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Cite this: Annu. Rep. Prog. Chem., Sect. A: Inorg. Chem., 2012, 108, 350–368

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REVIEW

Inorganic pharmaceuticals Alvin A. Holder DOI: 10.1039/c2ic90009b

This chapter reviews the literature reported during 2011 on some important advances in the area of inorganic pharmaceuticals. Research highlights for the respective metals during the year are also given.

Highlights The main highlights include: (I) a unique process using boronolectin in MALDI-MS imaging for the histological analysis of cancer tissue expressing the sialyl Lewis X antigen;1 (II) a study of the effects of magnesium supplementation on testosterone levels;2 (III) an oxidovanadium(IV) Schiff base complex which was derived from Vitamin B6 and then tested for its insulin-like properties;3 (IV) water-soluble dinitrosyl iron complexes which can be used in the design of a novel class of drugs for treating erectile dysfunctions;4 (V) [Ni(dtc)2] which showed higher activity against the bacteria and fungi than the known antibiotics Tetracycline and Nystatin;5 (VI) Bombesinscontaining 99mTc ‘4+1’ complexes that are useful to detect tumours expressing the gastrinreleasing peptide receptor;6 (VII) 99mTc(CO)3-labeled pamidronate and alendronate for bone imaging;7 (VII) 2 + 1’’ complexes of the [M(CO)3]+ (M = Re, 99mTc) core which were successfully tested for selective staining of b-amyloid plaques of Alzheimer’s disease;8 and (IX) gold nanoparticle-cored poly(propyleneimine) dendrimers that were used as a new platform for multifunctional drug delivery systems.9

1. Introduction Reviews and featured articles have been published on the following topics: Current status and mechanism of action of platinum-based anticancer drugs,10 the radiobiological principles of boron neutron capture therapy,11 medical applications of inorganic fullerene-like nanoparticles,12 multifunctional nanovectors based on magnetic nanoparticles coupled with biological vesicles or synthetic liposomes,13 towards translation of 212Pb as a clinical therapeutic; getting the lead in,14 99mTc-centered one-pot synthesis for preparation of 99mTc radiotracers,15 multimodality and nanoparticles in medical imaging,16 generator-based PET radiopharmaceuticals for molecular imaging of tumours: on the way to theranostics,17 metallic radionuclides Department of Chemistry and Biochemistry, The University of Southern Mississippi, 118 College Drive, # 5043, Hattiesburg Mississippi 39406-0001, U.S.A. E-mail: [email protected]; Fax: 601-266-6075; Tel: 601-266-4767

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Annu. Rep. Prog. Chem., Sect. A: Inorg. Chem., 2012, 108, 350–368 This journal is © The Royal Society of Chemistry 2012

