(III) complexes

Trypanosomiasis, a parasitic disease, is caused by a protozoan parasite of Trypanosoma type [116]. It has two forms – African and American trypanosomiasis. African trypanosomiasis is caused by T. brucei parasite and is communicated by the bite of tsetse flies. Drugs that are used for African trypanosomiasis treatment depend upon the stage of the disease and the pathogen causing this disease. These include pentamidine, eflornithine, melarsoprol and suramin. American trypanosomiasis is caused by T. cruzi, a protozoan parasite [116]. Its treatment is based on two nitro heterocyclic drugs, 65 and 66 (Fig. 14), which show high activity in the severe phase of the disease. It also has a number of side-effects such as allergic dermopathy, peripheral polyneuropathy, loss in weight, vomiting, nausea and diarrhea [117].

Fig.14

Structures of nitro heterocyclic drugs, Nifurtimox (65) and Benznidazole (66).

Several attempts have been carried out to establish new trypanocidal metal-based compounds [8 –120] by three strategies: the coordination of metal with trypanocidal ligands, coordination of metal with DNA intercalators and metal complexes as direct inhibitors of parasite enzymes.

[AuCl₃(CTZ)], Au(III) complex with clotrimazole, shows high activity towards epimastigotes of T. cruzi parasite as compared to the free clotrimazole [121]. The efficiency of sodium tetrachloridoaurate(III) (Na[AuCl₄]) and Au(III) complex with tetrakis(1-methylpyridinium- 4-yl) porphyrin) have also been studied in order to inhibit the T. brucei growth [122]. While Au(III) porphyrin complex 67 (Fig. 15) was found to be effective towards parasites above 4.8μM whereas [AuCl₄]^– was found to be effective above 0.2μM [116]. The substitiuted Au(III) porphyrin complex proved to be effective against tumour cells. The high antitrypanosomial efficacy of [AuCl₄]^– was due to free radical generation which increased its activity towards T. brucei parasite in comparison to Au(III) porphyrin complex [116].

Fig.15

Au(III) porphyrin complex.

5 Conclusion

The meticulous examination of current research work for the evolution of gold(III) complexes makes it evident that these complexes may serve as potential antitumor and antimicrobial agents. After years of research and development, gold(III) complexes have shown promising outcomes to deal with the problem of cisplatin resistance. Determining the inhibition properties of gold(III) complexes towards purified enzymes is insufficient and further studies need to be extended in order to analyze more complex biological samples. As a result of high binding tendency of gold ions towards thiols, thiol–enzymes are largely regarded as principal targets for antitumor gold complexes. The poor selectivity and instability of extracellular thiols for cancer cells are the important factors that remain to be solved. The stability of gold(III) complexes towards thiols (serum albumin and extracellular glutathione) needs to be increased in order to improve their in vivo activity. Contemporary methods for novel gold(III) metal based drugs development should focus on the evolution of complexes bearing highly modified organic ligands in order to overcome the present-day disadvantages of chemotherapy. The introduction of nanotechnology interventions has introduced a new dimension in the utilization of gold complexes in the pharmaceutical chemistry. Formulation of these complexes as microcapsules, nanoparticles and micelles can enhance their bioavailability which in result increases their bioactivity and reduce toxicity. Thus, it can be concluded that huge progress has been attained for the utilization of gold(III) complexes in medicinal chemistry but still lots of efforts are required to explore these complexes to their fullest potential as anticancer and antimicrobial agents.

Footnotes

Acknowledgments

The work has been supported by undergraduate students of ARSD College working under STAR College Scheme, Department of Biotechnology, GOI, New Delhi, India.

References

Petersen

, Gold: Earth’s treasures, ABDO Publishing Company: Minneapolis (2013), 1–31.

Maia

P.I.S.

, Deflon

V.M.

and Abram

, Gold(III) complexes in medicinal chemistry, Future Med Chem 6(13) (2014), 1515–1536. doi:10.4155/fmc.14.87

Williams

M.L.

, Core chemistry of gold and its complexes, Inflammopharmacology 16 (2008), 110–111. doi:10.1007/s10787-007-0019-4

Kean

W.F.

, Forestier

, Kassam

, Buchanan

W.W.

and Rooney

P.J.

, The history of gold therapy in rheumatoid disease, Semin Arthritis Rheum 14 (1985) 180–186. https://doi.org/10.1016/0049-0172(85)90037-X

Zhao

and Ning

, China’s ancient gold drugs, Gold Bull 34 (2001), 24–29. doi:10.1007/BF03214805

Higby

G.J.

, Gold in medicine, Gold Bull 15(4) (1982), 130–140.

Parish

R.V.

, Gold in medicine-chrysotherapy Interdisc Sci Rev 17 (1992) 221–228. https://doi.org/10.1179/isr.1992.17.3.221

Shah

Z.A.

and Vohora

S.B.

