Review ArticleDevelopments in Platinum-Group Metals as DualAntibacterial and Anticancer Agents

Ayodele T. Odularu ,1 Peter A. Ajibade ,2 Johannes Z. Mbese ,1

and Opeoluwa O. Oyedeji1

1Department of Chemistry, University of Fort Hare, Private Bag X1314, Alice 5700, South Africa2School of Chemistry and Physics, University of KwaZulu-Natal, Pietermaritzburg Campus, Scottsville 3209, South Africa

Correspondence should be addressed to Ayodele T. Odularu; 201106223@ufh.ac.za

Received 8 May 2019; Accepted 10 June 2019; Published 6 November 2019

Academic Editor: Liviu Mitu

Copyright © 2019 Ayodele T. Odularu et al. +is is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Platinum-group (PG) complexes have been used as antibacterial and anticancer agents since the discovery of cisplatin.+e scienceworld still requires improvement on these complexes because of multidrug and antineoplastic resistances. +is review observesdiscoverers and history of these platinum-groupmetals (PGMs), as well as their beneficial applications.+e focus of this study wasbiological applications of PGMs in relation to human health. Sandwich and half-sandwich PGM coordination compounds andtheir metal nanoparticles give improved results for biological activities by enhancing efficient delivery of both antibacterial andanticancer drugs, as well as luminescent bioimaging (biomarkers) for biological identifications.

1. Introduction

According to McQuitty, Ellahioui et al., Marques, and Rajiniet al., many years ago, metals were considered for medicinaluses to treat diseases [1–4]. In order to enhance the activitiesof these metals, new developments in modern medicine arerecognized and confirmed because of the high efficiencies ofvarious metal-based drugs to overcome the drawbacks ofmetals on different diseases, such as bacteria and cancer[1, 2]. Cancer is rated the second most affecting disease inhumans globally after cardiovascular diseases [3]. On an-other note, resistance to antibiotics is a threat to publichealth against eliminating bacterial infections [5l]. In con-trolling these diseases and circumventing the drawbacksexperienced in the use of organic-based drugs, d-blockmetals called transition metals possess unique electronicstructures, which enable them to be versatile by modifyingthe properties of a certain molecule [1]. Among thesetransition metals are platinum-group metals (PGMs). +eyare a group of six transition d-block metallic elementsclustered together in the periodic table. +ese PGMs areiridium, osmium, palladium, platinum, rhodium, and

ruthenium. +ey are also called platidises, platinides, plat-inoids, platinum family, platinum group, platinum metals,or platinum-group elements (PGEs). +ey possess similarphysical and chemical characteristics and have propensity tobe in the same mineral ores’ deposits. In addition, there is asubclassification into the iridium-group platinum-groupelements (IPGEs: Ir, Os, and Ru) and the palladium-groupplatinum-group elements (PPGEs: Rh, Pd, and Pt) on thebasis of their performances in geological systems.+e PGMscoordination compounds belong to conventional chemo-therapy (single and combination therapy), as well as com-plementary and alternative medicine (CAM). Multiple drugresistance, adverse side effects, little therapeutic indices,high-dose requirements, reduced bioavailability, and non-specific cell/organ targeting are some of the drawbacks ofconventional chemotherapy and CAM, which brought in apause in progress and success [6]. +ese drawbacks warrantan urgent need to design and develop chemotherapy whichcan target the bacterial and cancerous cells. In this manner, itwill control the drawbacks and at the same time increase thetherapeutic effectiveness. Chemists are using novel ways toimprove delivery methods in the field of metallodrugs with

HindawiJournal of ChemistryVolume 2019, Article ID 5459461, 18 pageshttps://doi.org/10.1155/2019/5459461

new developments and modifications of existing drugs.Many yeas ago till today, multipurpose materials, such asbio-macromolecular scaffolds, inorganic carriers, lipids,polymers, and polymeric hydrogels, have been used to de-liver chemotherapeutics to targeted cancer cells with en-hanced effectiveness. Additionally, in the last twenty years,nanotechnology emergence has made positive impacts onclinical therapeutics [6–9]. Nanomedicine, a division ofnanotechnology, entails the use of nanoscale drug carriers,which have potentials to overcome these drawbacks byenhancing therapeutic effectiveness through active cellularuptake and reduced toxicity, and help to improve perme-ability and retention. +ese nanocarriers containing che-motherapeutics achieve their aims when used incombination with molecules which bind to overexpressedantigens [6]. Presently, some nanoparticles-based chemo-therapeutics are clinically endorsed; others are in numerouspreclinical and clinical stages. Nevertheless, nanocarriershave many merits as drug carrier systems, but lack ofbiodegradation, reduced bioavailability, unstable circula-tion, insufficient tissue distribution, and possible toxicity arechallenges over the safety, most especially when it comes tolong administration. +is study aimed to explore the historyof PGMs, general uses, and extensive biological relevance ofPGMs with their nanoparticles to human health.

2. The PGMs

All six PGMs (iridium, osmium, palladium, platinum,rhodium, and ruthenium) are reviewed to obtain the sig-nificance of this study.

2.1. Iridium. Between 1803 and 1804, Smithson Tennant, aBritish chemist, discovered iridium in the dregs of crudeplatinum when it was dissolved using aqua regia (hydro-chloric acid and trioxonitrate(V) acid) [10–13].+e origin ofthe name was derived from the Latin word, “iris,” whichmeans, “rainbow.” Iridium is a d-block transition metal witha symbol of Ir, atomic number of 77, and atomic mass of192.217 [11]. Iridium has variable oxidation states from − IIIto +IX [14], but according to Liu et al, iridium has fourdifferent oxidation states, namely, +1, +2, +3, and +4. [15].+e main coordination numbers are 4 and 6 [15]. It formsorganoiridium coordination compounds. Liu et al. statedthat the inert and stable nature of iridium(III) could beappropriate characteristics for drug design. IrIII has a morestable oxidation than IrI with a higher oxidation number,which helps to provide broad basic variety from a wide rangeof ligands [15]. With regards to the relevance of ligands intargeting site, the characteristics of IrIII enable their co-ordination compounds to attain its target site devoid ofmodifications. Due to instability of Ir(III) complexes withbenzene ligands, they bind alternatively with cyclo-pentadienyl ligands. Iridium is the first member of theplatinum-group metals (PGMs). It is hard and a brittle whitesolid with a yellowish tinge. In addition, it is one of thedensest metals and most corrosive opposing metal everknown [10]. Iridium’s industrial production is from the by