in the development of diagnostic and therapeutic radiopharmaceuticals,18 multimodal radio- (PET/SPECT) and fluorescence imaging agents based on metallo-radioisotopes: current applications and prospects for development of new agents,19 radiometallated peptides for molecular imaging and targeted therapy,20 a practical guide to the construction of radiometallated bioconjugates for PET,21 inorganic approaches for radiolabelling biomolecules with fluorine-18 for imaging with PET,22 therapeutic applications of gold complexes: lipophilic gold(III) cations and gold(I) complexes for anti-cancer treatment,23 Pt-based composite nanoparticles for magnetic, catalytic, and biomedical applications,24 yolk/shell nanoparticles: new platforms for nanoreactors, drug delivery and lithium-ion batteries,25 nucleic acid-functionalized nanomaterials for bioimaging applications,26 the heterogeneous nature of Cu2+ interactions with Alzheimer’s amyloid-b peptide,27 complexes in context: attempting to control the cellular uptake and localisation of rhenium fac-tricarbonyl polypyridyl complexes,28 metal-based anti-diabetic drugs: advances and challenges,29 boron in drug discovery: carboranes as unique pharmacophores in biologically active compounds,30 visualising the hypoxia selectivity of cobalt(III) prodrugs,31 uses of nanoparticles in medicine,32–64 targeted and multifunctional arene ruthenium chemotherapeutics,65 zinc is decreased in prostate cancer: an established relationship of prostate cancer!,66 metal binding calixarenes with potential biomimetic and biomedical applications,67 biologically significant selenium-containing heterocycles,68 transition metal homeostasis: from yeast to human disease,69 metal-containing peptide nucleic acid conjugates,70 chemistry and applications of organotin(IV) complexes of Schiff bases,71 ruthenium anticancer compounds: myths and realities of the emerging metal-based drugs,72 beating cancer in multiple ways using nanogold,73 hair analysis as a biomonitor for toxicology, disease and health status,74 copper complexes of bis(thiosemicarbazones): from chemotherapeutics to diagnostic and therapeutic radiopharmaceuticals,75 strategies for in vivo imaging of enzyme activity: an overview and recent advances,76 porphyrin complexes of the period 6 main group and late transition metals,77 recent advances of discrete coordination complexes and coordination polymers in drug delivery,78 application of ferrocene and its derivatives in cancer research,79 nitrogendoped TiO2 thin films: photocatalytic applications for healthcare environments,80 bioinorganic and medicinal chemistry: aspects of gold(I)-protein complexes,81 the role of coordination chemistry in the development of copper and rhenium radiopharmaceuticals,82 organometallic ruthenium-based antitumour compounds with novel modes of action,83 pyrone derivatives and metals: from natural products to metal-based drugs,84 ferrocene–indole hybrids for cancer and malaria therapy,85 nitrosyl iron complexes-synthesis, structure and biology,86 how environment affects drug activity: localisation, compartmentalisation and reactions of a vanadium insulin-enhancing compound, dipicolinatooxovanadium(V),87 anti-diabetic effects of a series of vanadium dipicolinate complexes in rats with streptozotocin-induced diabetes,88 potentiality of vanadium compounds as anti-parasitic agents,89 metal complexes as DNA intercalators,90 and the medicinal chemistry of novel iron chelators for the treatment of cancer.91

2. Boron There have been reports of the use of Boron neutron capture therapy in chemotherapy,92–99 and there was also a report of a unique process using boronolectin in MALDI-MS imaging for the histological analysis of cancer tissue expressing the sialyl Lewis X antigen.1


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3. Magnesium A study was carried out in order to assess how four weeks of magnesium supplementation and exercise affect the free and total plasma testosterone levels of sportsmen practising tae kwon do and sedentary controls at rest and after exhaustion.2 The results showed that supplementation increased free and total testosterone values in both groups but that the increases were higher in those who exercise versus sedentary individuals.2

4. Calcium The use of biomimetic hydroxyapatite porous microspheres with co-substituted essential trace elements for use in drug release,100 and a biomimetic fabrication of alginate/CaCO3 hybrid beads for dual-responsive drug delivery under compressed CO2 have been described.101

5. Silicon A mesoporous silica nanoparticle (MSN)-based pH-responsive nano drug delivery system (hydrophobic drugs@micelles@MSNs) was constructed by a one-pot selfassembly strategy, exhibiting improved drug efficacy against both drug-resistant and drug-sensitive cancer cells.102

6. Scandium Macrocyclic complexes of scandium radionuclides were reported as precursors for diagnostic and therapeutic radiopharmaceuticals.103

7. Titanium A marked synergistic effect in anti-tumour activity of salen titanium(IV) complexes bearing two differently substituted aromatic rings was reported,104 and at the same time it was reported that trans titanium(IV) complexes of salen ligands can also exhibit high anti-tumour activity.105 A very unique piece of research was conducted in order to understand bactericidal performance on ambient light activated TiO2– InVO4 nanostructured films, where it was found that in comparison to unmodified TiO2 films, the new TiO2–InVO4 films exhibited enhanced bactericidal activities under ambient light illumination.106 Also, novel ZnO/TiO2 composite nanofibers which were fabricated by an electrospinning method were reported to show excellent antimicrobial activity against gram-negative Escherichia coli and gram-positive Staphylococcus aureus under UV irradiation and in the absence of light.107 Multimodal imaging–therapeutic nanoprobe TiO2@RhdGd was prepared and successfully used for in vitro and in vivo cell tracking as well as for killing of cancer cells in vitro.108