, Antioxidant/restorative effects of calcined gold preparations used in Indian systems of medicine against global and focal models of ischaemia, Pharmacol Toxicol 90 (2002), 254–259. doi:10.1034/j.1600-0773.2002.900505.x

Kouodom

M.N.

, Boscutti

, Celegato

, Crisma

, Sitrand

, Aldinucci

, Formaggio

, Ronconi

and Fregona

, Rational design of gold(III)-dithiocarbamato peptidomimetics for the targeted anticancer chemotherapy, J Inorg Biochem 117 (2012), 248–260. doi:10.1016/j.jinorgbio.2012.07.001

10.

Chopra

A.S.

, Ayurveda, H. Selin Springer Science & Business Media: Norwell, 2003, pp. 74–111.

11.

Singh

R.H.

and Mishra

L.C.

, Psychiatric disorders, Mishra

L.C.

, Ed., Washington, DC, 2004, pp. 439–452.

12.

Champion

G.D.

, Graham

G.G.

and Zieglar

J.B.

, The Gold complexes, Ballieres Clin Rheumatol 4 (1990), 491–534.

13.

Parish

R.V.

and Cottrill

S.M.

, Medicinal gold compounds, Gold Bull 20 (1987), 3–12. doi:10.1007/BF03214653

14.

Gottlieb

N.L.

, Comparative pharmacokinetics of parenteral and oral gold compounds, J Rheumatol 9 (1982), 99–109.

15.

Snyder

R.M.

, Mirabelli

and Crooke

S.T.

, The cellular pharmacology of auranofin, Semin Arthritis Rheum 17 (1987), 71–80. doi:10.1016/0049-0172(87)90017-5

16.

Hassan

, Abd alqadeem mohammed

, Philip

, Hameed

A.A.

and Yousif

, Gold (III) complexes as breast cancer drug, Sys Rev Pharm 8(1) (2017), 76–79. doi:10.5530/srp.2017.1.13

17.

Sadler

P.J.

, The biological chemistry of gold: A Metallo-drug and heavy-atom label with variable valency, Struct Bonding 29 (1976), 171–214. doi:10.1007/BFb0116521

18.

Maia

, Carneiro

Z.A.

, Lopes

C.D.

, Oliveira

C.G.

, Silva

J.S.

, Albuquerque

, Hagenbach

, Gust

, Deflond

V.M.

and Abram

, Organometallic gold(III) complexes with hybrid SNS-donating thiosemicarbazone ligands: Cytotoxicity and anti-trypanosoma cruzi activity, Dalton Trans 46 (2017), 2559–2571. doi:10.1039/C6DT04307K

19.

Arivalagan

, Ravichandran

, Rangasamy

and Karthikeyan

, Nanomaterials and its potential applications, Int J ChemTech Res 3 (2011), 534–538. ISSN:0974-4290.

20.

Koch

, An address on bacteriological research, Brit Med J 2(1546) (1890), 380–383.

21.

Benedek

T.G.

, The history of gold therapy for tuberculosis, J Hist Med Allied Sci 59 (2004) 50–89. https://doi.org/10.1093/jhmas/jrg042

22.

Fricker

S.P.

, Medical use of gold compounds: Past, Present and Future, Gold Bull 29 (1996), 53–60. doi:10.1007/BF03215464

23.

Forestier

, Rheumatoid arthritis and its treatment by gold salts. The results of six years’ experience, Lab Clin Med 20 (1935), 827–840.

24.

Milacic

, Fregona

and Dou

Q.P.

, Gold complexes as prospective metal-based anticancer drugs, Histol Histopathol 23 (2008), 101–108. ISSN: 0213-3911.

25.

Bertrand

and Casini

, A golden future in medicinal inorganic chemistry: The promise of anticancer gold organometallic compounds, Dalton Trans 43 (2014), 4209–4219. doi:10.1039/c3dt52524d

26.

Gimeno

M.C.

, The Chemistry of Gold Laguna

Ed., John Wiley & Sons: Weinheim, Germany, 2008. doi:10.1002/9783527623778.ch1

27.

Wanga

and Guo

, Towards the rational design of platinum(II) and gold(III) complexes as antitumour agents, Dalton Trans 12 (2008), 1521–1532. doi:10.1039/B715903J

28.

Marcon

, Carotti

, Coronnello

, Messori

, Mini

, Orioli

, Mazzei

, Cinellu

M.A.

and Minghetti

, Gold(III) Complexes with bipyridyl ligands: solution chemistry, cytotoxicity, and DNA binding properties, J Med Chem 45(8) (2002), 1672–1677. doi:10.1021/jm010997w

29.