product of nickel and copper mining and development.Iridium has various industrial applications as a platinumhardener for electrical contacts, for coating optical lenses topromote clear vision, and an alloy with osmium to producefountain pens and compass bearings [7]. Pharmaceuticalsfocusing on metal complexes of iridium are still at the earlystages [8]. Chen et al. used the existing antidiabetic drugcalled biguanide (N, N donor ligand) to ligate iridium(III)ion to obtain iridium.(III) biguanide coordination com-pounds [16]. +ese complexes were used as potent anti-microbial agents because biguanides were inactive whenadministered alone. Medically, organometallic complexes ofiridium(III) from research proved to have potentials foranticancer and antimicrobial activities [15–25]. In recenttimes, organoiridium(III) complexes showed potentials asanticancer agents. Among the most inert low-spin d6 me-tallic ions is Ir(III), since inertness and stability are essentialproperties for drug design and development [11]. Lu et al.reported the antibacterial and anticancer activities of somecyclometalated iridium(III) complexes [17].

On the other hand, sandwich and half-sandwich com-plexes are arene metal complexes which are well recognizedclasses of organometallic compounds [26]. A sandwichcompound has a metal between two arene ligands bound byhaptic covalent bonds, while half-sandwich compound has apolyhapto ligand bond to an MLn centre, where L is aunidentate ligand. Unidentate ligands used are mostlyhalides.

Adhikari et al. studied half-sandwich d6 metal complexes(iridium, rhodium, and ruthenium(II)) comprising 2-substituted-1,8-napthyridine ligands with unexpectedbonding modes (Figure 1). +e results gave less activecompounds than cisplatin (standard drug). On a similar butbetter note, Starha et al. used half-sandwich Ir(III) complexof N1-pyridyl-7-azaindole as an anticancer agent, whichexceeds the cytotoxicity of cisplatin at various human cancercells and 3D multicellular tumour spheroids [27]. Likewise,Hearn et al. used new action mechanisms of organometalliciridium(III) complexes to obtain better anticancer activitiesthan cisplatin against ovarian carcinoma cells (A2780) [28].+ey used cyclopentadienyl ligands containing N, N or C,N-chelates occupying the fourth and fifth sites and amonodentate chlorine ligand as the sixth site to synthesizefour half-sandwich organometallic IrIII cyclopendienylpseudo-octahedral complexes as effective cytostatic andcytotoxic anticancer agents. Lu et al. used some cyclo-metalated iridium(III) complexes as dual antibacterial andanticancer agent. Lu et al. cited the work of Mukherjee et al.,in which three cyclometalated iridium(III) coordinationcompounds containing functionalized dithiocarbamatespossessed dual anticancer and anticancer activities due todelocalised π electrons directly above the chelate ring. Luet al. based their research on four iridium(III) coordinationcompounds and one rhodium(III) coordination compoundagainst two human ovarian carcinoma cells (A2780 andSKOV3), two melanoma (skin) cell lines (A375 and A2058),one cervical cell line (HeLa), one hepatocarcinoma (liver)cell line (HepG2), and four bacterial strains (Enterococcusfaecalis, Escherichia coli, Klebsiella pneumoniae, and

2 Journal of Chemistry

Staphylococcus aureus). Lu et al. concluded from theirstudies that the first synthesized iridium(III) complexconsisting of 2-(p-tolyl)pyridine had a lower cyclometalatedligand compared to quinolone or isoquinoline-basedcyclometalated ligands of complexes 2 and 4 correspond-ingly resulting to its highest antibacterial activities. +ey gothigher bacterial activity in terms of higher zone of inhibitionwhen iridium was replaced with rhodium in complex 5. Onanother note, an amino substituent on the phenanthrolineligand made the first iridium(III) coordination compound asuperior anticancer agent than other studied complexes withthe exception of HepG2. In comparison, while Mukherjeeet al. used sulphur-nitrogen (S-N) donor ligands, Lu et al.used nitrogen-nitrogen (N-N) donor ligands to ligate iri-dium(III) ions. Lu et al.’s molecular structures for cyclo-metalated iridium(III) complexes and rhodium(III) complexare shown in Figure 2 [17].

Lucas et al. synthesized four iridium and one rutheniumarene complexes with (N, N), (N, O), and (O, O) co-ordination modes from different ligands. +e cytotoxicitypotency trend gave (N, O)> (O, O)> (N, N) for the fivesynthesized coordination compounds. +y discovered thatthe activities of (N, O) piano-stool coordination compoundsare the most effective to be compared with cisplatin based onprecision. +ey discovered that (N-O) complexes were moreeffective when compared to cisplatin. Among the five syn-thesized compounds, the chemical structure of ketoiminatecomplex is as shown in Figure 3. In summary, among thethree groups of aforementioned researchers for iridium(III)complexes, Lucas et al.’s results for cytotoxic activities werevery precise with cisplatin against HT-29 (colon) and(MCF-7) breast cancer cell lines. +e constancy in all thedonor ligands is the presence of nitrogen.

Ma et al. stated that bioimaging is the application ofmicroscopes or scanners for cell, tissue, organ, and organismvisualization. +ey further said that it supports the study ofbiological processes, clarifies the nature of signalling andconnections at a cellular and molecular level, and arrests thedrive of cellular molecules. Additionally, bioimaging cantrace metabolites that, when used as biomarkers, aid indisease identification and treatment reaction. In order to

produce high-quality images for biological monitoring,magnetic resonance, optical signals, and ultrasound havebeen employed [29]. Qualities such as ability for long-termobserving of a single sample, low cost, high detection sen-sitivity, and speedy response have speeded up the uses ofbioimaging in recent years. Among the luminescent tran-sition metal complexes which possess advantages as bio-imaging reagents are iridium(III) complexes [29]. +esequalities are (i) high room temperature quantum yields, (ii)high photochemical and physicochemical stabilities, (iii)large Stokes shifts which lower the excitation beam and innerfilter effects, (iv) long phosphorescence emission lifetimeswhich lower the interference of autofluorescence by theapplication of time-gated imaging techniques, (v) multi-chromophoric structures potentially allowing dual emissionunder single wavelength excitation, (vi) spherical molecularshape to lower harmful intermolecular impacts, such asaggregation, (vii) structural flexibility which enables prepa-ration of coordinated saturated or unsaturated complexes,(viii) synthetic flexibility for fine-tuning photophysicalproperty, and (ix) tunable phosphorescence emission spectra,to the extent of reaching the near-infrared region.