8. Vanadium For many years now, it has been reported that vanadium-containing compounds have insulin-like properties in vivo and in vitro. An oxidovanadium(IV) Schiff base complex which was derived from vitamin B6 was synthesised, characterised and tested for its insulin-like properties.3 A new insulin-like salicylic acid-derivatised kojic acid vanadyl complex was synthesized and characterized.109 The complex, bis ((5-hydroxy-4-oxo-4 H-pyran-2-yl) methyl 2-hydroxy-benzoatato)oxovanadium(IV) (BSOV) 1, was evaluated for its insulin-like effects using streptozotocin (STZ)-induced

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diabetic rats. It was found that, against bis(maltolato) oxovanadium (BMOV) 2 as a positive control, 1 effectively lowered blood glucose levels, ameliorated damages of hepatic and renal function in diabetic rats, and improved lipid metabolism. The signs of potential alteration of renal function caused by BSOV 1 and BMOV 2 were observed and discussed.109 Overall, the experimental results suggest that 1 is a potent hypoglycemic agent and we look forward to further studies using this strategy for insulin-like agents.109 Other insulin-like vanadium-containing compounds were also reported,110–115 while more recently, vanadium-containing compounds have been tested as anti-cancer agents, both chemotherapeutically and photodynamically.116–118

9. Chromium It was reported that chromium(D-phenylalanine)3 can alleviate high fat-induced insulin resistance and lipid abnormalities;119 while the synthesis, characterization, anti-hyperglycemic activity, oxidative DNA damage capacity, and acute toxicity of a chromium(III) malate complex [Cr2(LMA)3] were also reported.120 It was concluded that [Cr2(LMA)3] may represent a novel, proper chromium supplement with potential therapeutic value to control blood glucose and serum lipid in diabetes.120

10. Manganese In a communication, a simple, facile surface modification strategy was used to transfer hydrophobic manganese oxide nanoparticles (MONPs) into water by using polyaspartic acid (PASP).121 The researchers investigated the effect of the size of PASP-MONPs on MRI of normal liver and found that the particles with a core size of 10 nm exhibited greater enhancement than those with larger core sizes.121 Other manganese-containing species were also reported as MRI contrast agents.122,123

11. Iron The effects of oral iron supplementation on hematological and iron metabolism in elite soccer players from the Real Zaragoza SAD soccer team have been reported.124 Iron-containing particles were also reported for their use in imaging studies.125–128 The association between fractional exhaled nitric oxide (FeNO) and cat dander in asthmatic children has been studied by several researchers.129 There was a study of water-soluble dinitrosyl iron complexes with thiol-containing ligands (cysteine or glutathione) which can be used as a base in the design of a novel class of drugs for treating erectile dysfunctions.4 Three ferrocene complexes vectorized with estrogens and vitamin D2 were synthesised and fully characterised by spectroscopic, electrochemical and computational methods and assessed as cytotoxic agents.130 A combined experimental and theoretical study outlines ribonucleotide reductase inhibition by metal complexes of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine).131 The impact of metal on the DNA photocleavage activity and cytotoxicity of ferrocenyl terpyridine


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3d metal complexes was also reported.132 Novel iron-containing complexes were also assessed as anti-bacterial133 and anti-malarial agents.134

12. Cobalt Mixed ligand cobalt(II) picolinate complexes with polypyridine ligands (dpq, bpg, bpy, phen, dppz) and water were synthesised, characterised and DNA binding and photocleavage studies carried out.135 A novel dinuclear cobalt(III) complex with the condensation product of 2-acetylpyridine and malonic acid dihydrazide, N 0 ,N 0 -2bis[(1E)-1-(2-pyridyl)ethylidene]propanedihydrazide was synthesised and characterised by elemental analysis, NMR and infrared spectroscopy, and X-ray crystal analysis.136 The complex showed a moderate activity towards Artemia salina. The highest cytotoxic potential of the complex was observed on the epithelial breast cancer (MDA-361) cell line. The complex induced apoptosis, of which the early apoptotic cells comprising 28.18%, compared to 5.64% of control cells in the same phase. The interaction of the complex with calf thymus DNA was monitored by blue shift and hyperchromism in the UV–visible spectra. The observed intrinsic binding constant (Kb = 4.2 105 M1), together with structural analysis of the complex, indicated that there was groove binding.136

13. Nickel The [Ni(dtc)2] was prepared by reacting [NiL](ClO4)2 (L = 3,7-bis(2-aminoethyl)1,3,5,7-tetraazabicyclo(3.3.1)nonane) with sodium diethyldithiocarbamate,5 and tested for antibacterial and antifungal activities.5 It showed higher activity against the bacteria and fungi than antibiotics Tetracycline and Nystatin.5