Massai

, Cirri

, Michelucci

, Bartoli

, Guerri

, Cinellu

M.A.

, Cocco

, Gabbiani

and Messori

, Organogold(III) compounds as experimental anticancer agents: Chemical and biological profiles, Biometals 29 (2016), 863–872. doi:10.1007/s10534-016-9957-x

30.

Buckley

R.G.

, Elsome

A.M.

, Fricker

S.P.

, Henderson

G.R.

, Theobald

B.R.C.

, Parish

R.V.

, Howe

B.P.

and Kelland

L.R.

, Antitumor properties of some 2-[(Dimethylamino)methyl]phenylgold(III) complexes, J Med Chem 39 (1996), 5208–5214. doi:10.1021/jm9601563

31.

Charlton

R.J.

, Harris

C.M.

, Patil

and Stephenson

N.C.

, Five-coordinate gold(III) complexes of 2,2’-biquinolyl Inorg Nucl Chem Lett 12 (1966) 409–414. https://doi.10.1016/S0020-1650(66)80008-9

32.

Glišić

B.Ɖ.

and Djuran

M.I.

, Gold complexes as antimicrobial agents: An overview of different biological activities in relation to the oxidation state of the gold ion and the ligand structure, Dalton Trans 43 (2014), 5951–5969. doi:10.1039/c4dt00022f

33.

Wein

A.N.

, Stockhausen

A.T.

, Hardcastle

K.I.

, Saadein

M.R.

, Peng

B.S.

, Wang

, Shin

D.M.

, Chen

G.Z.

and Eichler

J.F.

, Tumor cytotoxicity of 5,6-dimethyl-1,10-phenanthroline and its corresponding gold(III) complex, J Inorg Biochem 105 (2011), 663–668. doi:10.1016/j.jinorgbio.2011.01.006

34.

Ronconi

, Marzano

, Zanello

, Corsini

, Miolo

, Macca

, Trevisan

and Fregona

, Gold(III) dithiocarbamate derivatives for the treatment of cancer: Solution chemistry, DNA binding, and hemolytic properties, J Med Chem 49 (2006), 1648–1657. doi:10.1021/jm0509288

35.

Dash

K.C.

, Schmidbuar

, Sigel

H.E.

and Dekker

, Gold complexes as Metallo drugs, Met Ions Biol Syst 14 (1982), 179–205.

36.

Shaw III

C.F.

, The biochemistry of gold, Schmidbaur

, Ed., John Wiley & Sons: Chichester, United Kingdom, 1999.

37.

Sadler

P.J.

and Sue

R.E.

, The chemistry of gold drugs, Keppler

B.K.

, Ed., VCH Publ: Weinhein, 1994.

38.

Kung

K.K.Y.

, Lo

V.K.Y.

, Ko

H.M.

, Li

G.L.

, Chan

P.Y.

, Leung

K.C.

, Zhou

, Wang

M.Z.

, Che

C.M.

and Wonga

M.K.

, Cyclometallated Gold(III) complexes as effective catalysts for synthesis of propargylic amines, chiral allenes and isoxazoles, Adv Synth Catal 355 (2013), 2055–2070. doi:10.1002/adsc.201300005

39.

V.K.Y.

, Liu

, Wong

M.K.

and Che

C.M.

, Gold(III) salen complex-catalyzed synthesis of propargylamines via a three-component coupling reaction, Org Lett 8(8) (2006), 1529–153. doi:10.1021/ol0528641

40.

Zhou

C.Y.

, Chan

P.W.H.

and Che

C.M.

, Gold(III) porphyrin-catalyzed cycloisomerization of allenones, Org Lett 8 (2006), 325–328. doi:10.1021/ol052696c

41.

Hamdi

M.Z.

and Mustafa

I.A.

, Mixed ligand complexes of gold (III) with some amino acids and dithiocarbamates or dithiophosphates, Sci J Analyt Chem 1 (2013), 21–27. doi:10.11648/j.sjac.20130102.13

42.

Freeman

H.C.

, Metal complexes of amino acids and peptides, Eichhorn, Ed., Inorganic biochemistry. Elsevier: Amsterdam, 1973, pp. 121–166.

43.

Hossain

M.A.

, Islam

M.S.

, Alam

M.A.

and Sultan

, Synthesis, physiochemical studies and antimicrobial screening of metal complexes of Fe(III) and Au(III) with aminoacids, Int J Sci Tech Res 2(7) (2013), 210–217.

44.

Manav

, Mishra

A.K.

and Kaushik

N.K.

, In vitro antitumour and antibacterial studies of some Pt(IV) dithiocarbamate complexes, Spectrochim Acta 6(1) (2006), 32–35. doi:10.1016/j.saa.2005.09.023

45.