Ma et al. introduced concept of nanoparticles, wherebyiridium(III) complex-assisted nanoparticles were used forbiological applications [29].

An application of bioimaging is bioanalytical labelling,which has made nanomaterials enjoy remarkable growth. Asa result, luminescent nanoparticles (NPs) have been usedwidely in the biological andmedical fields, such as assembledmolecular control, biological therapeutics, disease di-agnostics, drug delivery, genomic studies, pharmaceuticalscreening, protein purification, and proteomic studies. Iri-dium(III) complexes are good precursors,which supportnanomaterials for luminescent sensing, highlighting thosewhich can be used for intracellular imaging. In addition,combination of iridium(III) complexes with nanomaterials,such as inorganic NPs, polymer NPs, upconversion NPs, andquantum dots, has contributed to the fields of drug delivery,intracellular sensing, and photodynamic therapy. In specific,the combination of iridium(III) complexes with several NPsmight enhance a variety of their properties, such as aqueoussolubility, cellular distribution, cytotoxicity, and uptakeefficiency, in order to improve bioimaging applications [29].

2.2. Osmium. Likewise, between 1803 and 1804, SmithsonTennant also discovered osmium, whose name has a Greekorigin, “osmic,” which means smell, scent, or odour [10, 13].+e discovery of osmium was linked with platinum, due tothe fact that osmium was the black residue which remainedafter the dissolution of platinum in aqua regia [10, 13].According to Arbiaster, it is the densest element at alltemperatures and ambient pressure [30]. It is a bluish white,hard, and lustrous metal which is solid at room temperature.It exists in nature both as a free element and in combinedstate with copper and nickel as alloys. +e major source ofextraction is a by-product of refinery of copper and nickel.Osmium is found in the mineral of iridosule, as well as inplatinum-bearing river sands in North America, South

N NN

M

Cl

Cl

M = Ir, Rh, Ru

Figure 1: Half-sandwich d6 metal complexes comprising 2-substituted 1, 8-napthyridine ligands with unexpected bondingmodes.

Journal of Chemistry 3

America, and Urals. Osmium has variable oxidation states of+3, +4, +6, and +8, but sometimes 0, +1, +2, +5, and +7.Osmium is a transition metal, a PGM with an atomicnumber of 76 and a mass number of 190.23. It has anelectronic configuration of [Xe] 4f145d66s2. +e assumptionthat osmium is very toxic and volatile makes the pure formto be hardly used [31]. For industrial application, osmium isused as alloys when mixed with other metals due to its hightolerance to corrosion and wearing. Osmium is also founduseful in the technology of light bulb. Instruments such aselectrical contacts, phonograph needles, and pivots areproduced from alloys of osmium [30]. +e natural combi-nation with iridium is used to make fountain pen tips.Osmium tetroxide, though a very strong, toxic oxidant, isuseful for detecting fingerprints and stain fatty tissues formicroscope slides. Medically, osmium complexes of valencesII and VI are used as anticancer and antimicrobial agents

[32–43]. Starha et al.’s synthesized half-sandwich Os(II)complex ([Os(s6-pcym) (bphen) (dca)]PF6) as shown inFigure 4 exhibited good in vitro cytotoxity against A2780human ovarian carcinoma cells, slightly above cisplatin [44].In the case of Fu et al., they synthesized two chloro and twoiodido (four) chiral Os(II) arene anticancer complexes [45].+e four Os(II) coordination compounds are shown inFigure 5. +e two iodido complexes showed higher anti-cancer activities (lesser inhibition concentration (IC) values)to A2780 human ovarian cancer cells than cisplatin and weremore active than the two chlorido derivatives. Similarly,Romero-Canelon et al. stated that organometallic half-sandwich [M(p-cymene) (azo/imino-pyridine)X]+, whereM�Ru(II) or OsII and X�Cl or I, showed potent anti-proliferative action toward a range of cancer cells. Here,iodide complexes are also more effective than the chloroanalogues, but not cross-resistant to cisplatin and oxaliplatin

N

N

NH2

N

N

Ir

PF6

(a)

NH2

Ir

PF6

N

N

N

N

(b)

Ir

PF6

N

N

N

N

(c)

Ir

PF6

N

N

N N

N

(d)

PF6

N

N

N

Rh

N

(e)

Figure 2: Molecular structure of cyclometalated iridium(III) complexes (a–d) and cyclometalated iridium(III) complex (e).

4 Journal of Chemistry

[46]. Starha et al.’s study focused on nitrogen-oxygen donorligands, while Romero-Canelon et al.’s study focused on theuse of nitrogen-nitrogen donor ligands. Additionally, Zhangand Sadler synthesized organometallic osmium(II) com-pounds and reported that Os(II) arene complexes withguaranteed phenylazopyridine ligands (nitrogen-nitrogendonor ligands) were more effective and inert to iodide as theunidentate ligand [47]. One of the arene structures is shownin Figure 6. +ey further stated that they were not only moreeffective than cisplatin in the NCI-60 cell line but also forty-nine times more effective on average in a Sanger plan of 809cancer cell lines and active in vivo. +e Os(II/III) anticanceragents designed previously as analogues of Ru(II/III)complexes are Os-RAPTA-C, Os-RM175, and Os-NAMI-A[48]. In recent times, organometallic arene Os(II) azopyr-idine complex FY26 exhibits high anticancer activity andmechanism of reaction (Figure 7). Arene Os(II) azopyridinecomplex FY26 is a prodrug, which has the ability to beactivated catalytically by cellular glutathione (GSH) andincreases the level of intracellular reactive oxygen species(ROS) in cancer cells extensively [48]. Gichumbia et al.synthesized three half-sandwich Os(II) complexes, [(s6-benzene)OsCl(C5H4N-2-CH�N-C6H5X)] (where X� p-