14. Copper A new site-targeted molecular imaging contrast agent based on a nanocolloidal suspension of lipid-encapsulated, organically soluble copper(II) ions has been developed.137 Concentrating a high payload of copper(II) ions per nanoparticle, this agent provides a high per-particle r1 relaxivity, allowing sensitive detection in T1-weighted MRI when targeted to fibrin clots in vitro.137 The particle also exhibits a defined clearance and safety profile in vivo.137 Studies involving DNA and cancer cells were also reported for several copper-containing complexes.138–141

15. Zinc There was an interesting response to the commentary ‘‘Zinc is decreased in prostate cancer: an established relationship of prostate cancer!’’142 Interesting anti-cancer studies were reported with the use of several zinc-containing compounds.143–147 There was a report of the synthesis, physical, chemical, and biological studies of [Zn(GTSC)]3 3.148 When compared with the well-studied complex, [Zn(ATSM)], which was used as a reference, [Zn(GTSC)]3 had 2.5-fold higher fluorescence. When cellular fluorescence was measured using flow cytometry, it was observed that 3 had 3.4-fold to 12-fold higher fluorescence than [Zn(ATSM)] in various cell lines of different tissue origin.148 Confocal fluorescence microscopy results showed that 3 appeared to have a nuclear localization within 30 min of addition to MCF7 cells. Moreover, 3 showed minimal cytotoxicity, compared to that with [Zn(ATSM)], suggesting that it may be less deleterious to cells when used as an imaging agent, leading to the conclusion that it could potentially serve as a biocompatible

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fluorescent imaging agent for live cells.148 Results from an investigation into an in vivo model of STZ-induced diabetic rats demonstrated that [Zn(dmpp)2] significantly lowered the blood glucose levels of individuals.149 Another study was carried out in order to elucidate the effects of zinc supplementation on the biokinetics of 65Zn in whole body, liver and its biodistribution in diabetic rats.150

16. Gallium The gallium(III) complex of a new tripodal 3,4-HP 4 chelator has been studied in terms of its physicochemical and in vivo properties aimed at potential application as a probe for nuclear imaging.151 In particular, based on spectrophotometric titrations, the hexa-coordinated (1 : 1) gallium complex appeared as the major species in a wide physiological acid-neutral pH range and its high stability (pGa = 27.5) should avoid drug-induced toxicity resulting from Ga(III) accumulation in tissues due to processes of transmetallation with endogenenous ligands or demetallation.151 A multinuclear (1H and 71Ga) NMR study gave some insights into the structure and dynamics of the gallium(III) chelate in solution, which were consistent with the tris-(3,4-HP) coordination and an eventual pseudo-octahedral geometry.151 Biodistribution and scintigraphic studies of the 67Ga(III) labelled chelate, carried out in Wistar rats, confirmed the in vivo stability of the radiolabelled complex, its non interaction with blood proteins, and its quick renal clearance.151 These results indicated good perspectives for potential application of extra-functionalised analogues in radiodiagnostic techniques.151

17. Niobium Several researchers synthesised, characterised, and studied the anti-cancer properties of a new water-soluble peroxo niobium complex K3[Nb(Asc)(O2)3]4H2O, as well as that of L-ascorbic acid, in human leukemic cells.152 The cytotoxic activity of the complex on HL-60 and K562 human leukemia cell lines was investigated by assessing vital cellular mechanisms, such as the metabolic activity MTT and the proliferation capacity (growth curves) of leukemia cells, as well as the structural integrity of cell membrane (trypan blue assay). The complex exerted an increased anti-proliferative effect primarily on HL60 human leukemia cells, compared to L-ascorbic acid alone, as well as an inhibitory effect on necrosis caused by L-ascorbic acid. The results supported a concentration- and time-dependent enhanced anti-leukemic effect of the complex, suggesting its significance as a promising tool in the confrontation of leukemia.152