Hogarth

, Metal-dithiocarbamate complexes: Chemistry and biological activity, Mini Rev Med Chem 12(12) (2012) 1202–1215. https://doi.org/10.2174/138955712802762095

46.

Greene

, Hosea

and Mc Pherson

, Henzl

Alexander

M.D.

Darnall

D.W.

, Interaction of gold(I) and gold(III) complexes with algal biomass, Environ Sci Technol 20 (1986), 627–632. doi:10.1021/es00148a014

47.

Rajasekar

, Ramachandramoorthy

and Paulraj

, Microwave assisted synthesis, structural characterization and biological activities of 4-aminoantipyrine and thiocyanate mixed ligand complexes, Res J Pharmaceutical Sci 1 (2012), 2–27. ISSN: 2319–555X.

48.

Kauffman

G.B.

, The role of gold in alchemy: Part I, Gold Bull 18(1) (1985), 31–44. doi:10.1007/BF03214684

49.

Kauffman

G.B.

, The role of gold in alchemy: Part II, Gold Bull 18(2) (1985), 69–78. doi:10.1007/BF03214689

50.

Kauffman

G.B.

, The role of gold in alchemy: Part III, Gold Bull 18(3) (1985), 109–119. doi:10.1007/BF03214693

51.

Shaw

C.F.

, Gold-based therapeutic agents, Chem Rev 99 (1999), 2589–2600. doi:10.1021/cr980431o

52.

Shaw

C.F.

, Gold complexes with anti-arthritic, anti-tumour and anti-HIV activity, Farrell

N.P.

, Ed. Royal Society of Chemistry: Cambridge, UK, 1999, pp. 26–57. doi:10.1039/9781847552242-00026k

53.

Simon

T.M.

, Kunishima

D.H.

, Vibert

G.J.

and Lorber

, Screening trial with the coordinated gold compound auranofin using mouse lymphocyte leukemia, Cancer Res 41 (1981), 94–97.

54.

Becker

, Gromer

, Schirmer

R.H.

and Müller

, Thioredoxin reductase as pathophysiological factor and drug target, Eur J Biochem 267 (2000), 6118–6125. doi:10.1046/j.1432-1327.2000.01703.x

55.

Gromer

, Arscott

L.D.

, Williams

C.H.

, Schirmer

R.H.

and Becker

, Human placenta thioredoxin reductase, J Biol Chem 273 (1998), 20096–20101. doi:10.1074/jbc.273.32.20096

56.

Williams

C.H.

, Arscott

L.D.

, Müller

, Lennon

B.W.

, Ludwig

M.L.

, Wang

P.F.

, Veine

D.M.

, Becker

and Schirmer

R.H.

, Thioredoxin reductase, Eur J Biochem 267 (2000), 6110–6117. doi:10.1046/j.1432-1327.2000.01702.x

57.

Urig

, Fritz-Wolf

, Reau

, Herold-Mende

, Toth

, Davioud-Charvet

and Becker

, Undressing of phosphine gold(I) complexes as irreversible inhibitors of human disulfide reductases, Angew Chem Int Ed 45 (2006), 1881–1886. doi:10.1002/anie.200502756

58.

Rigobello

M.P.

, Messori

, Giordano

, Cinellu

M.A.

, Bragadin

, Folda

, Scutari

and Bindoli

, Gold complexes inhibit mitochondrial thioredoxin reductase: Consequences on mitochondrial functions, J Inorg Biochem 98 (2004), 1634–1641. doi:10.1016/j.jinorgbio.2004.04.020

59.

Rosenberg

, Camp

L.V.

, Trosko

J.E.

and Mansour

V.H.

, Platinum compounds: A new class of potent antitumour agents, Nature 222 (1969), 385–386. doi:10.1038/222385a0

60.

O’Dwyer

P.J.

, Stevenson

J.P.

, Johnson

S.W.

, Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug, Liert

, Ed. John Wiley & Sons Inc: New York, 1999, pp. 31–72.

61.

Wong

and Giandomenico

C.M.

, Current status of platinum-based antitumor drugs, Chem Rev 99 (1999), 2451–2466. doi:10.1021/cr980420v

62.

Messori

, Abbate

, Marcon

, Orioli

, Fontani

, Mini

, Mazzei

, Carotti

and OȼConnell

, and Zanello

. Gold(III) complexes as potential antitumor agents: Solution chemistry and cytotoxic properties of some selected gold(III) compounds, J Med Chem 43 (2000), 3541–3548. doi:10.1021/jm990492u

63.

Bruijnincx

P.C.

and Sadler

P.J.

, New trends for metal complexes with anticancer activity, Curr Opin Chem Biol 12 (2008), 197–206. doi:10.1016/j.cbpa.2007.11.013

64.

Jamieson

E.R.

and Lippard

S.J.