F(1), p-Cl(2), p-CH3 (PF6)), as shown in Figure 8. In vitrotests were carried out on the complexes against Caco-2(human epithelial colorectal adenocarcinoma), HepG2(human heptocellular carcinoma), and MCF-7 (humanbreast adenocarcinoma) tumour cell lines, and HE293(human kidney) nontumour cell line. Complex 2, the mostantiproliferative complex, with Cl and its pyridyl-imine li-gand (4-(chlorophenyl)-pyridin-2-yl-methylene amine), wasable to undergo antibacterial screening against selectedGram-negative and Gram-positive bacterial strains, such asdrug resistant Enterococcus faecalis and methicillin-resistantStaphylococcus aureus ATCC 43300. It showed moderateactivities. In essence, complex 2 is a dual prospective an-tibacterial and potent anticancer agent [49]. Comparing thehalide substituents, Zhang andHuang reported that chloridoand iodido functionalized coordination compounds werepotent similarly, while the bromido analogues yielded theleast active compounds in vitro [48]. Additionally, theystated the luminescent bioimaging properties of Os(III)complexes [48]. All the aforementioned researchers usednitrogen-nitrogen donor ligands which all show their higherpotencies when compared with cisplatin and their effec-tiveness as antibacterial agents. According to Zhang andHuang polypyridyl Os(II) coordination compounds haveprospective advantages in luminescent cell imaging andphotodynamic therapy because of their good photophysicaland photochemical characteristics, such as high photo-stability, long-wavelength metal-ligand charge transfer(MLCT), and near-infrared (NIR) emission [48].

2.3. Palladium. In 1802, William Hyde Wollaston discov-ered palladium, but due to a controversy which arose, thecredit of discovery was given to Richard Chenevix [50]. +eorigin of the name came from Pallas (Greek goddess ofwisdom), a name given to an asteroid. It is mined from oresof copper, mercury, nickel, and platinum. It is a transitionmetal, as well as a PGM, with a symbol of Pd, atomic numberof 46, and atomic mass of 106. It is a white solid with a cubiccrystal structure. Palladium is the least dense metal in theplatinum group. +e leading producers of palladium whichmanufacture about 40% of the yearly supply worldwide areRussia and South Africa. +e industrial applications involveautomobile catalytic converters because of the ease of diffusionwith hydrogen gas in the making of jewellery and medicalinstruments. Palladium has medical application in the timelytreatment of tuberculosis, but other options were sought due todeleterious drawbacks. Other medical applications of palla-dium are their activities as anticancer and antimicrobial agents[51–57]. Ahmad et al. synthesized Pd(II) complex,[Pd(PPh3)2(Imt)2Cl2.3.5H2O], where Imt is imidazolidine-2-thione, and screened it against two Gram-negative bacteria(Escherichia coli and Pseudomonas aeruginosa) and two yeasts(Candida albicans and Saccharomyces cerevisiae) [55]. +eyconcluded that moderate activities were obtained from theantibacterial test, while significant activity was obtained fromthe yeast test.

Bakalova et al. synthesized four Pt(II), Pt(IV), Pd(II),and Pd(IV) coordination compounds using 3-amino-

NM

N

O

O

Cl

Cl

+

Figure 4: Synthesized half-sandwich Os(II) complex ([M(s6-ocym)(bphen) (dca)]PF6).

Ir

N

Ph

Cl

O

F

Figure 3: Iridium(III) ketoiminate complex.

Journal of Chemistry 5

α-tetralonespiro-5′-hydantoin as carrier ligand (Figure 9).All compounds were screened in vitro against SKW-3 hu-man tumour cell line. Pt(II) coordination compound

exhibited higher antitumour activity than Pd(II) coordinationcompounds but lower activity than cisplatin [56]. Althoughdifferent ligands were used and on a different mode of ap-plication, Ajibade and Idemudia reported the antibacterialefficacy of palladium complex with diaminopyrimidine of

C

N

H

HCl

Os

H3C

H3C

H3CPF6

N

H3C

(a)

PF6

C

NH

H

Cl

Os

N

H3C

H3C

H3C

H3C

(b)

PF6

C

N

H

HI

Os

N

H3C

H3C

H3C

H3C

(c)

PF6

C

NH

H

I

Os

N

H3C

H3C

H3C

H3C

(d)

Figure 5: Chloro and iodido Os(II) arene anticancer complex.

N

Os

I

N

N

N

+

Figure 6: Osmium(II) arene anticancer complex with phenyl-azopyridine ligands.

Os

N

I

N

NN

+

Figure 7: Osmium(II) azopyridine complex FY26.

6 Journal of Chemistry

nitrogen coordination mode (Figure 10) to be more potentthan the platinum counterpart [58]. Contrary to Bakalova etal., Pt(II) showed higher efficiency as an antitumour agentthan Pd(II) complex. Similar to Ajibade and Idemudiia,Wabamare et al. stated that the higher potency in-vitro an-tibacterial and antifungal activities of Pd(II) chiral Schiff baseligand complexes when compared with Ni(II) analoguesagainst two Gram negative and Gram positive bacteria(Escherichia coli and Staphylococcus aureus), two fungi (As-pergillus niger (mold) and Candida albicans (yeast)) and earpathogens [59]. +ey used mixed donor ligands containingnitrogen and oxygen atoms. Fong et al. were able to showfrom their proteomics data that stable cyclometalated plati-num(II) N-heterocyclic carbene (NNC) complexes have bothin vitro and in vivo anticancer activities [60]. According toZhang and Sadler, the presence of biological thiols enablespalladium(II) complexes to be stable. +eir in vivo antibac-terial studies showed their efficiencies to prevent tumourgrowth in an exposed rat model [47]. +eir two palladium(II)complexes are shown in Figure 11. +e challenge of usingpalladium complexes as anticancer and antimicrobial agentsis the labile nature they possess compared with platinumcomplexes [47]. Elhusseiny and Hassan reported the dualactivities of synthesized square planar Pd(II) complexes asantimicrobial and anticancer agents [51]. +ey used thenanoprecipitation method to prepare new thermally stablesphere-shaped aramides nanoparticles comprising flexiblelinkage ligands.+e aramide nanoparticles were used to ligatePd(II) ions to form Pd(II) complexes. +e Pd(II) complexeswere screened against Staphylococcus aureus (Gram-negativebacteria), Escherichia coli (Gram-positive bacteria), Asper-gillus flavus (filamentous fungi), and Candida albicans(yeast), using the improved Kirby-Bauer disc diffusionmethod. +eir polyamides having sulfones showed highefficiency as antibacterial and antifungal agents. All testedcompounds are promising antimicrobial agents becausethey have lower zones of inhibitions than the standarddrugs, namely, tetracycline and amphotericin, respectively,but higher zones of inhibitions than their correspondingligands [51]. In the case of anticancer studies, the com-plexes were screened against three cell lines (breast car-cinoma (MCF-7), colon carcinoma (HCT 116), and livercarcinoma (HEPG2)). Elhusseiny et al. reported thatamong the twelve synthesized Pd(II) complexes, three of