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18. Molybdenum Four new water soluble molybdenocene complexes, [(Z5-C5H5)2Mo(L)]Cl (L = 6-mercaptopurine (5), 2-amino-6-mercaptopurine, ()-2-amino-6-mercaptopurine ribose and 6-mercaptopurine ribose), were synthesized in aqueous solution at pH 7.0 and characterised by spectroscopic methods.153 The anti-proliferative activities of the new species were investigated in HT-29 colon and MCF-7 breast cancer cell lines. The incorporation of molybdenocene (Cp2Mo2+) into the thionucleobases or thionucleosides decreased their cytotoxic activities in HT-29 colon cancer cell line. In contrast, in the MCF7 cell line, [Cp2Mo(2-amino-6-mercaptopurine)]Cl showed a high cytotoxic activity.153 This is most likely a consequence of the enhanced lipophilic character of the thionucleobase combined with synergism between Cp2Mo2+ and the thionucleobase ligand.153

19. Technetium Imaging applications were reported for bombesins-containing 99mTc ‘4 + 1’ complexes that are useful to detect tumours expressing the gastrin-releasing peptide receptor,6 along with 99mTc(CO)3-labeled pamidronate and alendronate for bone imaging,7 and the first examples of 99mTc bioconjugates that combine specific cell targeting with nuclear internalisation, a crucial issue to explore use of 99mTc in Auger therapy.154

20. Ruthenium It was hypothesised that L-ascorbic acid may act as a reducing agent for Ru(III) compounds such as indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) 6, an investigational anticancer drug which was supposed to be activated by reduction, prior to binding to cellular target proteins.155 The results indicated that application of high doses of L-ascorbic acid might increase the anti-cancer effects of 6.155 The cation cis-[Ru(bpy)2(5CNU)2]2+ was synthesised and investigated for use as a potential light-activated dual-action therapeutic agent.156 The complex was found to undergo efficient photoinduced 5CNU ligand exchange for solvent water molecules, thus simultaneously releasing biologically active 5CNU and generating [Ru(bpy)2(H2O)2]2+. The latter species was found to bind covalently to double stranded DNA, such that photolysis results in the generation of three equivalents of potential therapeutic agents from a single molecule.156

Interactions of arene–Ru(II)–chloroquine complexes of known anti-malarial and anti-tumour activity were studied with human serum albumin and transferrin.157

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In such studies, it was concluded that the arene–Ru(II)–chloroquine complexes, which are known to be active against resistant malaria and several lines of cancer cells, also displayed a good transport behaviour that makes them good candidates for drug development.157 Three novel Ru(II) complexes of the general cation, [Ru(N–N)2(Norharman)2]2+ (N–N = bpy 7, phen 8, DIP 9, and Norharman = a naturally occurring b-carboline alkaloid), have been synthesised and characterised.158 The cellular uptake efficiencies, in vitro cytotoxicities and apoptosis-inducing properties of these complexes were also carried out.158 Notably, compounds 7–9 exhibited potent anti-proliferative activities against a panel of human cancer cell lines with IC50 values lower than those of cisplatin.158 Further studies show that compounds 7–9 can cause cell cycle arrest in the G0/G1 phase and induce apoptosis through mitochondrial dysfunction and reactive oxygen species generation.158 In vitro DNA binding studies were also carried out in order to provide information about the possible mechanism of action.158

Nitric oxide (NO) plays an important role in the control of the vascular tone, but the most often employed NO donors have limitations due to their harmful sideeffects. A study was reported where new NO donors were synthesised in order to minimise such undesirable effects.159 As such, cis-[Ru(bpy)2(py)NO2](PF6) was reported as a new nitrite complex, which was tested as a vasodilator in the presence of a vascular tissue.159 The synthesis and photophysical and biological investigation of Ru(II)-polypyridyl stabilised water-soluble, luminescent gold nanoparticles were also reported.160 The luminescent gold nanoparticles were found to bind to DNA and undergo rapid cellular uptake, while being localised within the cell cytoplasm and nucleus within four hours.160

21. Rhodium An interesting article presented work of an examination of the biological fate of rhodium metalloinsertors bearing dipyridylamine ancillary ligands in cells deficient in mismatch repair (MMR) versus those that were MMR-proficient.161 These complexes were shown to exhibit accelerated cellular uptake which permitted the observation of various cellular responses, including disruption of the cell cycle, monitored by flow cytometry assays, and induction of necrosis, monitored by dye exclusion and caspase inhibition assays, that occurred preferentially in the MMRdeficient cell line.161 These cellular responses provided insight into the mechanisms underlying the selective activity of this novel class of targeted anti-cancer agents.161 There were reports of the insight into the photoinduced ligand exchange reaction pathway of cis-[Rh2(m-O2CCH3)2(CH3CN)6]2+ with a DNA Model Chelate162 and