, Structure, recognition and processing of cisplatin–DNA adducts, Chem Rev 99 (1999), 2467–2498. doi:10.1021/cr980421n

65.

Jung

and Lippard

S.J.

, Direct cellular responses to platinum-induced DNA damage, Chem Rev 107 (2007), 387–1407. doi:10.1021/cr068207j

66.

Sadler

P.J.

and Sue

R.E.

, The chemistry of gold drugs, Met Based Drugs 1 (1994), 107–144. doi:10.1155/MBD.1994.107

67.

Ott

, On the medicinal chemistry of gold complexes as anticancer drugs, Chem Rev 253 (2009), 1670–1681. doi:10.1016/j.ccr.2009.02.019

68.

Zou

, Lum

C.T.

, Lok

C.N.

, Zhang

J.J.

and Che

C.M.

, Chemical biology of anticancer gold(III) and gold(I) complexes, Chem Soc Rev 44 (2015), 8786–8801. doi:10.1039/C5CS00132C

69.

Hickey

J.L.

, Ruhayel

R.A.

, Barnard

P.J.

, Baker

M.V.

, Berners-Price

S.J.

and Filipovska

, Mitochondria-targeted chemotherapeutics: The rational design of gold(I)-Heterocyclic carbene complexes that are selectively toxic to cancer cells and target protein selenols in preference to Thiols, J Am Chem Soc 130(38) (2008), 12570–12571. doi:10.1021/ja804027j

70.

Shi

, Jiang

, Zhao

, Zhang

, Lin

, Ding

and Guo

, DNA binding properties of novel cytotoxic gold(III) complexes of terpyridine ligands: The impact of steric and electrostatic effects, J Biol Inorg Chem 11 (2006), 745–752. doi:10.1007/s00775-006-0120-y

71.

Cinellu

M.A.

, Maiore

, Manassero

, Casini

, Arca

, Fiebig

H.H.

, Kelter

, Michelucci

, Pieraccini

and Gabbiani

, and Messori

, [Au₂(phen^2Me)₂(μ-O)₂] a novel dinuclear gold(III) complex showing excellent antiproliferative properties ACS Med Chem Lett 1 (2010), 336–339. doi: 10.1021/ml100097f

72.

Che

C.M.

, Sun

R.W.Y.

, Yu

W.Y.

, Ko

C.B.

, Zhu

and Sun

, Gold(III) porphyrins as a new class of anticancer drugs: Cytotoxicity, DNA binding and induction of apoptosis in human cervix epitheloid cancer cells, Chem Commun 14 (2003), 1718–1719. doi:10.1039/b303294a

73.

Chow

K.H.M.

Sun

R.W.Y.

, Lam

J.B.B.

, Li

C.K.

, Xu

, Ma

D.L.

, Abagyan

, Wang

and Che

C.M.

, A Gold(III) Porphyrin Complex with Antitumor Properties Targets the Wnt/β-catenin Pathway, Cancer Res 70 (2010), 329–337. https://dx-doi-org.web.bisu.edu.cn/10.1016/j.ica.2012.12.013

74.

Lum

C.T.

, Sun

R.W.Y.

, Zou

and Che

C.M.

, Synthesis of stable gold(III) pincer complexes with anionic heteroatom donors, Chem Sci 5 (2014), 1579–1584. doi:10.1021/om500663m

75.

, Chen

, You

, Hu

, Zheng

, Kwong

W.Y.

, Zou

and Che

C.M.

, A cancer-targeted nanosystem for delivery of gold(III) complexes: Enhanced selectivity and apoptosis-including efficacy of a gold(III) porphyrin complex, Angew Chem Int Ed 53(46) (2014), 12532–12536. doi:10.1002/anie.201407143

76.

Yan

J.J.

, Chow

A.L.F.

, Leung

C.H.

, Sun

R.W.Y.

, Ma

D.L.

and Che

C.M.

, Cyclometalated gold (III) complexes with N-heterocyclic carbene ligands as topoisomerase I poisons, Chem Commun 46 (2010), 3893–3895. doi:10.1039/C2CC00029F

77.

Zhang

J.J.

, Lu

, Sun

R.W.Y.

and Che

C.M.

, Organogold(III) supramolecular polymers for anticancer treatment, Angew Chem, Int Ed 51 (2012), 4882–4886. doi:10.1002/anie.201108466

78.

Zou

, Lum

C.T.

, Chui

S.S.Y.

and Che

C.M.

, Gold(III) complexes containing N-Heterocyclic carbene ligands: Thiol “Switch-on” fluorescent probes and anti-cancer agents, Angew Chem, Int Ed 52 (2013), 2930–2933. doi:10.1002/anie.201209787

79.

Zou

, Lum

C.T.

, Lok

C.N.

, To

W.P.