them at 10mg/ml concentration showed highest efficien-cies against three cancer cell lines (HCT116, HEPG2, andMCF-7). +ese three Pd(II) complexes also showed highestefficiencies as antibacterial and antifungal agents [51]. +eyconcluded that the presence of chloro groups in Pd(II)complexes resulted in their highest biological actions. Inaddition to the chloro groups, majority of the donor ligandsused contained nitrogen and nitrogen to enhance biologicalactivities as evident in the figures.

2.4. Platinum. In 1748, Antonio de Ulloa, a Spanish sci-entist, was given the recognition for discovery of platinum[61–64]. Platinum is a transition metal with a symbol of Pt,atomic number of 78, and atomic mass of 195.084. Platinumhas the origin from Spanish word, “platina,” which meanslittle silver. +e commercial production is from the residuefrom the refinery of copper and nickel like other PGMs.Platinum is a silvery-white precious metal, which is mal-leable, ductile, does not easily oxidize in air, and occursfreely in nature and in combined state with iridium. +eleading manufacturer of refined platinum is the MerenskyReef in the Bushveld Igneous Complex (BIC) in SouthAfrica. It manufactures 80% of the world’s production, andthe alluvial deposit is found in Ural Mountains in Russia andin western American states. Platinum has numerous ap-plications. +e industrial and chemical applications aremaking jewellery and coinage, cigarette lighters, crucibles,catalysts, catalytic converters for automobiles, handwarmers, oxygen sensors, pipelines, strong magnets, sparkdrugs, and turbine engines. Pre-Columbian Americans usedit to make artefacts. In the years between 1889 and 1960, 90%of platinum alloy was used as the international standard todefine one meter. +ere has been progress of platinum drugsfrom cisplatin to third-generation drugs [65]. In medicine,platinum is used to build dental crowns and dentistry in-strument and used as antitumour agents. Platinum is appliedboth as anticancer and antimicrobial agents [65]. FromBarnett Rosenberg et al.’s article in “Nature,” they carried out

Os N

N

Cl

XPF6

Figure 8: Molecular structure of [(s6-benzene)OsCl(C5H4N-2-CH�N-C6H5X)] (where X� p-F(1), p-Cl(2), p-CH3 (PF6)).

O

OHN

N

NH2 NH2

NH2NH2

M

ON

Cl

Cl

Cl

Cl

Cl

Cl

O NH

O

OHN

N

ON

O NH

M

Figure 9: Four Pt(II), Pt(IV), Pd(II), and Pd(IV) coordinationcompounds using 3-amino-α-tetralonespiro-5′-hydantoin as car-rier ligand (where M�Pd or Pt).

Journal of Chemistry 7

a research on the potential impacts of electromagnetic field ondevelopment in bacteria [66]. +e research involved platinumelectrodes, ammonium chloride as electrolyte, and concen-trations in parts per million of specific group of VIIIb of the

d-block metallic compounds in the culture media [66–71].+ey observed that there was a chemical reaction betweenammonium chloride and the inert platinum electrodes, whichled to the formation of trans-dichlorodiamineplatinum. +is

NH2

NH2

N

N

H2N

OCH3

OCH3OCH3

M

N

N

ClClOCH3CH3O

CH3O

(a)

NH2

NH2

H2NOCH3

OCH3

OCH3

OCH3

CH3O

CH3O

N

N

M

N

N

NCSSCN

(b)

NH2

NH2

H2N

H2N

N

N

M

Cl

Cl

Cl

ClN

N

(c)

NH2

NH2

H2N

H2N

Cl

Cl

N

N

M

NCS

SCN

N

N

(d)

Figure 10: Palladium complex with diaminopyrimidine ligands (where M� palladium or platinum).

N

N N

N

R R

RR

Pd

Cl

Cl

R = CH2CH2CH2CH3

(a)

N

NPd

R R

R = CH3CH2CH2CH3CH2CH2CH2CH3

(b)

Figure 11: Palladium(II) NHC complexes.

8 Journal of Chemistry

was inactive on the bacteria, but when exposed to light, itwas converted to cis-dichlorodiamineplatinum, known ascisplatin, which had inhibition on the bacterial cell di-vision [66–68]. A study of the literature on cisplatinrevealed that it was synthesized in 1848, resynthesized in1890, and referred to as Peyrone’s chloride, which led to thediscovery of the isomerism and initiation of coordinationchemistry [66–68]. Platinum was found to possess anti-bacterial properties [65–67]. Biophysicist, BarnettRosenberg, incidentally discovered cisplatin as havingpotentials and potencies as efficient anticancer agents[66–68]. In 1964, the first metallocomplex anticancer drugnamed cisplatin [Pt Cl2.(NH3)] was discovered. It startedthe development of metal-based anticancer drugs. Be-tween 1977 and 1978, the United States Food and DrugAdministration (FDA) endorsed cisplatin. +e thera-peutic application of cisplatin in the study of cancer hadled to treatment of various types of cancer, such asbladder, ovaries, and head and neck malignancies [66–68].+e side effects of emetogenesis, nephrotoxicity, neuro-toxicity, and ototoxicity that cancer patients experiencedled to synthesis of carboplatin which had less toxicitycompared with cisplatin [68]. Lack of selectivity of cis-platin led to other analogues of cisplatin with potentialsfor anticancer activities. Some examples are carboplatin,nedaplatin, ZD0437, AMD473, and oxaliplatin. Somechemical structures of some platinum anticancer drugsare shown in Figure 12 [67]. Ndagi et al., Kostova et al.,and Manav et al., reported the impact of metal complexesin terms of improving compounds design to reducetoxicity, control drug resistance, and appreciate the actionmechanisms in medicine [69, 72, 73]. Kostova et. alshowed eight platinum(II) and platinum(IV) molecularstructures having nitrogen-nitrogen donors and nitrogen-oxygen donors. +ey stated that there was no significantchange in the effectiveness of Pt(II) or Pt(IV) co-ordination compounds to produce cytotoxicity in mul-ticellular tumour spheroids (MCTS) compared tomonolayer cultures. +ey suggested combination therapyas a promising approach to fight against cancer becausecombining drugs with diverse modes of action oftensynergises their impacts. Ajibade and Idemudia reportedthe antibacterial activities of platinum(II) complex withdiaminopyrimidine ligand (nitrogen and nitrogen co-ordination modes) [58]. +eir minimum inhibitionconcentration (MIC) and minimum bacterial concen-tration (MBC) confirmed that Pt(II) complexes were lessactive than their group member Pd(II) complexes. Sim-ilarly, on antibacterial activities, Manav et al. reported andstudied Pt(IV) dithiocarbamato complexes (sulphur andsulphur coordination modes). From their in vitro bacterialstudy, they discovered that the complexes when testedagainst E. coli, B. subtilis, P. aeruginosa K (PAK), P.aeruginosa, and Z. mobilis bacterial strains showed lessactivities (Table 1).