, Low

K.H.

and Che

C.M.

, A binuclear gold(I) complex with mixed bridging diphosphine and bis(N-Heterocyclic carbene) ligands shows favorable thiol reactivity and inhibits tumor growth and angiogenesis in vivo, Angew Chem, Int Ed 53 (2014), 5810–5814. doi:10.1002/anie.201400142

80.

Tiekink

E.R.T.

, Anti-cancer potential of gold complexes, Inflammopharmacology 16 (2008), 138–142. doi:10.1007/s10787-007-0018-5

81.

Calamai

, Carotti

, Guerri

, Messori

, Mini

, Orioli

and Speroni

G.P.

, Biological properties of two gold(III) complexes: AuCl₃(Hpm) and AuCl₂(pm), J Inorg Biochem 66 (1997), 103–109. doi:10.1016/S0162-0134(96)00190-0

82.

Nobili

, Mini

, Landini

, Gabbiani

, Casini

and Messori

, Gold compounds as anticancer agents: Chemistry, cellular pharmacology, and preclinical studies, Med Res Rev 30 (2010), 550–580. doi:10.1002/med.20168

83.

Bindoli

, Rigobello

M.P.

, Scutari

, Gabbiani

, Casini

and Messori

, Thioredoxin reductase: A target for gold compounds acting as potential anticancer drugs, Coord Chem Rev 25 (2009), 1692–1707. doi:10.1016/j.ccr.2009.02.026

84.

Gabbiani

, Scaletti

, Massai

, Michelucci

, Cinellu

M.A.

and Messori

, Medicinal gold compounds form tight adducts with the copper chaperone Atox-1: Biological and pharmacological implications, Chem Commun 48(95) (2012), 11623–11625. doi:10.1039/c2cc36610j

85.

Martins

A.P.

, Marrone

, Ciancetta

, Cobo

A.G.

, Echevarrya

, Moura

T.F.

, Re

, Casini

and Soveral

, Targeting aquaporin function: Potent inhibition of aquaglyceroporin-3 by a gold-based compound, PLoS One 7(5) (2012), e37435. doi:10.1371/journal.pone.0037435

86.

Martins

A.P.

, Ciancetta

, Almeida

, Marrone

, Re

, Soveral

and Casini

, Aquaporin inhibition by gold(III) compounds: New insights, Chem Med Chem 8(7) (2013), 1086–1092. doi:10.1002/cmdc.201300107

87.

Teo

R.D.

, Gray

H.B.

, Lim

, Termini

, Domeshek

and Gross

, A cytotoxic and cytostatic gold(III) corrole, Chem Commun 50 (2014), 13789–13792. doi:10.1039/C4CC06577H

88.

Casini

, Hartinger

, Gabbiani

, Mini

, Dyson

P.J.

, Keppler

B.K.

and Messori

, Gold(III) compounds as anticancer agents: Relevance of gold-protein interactions for their mechanism of action, J Inorg Biochem 102 (2008), 564–575. doi:10.1016/j.jinorgbio.2007.11.003

89.

Ronconi

, Giovagnini

, Marzano

, Bettio

, Graziani

, Pilloni

and Fregona

, Gold dithiocarbamate derivatives as potential antineoplastic agents: Design, spectroscopic properties, and in vitro antitumor activity, Inorg Chem 44 (2005), 1867–1881. doi:10.1021/ic048260v

90.

Giovagnini

, Ronconi

, Aldinucci

, Lorenzon

, Sitran

and Fregona

, Synthesis, characterization, and comparative in vitro cytotoxicity studies of platinum(II), palladium(II), and gold(III) methylsarcosine dithiocarbamate complexes, J Med Chem 48(5) (2005), 1588–1595. doi:10.1021/jm049191x

91.

Milacic

, Chen

, Ronconi

, Landis-Piwowar

K.R.

, Fregona

and Dou

Q.P.

, A novel anticancer gold(III) dithiocarbamate compound inhibits the activity of a purified 20S proteasome and 26S proteasome in human breast cancer cell cultures and xenograft, Cancer Res 66 (2006), 10478–10486. doi:10.1158/0008-5472.CAN-06-3017

92.

Saggioro

, Rigobello

M.P.

, Paloschi

, Folda

, Moggach

S.A.

, Parsons

, Roncoini

, Fregona

and Bindoli

, Gold(III)-dithiocarbamato complexes induce cancer cell death triggered by thioredoxin redox system inhibition and activation of ERK pathway, Chem Biol 14 (2007), 1128–1139. doi:10.1016/j.chembiol.2007.08.016

93.

Fan

, Lorenzon

, Stefani

S.L.