Additionally, one of the complexes tested for its in vitroantitumour activities against adenocarcinoma (humancolour) cell line at various concentrations between 10 μMand 10 pM showed good activity at 100 and 10 μM solutions,

but further dilutions gave proliferation. :e in vivo testingon various organs, such as the bladder, brain, kidney, andliver, of rabbits exhibited no adverse effect. Dimethy lsulf-oxide (DMSO) was used as negative control, while 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide(MTT) was used as positive control. On a different note,Andrew and Ajibade stated the cytotoxic activities of plat-inum(II) complex with 1-phenylpiperazine dithiocarbamatoligand (sulphur and sulphur coordination modes) to be lessactive when compared to the standard drug, parthenolide[74]. +e cancer cell lines used for the study were TK10(renal), UACC62 (melanoma), and MCF-7 (breast). +e cellgrowth inhibition (IC50) accordingly was >100, >100, and66.82, as against the IC50 of parthenolide given as 4.64, 11.37,and 3.52, respectively (Table 2).

Drug design influences the development of improvedplatinum and palladium-based polyamine anticancer agentswith a focus on controlled delivery to promote less toxiccytotoxic activity [69, 75–80].

Fast development of nanobiotechnology enables thepossibility of targeted delivery of antibacterial and anti-cancer platinum agents to deliver platinum drugs to bacterialand cancer sites [77]. In this manner, it reduces toxicity andincreases drug efficiency. +is progress in the use ofnanodelivery strategies is increasing, whereby platinumwarheads were incorporated into nanomedicine concepts.Nanoparticles designed to deliver platinum(IV) complexesinclude carbon nanotubes, carbon nanoparticles, goldnanoparticles, quantum dots, polymeric micelles, upcon-version nanoparticles, and nanoformulations (coordinationpolymers, metal-organic frameworks, peptides, proteins,and supramolecular self-assembled structures) [76–79].Inorganic nanoparticles-based drug carriers with excep-tional theranostic effects are relevant and better thanpolymeric and lipid nanoparticles [77].

2.5. Rhodium. Rhodium with the symbol Rh is a transitionmetal, PGM, and has atomic number of 45 and atomic massof 102.9055. William Hyde Wollaston, an English chemist,who discovered palladium, also discovered rhodium wheninvestigating platinum ores from Peru in London in 1803[50, 81]. Hippolyte-Victor Collet-Descotilis drew Wollas-ton’s attention to the option of a novel element, which had ared colour [50]. +e origin of rhodium came from Greekword, “rhodon,” meaning rose. +e commercial pro-duction of rhodium is got from byproduct of refinery ofores of nickel-cobalt sulfides. It is a hard, silvery-whitelustrous metal with a low density. It is has high reflectanceand is very resistant to corrosion. It is nonreactive to mostacids and does not form oxides. +e industrial andchemical applications include their use as alloys tostrengthen resistance to corrosion of palladium andplatinum, as electrical contact substance due to its lowelectrical resistance, and for making jewelleries anddecorations. +e medical applications involve acting asanticancer and antimicrobial agents in the Rh(I), Rh(II),and Rh(III) states [25, 82–94]. Jeremic et al. stated thatRhIII complexes are isoelectronic with RhII and PtIV

Journal of Chemistry 9

coordination compounds, which offer a variety of effectiveantitumour agents [83].+ey further noted their geometryas octahedral and their biological activities as being an-timicrobial and antitumour. Additionally, Geldmacheret al. reported that rhodium compounds have significantantitumour activities but are less active than anticanceragents because of their toxic effects. Monomeric square

H3N

H3N

Pt

Cl

Cl

(a)

H3N

H3NPt

O

O

O

O

(b)

H3N

H3N

PtO

O

O

(c)

H3N

PtN

CH3

Cl

Cl

(d)

H3NPt

CH3

Cl

Cl

(e)

Pt

H2N

H2N O

O

O

O

(f)

H3N

Pt

NH2

OCCH3

OCCH3

Cl

Cl

(g)

Pt Pt Pt

NH3 NH3

NH3 NH3

NH3

NH3NH2(CH2)6H2N

NH2(CH2)6H2N4+Cl

Cl

(h)

Figure 12: Pt(II) and Pt(IV) anticancer drugs. (a) Cisplatin. (b) Carboplatin. (c) Nedaplatin. (d) ZD0437. (e) AMD473. (f ) Oxaliplatin. (g)JM216. (h) BBR3464.

Table 1: Antibacterial activities of platinum(IV) dithiocarbamato complexes in μM.

Pt(IV) complex Z. mobilis B. subtilis K. aeroginosa E. coli P. aeruginosa[Pt(L1)2Cl2] + ++ _ _ +[Pt(L3)2Cl2] ++ _ _ _ +[Pt(L4)2Cl2] _ ++ _ + +L1 � morpholine dithiocarbamate, L3 � N-(methyl, cyclohexyl dithiocarbamate, and L4 � N-(ethyl, cyclohexyl dithiocarbamate).

Table 2: Comparison of studied Pt(II) complex and parthenolideagainst three cancer cell lines in μM.

+ree cancer cell linesStudied compounds TK10 UACC62 MCF-7Pt(II) complexes >100 >100 66.82Parthenolide 4.64 11.37 3.52

10 Journal of Chemistry

planar Rh(I), Rh(II) dimeric μ-acetato dimers, and octa-hedral Rh(III) coordination compounds have shown remarkableantitumour properties [94]. Some rhodium compounds are inphase I anticancer clinical trials [95]. Rhodium has a disad-vantage of nephrotoxicity when applied as anticancer agent [95].In order to improve the antibacterial and anticancer propertiesof rhodium, it could act as half-sandwich with PGMs [96].Markham et al. reported six Rh(III) complexes with Rh(III)complexes (Figure 13) with the general formula, [RhIII(∗Cp)Cl(X,y)]n+ coordination compounds {X, Y�Cl, PTA, n� 0(2);X, Y� en, n� 1 (3, Cl− salt; 4, PF6- salt) X, y� acac, n� 0 (5); X,Y� cur, n� 0 (6), where ∗Cp� pentamethylcyclopentadienato,curH� curcumin; PTA� 1, 3, 5-triaza-7-phosphatricyclo[3.3.1.1]decane; en� 1,2-ethanediamine, acac� acetylacetonate� 2,4-pentanedionato(1− )} were prepared from [Rh(∗Cp)(μ-Cl)Cl]2 (1). Among the six Rh(III) complexes, only complex 6showed cytotoxic action against human epithelial A549 lungcancer cell line [97]. Jeremic et al. in line with Markham et al.synthesized two Rh(III) complexes ([Rh(ed3a) (OH2)]·H2O,(2)�Na[Rh(ed3a) (Cl)]·H2O) and discovered the complex withhydroxyl group (1) gave higher cytotoxic activity againstMRC-5,MCF-7, A549, HT-29, and HeLa cancer cell lines (Table 3). Asstated earlier, Adhikari et al. studied half-sandwich rhodium(II))complex comprising 2-substituted 1,8-napthyridine ligands withunexpected bonding modes, but the result was less active thanthat of cisplatin (Figure 1). +e nanoparticles could also act asnanovehicles for anticancer drugs [97].

2.6. Ruthenium. Ruthenium with the symbol Ru is a d-blocktransition metal, PGM, and has an atomic number of 44 anda mass number of 101.0 [98]. In 1808, Jedrzej Sniadecki, aPolish chemist, discovered ruthenium in South America andnamed it “vestium” after the asteroid Vesta [98]. In 1928,Gottfried W. Osann, a Russian chemist, rediscovered ru-thenium due to inability to confirm Jedrzej Sniadecki’sdiscovery [99]. In 1944, Karl Karlovich Klaus (Carl ErnstClaus), another Russian chemist, did a second discovery ofruthenium, also due to inability to prove Gottfried W.Osann’s discovery which was able to be verified [99, 100].+is made authorities to refer to him as the discoverer. +eorigin of the name has a derivation from,“Ruthenia,”meaning Russia [100]. +e sources of ruthenium are in-digenous in mineral ores in Ural Mountains, NorthAmerica, and South America. It can also be found inpyroxinite in South Africa. Ruthenium is a hard whitemetal and also a transition metal that is rare. Ruthenium isthe only element with two electrons in the outermost shellin Group 8. It has no less than eight oxidation states; thecommonest are +2, +3, and +4. Ruthenium tetroxide isvery toxic and has the tendency to be explosive. Ruthe-nium has chemical and industrial applications, whichinclude corrosion resistance when mixed with titanium, asplatinum alloys, as catalysts, and as superconductor whenalloyed with molybdenum at a temperature below 10 K.Ruthenium, rhodium, and iridium complexes are the mostactive and chosen hydrogen transfer catalysts. Among thethree complexes of iridium, rhodium, and ruthenium,ruthenium complexes are superior due to their low cost

and high activity [101]. Of all ruthenium compounds,arene ruthenium compounds have robust metal-organicmolecules which are essential for organometallic chem-istry development [101]. +ree major characteristics makeruthenium compounds suitable for medical applicationssuch as ability to imitate iron to bind to certain biologicalmolecules, slow rate of ligand exchange, and the variableoxidation states [102, 103]. +ey can be applied as anti-cancer and antimicrobial agents for oxidation states of +2,+3, and +4 [24, 103–121]. In history, ruthenium complexesexamined were chloro-ammine-Ru(III) compounds. In1980, Allardyce et al. gave an account of the anticancerpotentials of fac chloro-ammine-Ru(III) compounds inmodels of murine, but there was discontinuation due tosolubility problems [103]. In 1984, researchers worked onthe anticancer properties of ruthenium(II) complex, cis-[RuCl2 (DMSO)4], and found that it was noncytotoxic inboth in vitro and in vivo activities, except at maximumdose [122]. In 1988, trans-[RuCl2 (DMSO)4] proved morepotent, though more toxic than the cis isomer againstLewis lung carcinoma and primary tumour metastases.Scolaro et al. proved that nonplatinum potent complexessuch as isostructural Ru (III) complexes, [ImH] trans-[RuCl4 (Im)2 and [IndH] trans-[RuCl4 (Ind)2)] (ICR, KP1019), were more active than platinum against colorectalautochthonous tumours [123, 124]. In early 90s, [Na]trans-[RuCl4 (Im) (DMSO-S)] (NAMI), which is similar toKP 1019, was prepared, having an S-bonded DMSO tosubstitute an imidazole [104]. Later on, at the preclinicalstage, imidazolium salt [ImH] trans-RuCl4 (Im) (DMSO-S) substituted NAMI and was named NAMI-A [105].NAMI-A has the potentials to efficiently inhibit devel-opment and growth of pulmonary metastases in all in vivoactivities of solid tumours. Historically, the three classes ofanticancer ruthenium compounds, Ru-DMSO, Ru(III)complexes of [LH] trans-[RuCl4(L)2], and organometallicRu(II) arene [(η6-arene)Ru(en)Cl] [PF6], have generalbiological and chemical properties. Among the organo-metallic Ru(II) arene [(η6-arene) Ru (en) Cl] [PF6] com-pounds are [Ru(η6-arene)Cl2(PTA)] (RAPTA) derivatives(RAPTA-C, oxalo-RAPTA-C, carbo-RAPTA-C andRAPTA-T) [125–127]. +e three classes were verified to beactive in vivo [118]. NAMI-A and KP 1019 are currently inphase II clinical trials. A main challenge in the use ofruthenium complexes as therapeutic agents is restrictedstability in aqueous solutions, which had led to reassess-ment of their medical applications [112]. Some sandwichand half-sandwich ruthenium(II) complexes with anti-cancer activities are shown in Figures 14(a)–14(d). Re-cently, Heterobimetallic coordination half-sandwichcompounds of Ir (III) and Ru(II) yield improved anti-cancer activities due to the possession of chelating ligandsand reduction-oxidation features [128–132], while Tellezet al. obtained better results with a half-sandwich mixtureof iridium, rhodium, and ruthenium coordination com-pounds [132].