, Giovagnini

, Colombatti

and Fregona

, Antiproliferative and apoptotic effects of two new gold(III) methylsarcosinedithiocarbamate derivatives on human acute myeloid leukemia cells in vitro, Anti-Cancer Drugs 18 (2007), 323–332. doi:10.1097/CAD.0b013e328011ae98

94.

Fan

, Yang

C.T.

, Ranford

J.D.

, Vittal

J.J.

and Lee

P.F.

, Synthesis, characterization and biological activities of 2-phenylpyridine gold(III) complexes with thiolate ligands, Dalton Trans 17 (2003), 3376–3381. doi:10.1039/ b307610e

95.

Messori

, Marcon

, Cinellu

M.A.

, Coronnello

, Mini

and Gabbiani

, Solution chemistry and cytotoxic properties of novel organogold (III) compounds, Bioorg Med Chem 12 (2004), 6039–6043. doi:10.1016/j.bmc.2004.09.014

96.

Coronnello

, Mini

, Caciagli

, Cinellu

M.A.

, Bindoli

, Gabbiani

and Messori

, Mechanisms of cytotoxicity of selected organogold (III) compounds, J Med Chem 48 (2005), 6761–6765. doi:10.1021/jm050493o

97.

Bottenus

B.N.

, Kan

and Jenkins

, Gold(III) bisthiosemicarbazonato complexes: Synthesis, characterization, radiochemistry and X-ray crystal structure analysis, Nucl Med Biol 37 (2010), 41–49. doi:10.1016/j.nucmedbio.2009.08.003

98.

Nakajima, Accumulation of gold by microorganisms, World J Microb Biot 19 (2003), 369–374. doi:10.1023/A:1023944905364

99.

Tiekink

E.R.T.

, Gold derivatives for the treatment of cancer, Crit Rev Oncol Hemaltol 42 (2002), 225–248. https://doi.org/10.1016/S1040-8428(01)00216-5

100.

Parish

R.V.

, Howe

B.P.

, Wright

J.P.

, Mack

, Pritchard

R.G.

, Buckley

R.G.

, Elsome

A.M.

and Fricker

S.P.

, Chemical and biological studies of dichloro(2-((dimethylamino)methyl)phenyl)gold(III), Inorg Chem 35 (1996), 1659–1666. doi:10.1021/ic950343b

101.

Parish

R.V.

, Biologically-active gold(III) complexes, Metal-Based Drugs 6 (1999), 271–276. https://dx-doi-org.web.bisu.edu.cn/10.1155/MBD.1999.271

102.

Parish

R.V.

, Mack

, Hargreaves

, Wright

J.P.

, Buckley

R.G.

, Elsome

A.M.

, Fricker

S.P.

and Theobald

B.R.C.

, Chemical and biological reactions of diacetato[2-(dimethylaminomethyl)-phenyl]gold(III), [Au(O₂CMe)₂(dmamp)], J Chem Soc Dalton Trans 1 (1996), 69–74. doi:10.1039/DT9960000069

103.

Dinger

M.B.

and Henderson

, Organogold (III) metallacyclic chemistry. Part 4. Synthesis, characterisation and biological activity of gold(III)-thiosalicylate and salicylate complexes, J Organomet Chem 560 (1998) 233–243. https://doi.org/10.1016/S0022-328X(98)00493-8

104.

Dinger

M.B.

and Henderson

, Organogold(III) metallacyclic chemistry. Part 2. Synthesis and characterisation of the first gold(III) ureylene complexes, J Organomet Chem 557 (1998) 231–241. https://doi.org/10.1016/S0022-328X(97)00712-2

105.

Cariado

J.J.

, Lopez-Arias

J.A.

, Macias

, Femandez-Lago

L.R.

and Salas

J.M.

, Au(III) Complexes of tris-dithiocarbamate derivatives of alpha-amino-acids— spectroscopic studies, thermal-behavior and antibacterial activity, Inorg Chem Acta 193 (1992), 229–235. doi:10.1016/S0020-1693(00)80357-6

106.

Hemmert

, Fabié

, Fabre

, Benoit-Vical

, Gornitzka

and Hemmert

, Synthesis, structures, and antimalarial activities of some silver(I), gold(I) and gold(III) complexes involving N-heterocyclic carbene ligands, Eur J Med Chem 60 (2013), 64–75. doi:10.1016/j.ejmech.2012.11.038

107.

Biot

, Castro

, Botté

C.Y.

and Navarro

, The therapeutic potential of metal-based antimalarial agents: Implications for the mechanism of action, Dalton Trans 41 (2010), 6335–6349. doi:10.1039/C2DT12225A

108.

World Malaria Report, World Health Organization (WHO), (2012) (http://www.who.int/malaria/publications/world_malaria_report_/report/en/), ISBN 978 92 4 156453 3.

109.