Zeng et al. reported the challenge faced with rutheniumnanoparticles, whereby their particle size and specificity oftarget of organs are hindrances to efficient antitumour

Journal of Chemistry 11

activities [133]. +ey suggested the solution of drug en-capsulation (developed nanomaterials) in order to providebiodistribution, pharmacokinetics, solubility, and toxicity.In addition, they stated that previous studies revealed enrap-tured Ru(II) coordination compounds in nanomaterial systemimproved their target and delivering into tumour cells.+e fourroles played by Ru(II) complexes in nanomaterial systems areto curtail drug release with better effectiveness, to work ascatalysts or drugs in the nanomaterial systems, to increase the

Rh

Rh

Cl

Cl

Cl

Cl

(a)

RhP

N

N

ClCl

N

(b)

Rh

ClH2N

NH2

+Cl–

(c)

Rh

ClH2N

NH2

PF6–

(d)

Rh

ClO

O

(e)

Rh

ClO

O

OHO

O–

HO

(f )

Figure 13: Molecular structures of (pentamethylcyclopentadienato) Rh(III) complexes. (a) [Rh(∗Cp)Cl(μ2–Cl)]2. (b) [Rh(∗Cp)Cl2(PTA)].(c) [Rh(∗Cp)Cl(en)]Cl. (d) [Rh(∗Cp)Cl(en)]PF6. (e) [Rh(∗Cp)Cl(acac)]. (f ) [Rh(∗Cp)Cl(cur)].

Table 3: Cytostatic activities of Rh(III) coordination compoundsand ed3a3 ligand against tumour strains in μM.

Compound IC50 (mM) MRC-5 MCF-7 A549 HT-29 HeLa(1) >100 >100 16.83 1.96 1.10(2) >100 >100 24.28 37.64 20.54Na2Hed3a >100 >100 18.01 >100 13.86Doxorubicin 0.12 0.75 7.86 0.32 1.17Cisplatin 0.45 1.5 36.12 22.05 2.02(1)� [Rh(ed3a) (OH2)]·H2O; (2)� [Rh(ed3a) (OH2)]·H2O.

12 Journal of Chemistry

photochemical efficiency and nanomaterials stabilities, and toact as theranostic tools to trace imported nanomaterials vialuminescence imaging [133].

3. Conclusion and Future Direction

Platinum-group metals are useful as a two-fold anticancerand antibacterial agent. +e most relevant among orga-noiridium coordination compounds are the coordinationcompounds of iridium(III). In the case of osmium co-ordination compounds, there exist osmium(II) andosmium(VI) as anticancer and antimicrobial agents. Forpalladium and platinum coordination compounds, themost relevant as antibacterial and anticancer are Pd(II)and Pt(II) respectively. Rhodium coordination com-pounds have Rh(I), Rh(II), and Rh(III) anticancer andantimicrobial agents, while ruthenium has Ru(II) andRu(III) anticancer and antimicrobial agents. Sandwichand half-sandwich PGMs enhance the antibacterial andanticancer activities of PGMs.

In summary, most researchers used nitrogen-nitro-gen coordination modes to synthesize Ir(III) complexes,but Lucas et al. obtained potent results using nitrogen-oxygen coordination modes. Iridium(III) complex-supported nanomaterials for luminescence sensing areapplied in intracellular imaging. Most researchers who

studied Os(III) complexes used nitrogen-nitrogen donorligands, and chloro and iodidosubstituents to enhanceanticancer activities. +ey showed higher potencies whencompared with cisplatin and their effectiveness as an-tibacterial agents. +ey are also reported to act as lu-minescent bioimaging. Chloro substituents also aidedPd(II) complexes in their biological applications. Labilechallenges of palladium nanoparticles brought limitationto its biological applications; therefore, the researchermentioned for the review had to apply the nano-precipitation method for the ligands’ syntheses, whileothers used green chemistry, outside this review. Platinumnanoparticles-based drug carriers with exceptionaltheranostic effects. Chloro substituents improve Pd(II)complexes for their biological applications. Chloro andhydroxyl substituents also improve rhodium complexesfor their biological applications. Rhodium nanoparticlescould act as nanovehicles for anticancer drugs. Chloro andammine substituents aided ruthenium complexes in theirbiological applications. Drug encapsulation was suggestedto control the particle charge challenge of rutheniumnanoparticles.

Future direction will involve the assessment of thedinuclear complexes of PGMs as antibacterial and anti-cancer agents with chloro and hydroxyl substituents, as wellas their nanocarrier and bioimaging activities.

Cl

ClCl

Cl

N

NH

N

NH

Ru

SO

–

H+

(a)

ClCl

ClCl

Ru

NNH

NNH

NNH+

H

–

(b)

Cl

Cl

Ru

PN

NN

(c)

Cl

Ru

NH2

NH2

+

[PF4]–

(d)

Figure 14: (a, b) Examples of ruthenium complexes and organometallic arene piano-stool ruthenium agents of Dyson; antimetastatic (c)RAPTA and (d) RAPTA-C complex. (a) NAMI-A, (b) KP 1019, (c) RAPTA, and (d) RAPTA-C.

Journal of Chemistry 13

Conflicts of Interest

+e authors declare no conflicts of interest.

Acknowledgments

+e authors appreciate Govan Mbeki Research and Devel-opment Centre (GMRDC) for financial assistance.

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