Navarro

, Gabbiani

, Messori

and Gambino

, Metal-based drugs for malaria, trypanosomiasis and leishmaniasis: Recent achievements and perspectives, Drug Discov Today 15 (2010), 1070–1078. doi:10.1016/j.drudis.2010.10.005

110.

Wasi

, Singh

H.B.

, Gajanana

and Raichowdhary

A.N.

, Synthesis of metal complexes of antimalarial drugs and in vitro evaluation of their activity against plasmodium falciparum, Inorg Chim Acta 135 (1987), 133–137. https://doi.org/10.1016/S0020-1693(00)83277-6

111.

Navarro

, Vásquez

, Sánchez-Delgado

R.A.

, Pérez

, Sinou

and Schrével

, Toward a novel metal-based chemotherapy against tropical diseases. 7. Synthesis and in vitro antimalarial activity of new gold–chloroquine complexes, J Med Chem 47 (2004), 5204–5209. doi:10.1021/jm049792o

112.

Gabbiani

, Messori

, Cinellu

M.A.

, Casini

, Mura

, Sannella

A.R.

, Severini

, Majori

, Bilia

A.R.

and Vincieri

F.F.

, Outstanding plasmodicidal properties within a small panel of metallic compounds: Hints for the development of new metal-based antimalarials, J Inorg Biochem 103 (2009), 310–312. doi:10.1016/j.jinorgbio.2008.10.004

113.

Sannella

A.R.

, Casini

, Gabbiani

, Messori

, Bilia

A.R.

, Vincieri

F.F.

, Majori

and Severini

, New uses for old drugs. Auranofin, a clinically established antiarthritic metallodrug, exhibits potent antimalarial effects in vitro: Mechanistic and pharmacological implications, FEBS Lett 582 (2008), 844–847. doi:10.1016/j.febslet.2008.02.028

114.

Khanye

S.D.

, Wan

, Franzblau

S.G.

, Gut

, Rosenthal

P.J.

, Smith

G.S.

, Chibale

K.C.

and Khanye

S.D.

, Synthesis and in vitro antimalarial and antitubercular activity of gold(III) complexes containing thiosemicarbazone ligands, J Organomet Chem 696 (2011), 3392–3396. doi:10.1016/j.jorganchem.2011.07.026

115.

Singh

and Rosenthal

P.J.

, Comparison of efficacies of cysteine protease inhibitors against five strains of plasmodium falciparum, Antimicrob Agents Chemother 45 (2001), 949–995. doi:10.1128/AAC.45.3.949-951.2001

116.

Brun

, Blum

, Chappuis

and Burri

, Human African trypanosomiasis, Lancet 375 (2010), 148–159. doi:10.1016/S0140- 6736(09)60829-1

117.

Navarro

, Gold complexes as potential anti-parasitic agents, Coord Chem Rev 253 (2009), 1619–1626. doi:10.1016/j.ccr.2008.12.003

118.

Cavalli

and Bolognesi

M.L.

, Neglected tropical diseases: Multi-target-directed ligands in the search for novel lead candidates against Trypanosoma and Leishmania, J Med Chem 52 (2009), 7339–7359. doi:10.1021/jm9004835

119.

Moreira

D.R.

, Leite

A.C.

, Santos

R.R.D.

and Soares

M.B.P.

, Approaches for the development of new anti-trypanosoma cruzi agents, Curr Drug Targets 10 (2009), 212–231. https://doi.org/10.2174/138945009787581140

120.

Fricker

S.P.

, Mosi

R.M.

, Cameron

B.R.

, Baird

, Zhu

, Anastassov

, Cox

, Doyle

P.S.

, Hansell

, Lau

, Langille

, Olsen

, Qin

, Skerlj

, Wong

R.S.

, Santucci

and Kerrow

J.H.

, Metal compounds for the treatment of parasitic diseases, J Inorg Biochem 102 (2008), 1839–1845. doi:10.1016/j.jinorgbio.2008.05.010

121.

Sánchez-Delgado

R.A.

, Navarro

, Lazardi

, Atencio

, Capparelli

, Vargas

, Urbina

J.A.

, Bouillez

, Noels

A.F.

and Masi

, Toward a novel metal based chemotherapy against tropical diseases 4. Synthesis and characterization of new metal-clotrimazole complexes and evaluation of their activity against Trypanosoma cruzi, Inorg Chim Acta 275–276 (1998), 528–540. https://doi.org/10.1016/S0020-1693(98)00114-5

122.

Nyarko

, Hara

, Grab

D.J.

, Habib

, Kim

, Nikolskaia

, Fukuma

and Tabata

, In vitro toxicity of palladium(II) and gold(III) porphyrins and their aqueous metal ion counterparts on Trypanosoma brucei brucei growth, Chem Biol Interact 148 (2004), 19–25. doi:10.1016/j.cbi.2004.03.004