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DNA binding modes and biological impact on human cancer cells of highly cytotoxic substitutionally inert rhodium(III) tris(chelate) complexes.163

22. Palladium There was a report of the synthesis, characterisation, and anti-cancer activity (against leukemia (K-562 CML), colon cancer (HCT-15), human breast adenocarcinoma (MCF-7), central nervous system (U-251 Glio) and prostate cancer (PC-3) cell lines) of new chiral Pd(II)-complexes which were derived from unsymmetrical a-diimine ligands.164 Another report was based on the synthesis and in vitro evaluation of palladium(II) salicylaldiminato thiosemicarbazone complexes against Trichomonas vaginalis,165 while several palladium-containing compounds were synthesised and evaluated for anti-proliferative activity in vitro against NCI-H460, A2780, and A2780cisR human cancer cell lines and non-cancerous renal LLC-PK1 cells.166

23. Silver There was a unique report of the development of bimetallic Au@Ag core–shell nanoparticles (NPs) where gold nanoparticles (Au NPs) served as the seeds for continuous deposition of silver atoms on its surface.167 Two silver-containing species were also reported and tested as anti-bacterial agents.167,168 Plasmonic nanoparticles have become a useful platform in medicine for potential uses in disease diagnosis and treatment; and in such cases, there was a report of plasmonic imaging of human oral cancer cell communities during programmed cell death by nuclear-targeting silver nanoparticles169

24. Tin A novel ferrocene-containing ligand 3-trifluoromethyl-5-ferrocenyl-pyrazol-1-ylacetic acid (LCOOH) and three organotin(IV) carboxylate derivatives [Ph4Sn2O(OCH3)(OOCL)]2, [BuSnO(OOCL)]6, and [Bu4Sn2O(OOCL2)2] were synthesised and structurally characterised by FT-IR, elemental analysis, 1H NMR, 119Sn NMR, X-ray crystallography, and cyclic voltammetry.170 Their anti-tumour activities were also evaluated against HepG2 human hepatocellular liver carcinoma cells, A549 human lung carcinoma cells, and B16-F10 melanoma cells.170

25. Antimony Three antimony(III) complexes: [Sb(2Fo4Ph)Cl2], [Sb(2Ac4Ph)Cl2], and [Sb(2Bz4Ph)Cl2] were synthesised with H2Fo4Ph, H2Ac4Ph, and H2Bz4Ph thiosemicarbazones.171 All three antimony(III) complexes exhibited anti-trypanosomal activity against the epimastigote and trypomastigote forms of Trypanosoma cruzi. [Sb(2Fo4Ph)Cl2] and [Sb(2Ac4Ph)Cl2] exhibited higher activity than the reference drugs benznidazole and nifurtimox.171

26. Gadolinium There were reports of several studies involving the synthesis and use of gadolinium as MRI contrast agents.172–176 The imaging of hypoxia is important for therapeutic decision making in various diseases. 68Ga is an important radionuclide for positron emission tomography (PET), and its usage is increasing, due to the development of the 68Ge/68Ga-generator. In a particular study, several researchers synthesized two 68 Ga-labeled DOTA-nitroimidazole derivatives and assessed their feasibilities as hypoxia imaging PET tracers.177

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27. Other lanthanides There was a report on targeting of anionic membrane species by lanthanide(III) complexes with may be improved MRI contrast agents for apoptosis.178 The synthesis of boehmite nanoparticles modified with lanthanides (Eu, Tb and Gd) was reported179 and in vitro assays with HeLa cells were carried out. The nuclear magnetic relaxation dispersion profiles of the two chelating moieties were studied.179 Imaging data from laser scanning confocal fluorescence microscopy and flow cytometry revealed that the nanoscaffolds were taken up by the cells, distributed throughout the cytoplasm and showed no toxicity. This platform was believed to be an alternative to silica-based inert matrices as imaging vehicles.179 It was reported that by thermal decomposition in the presence only of oleylamine, sub-10 nm hexagonal NaLuF4-based nanocrystals co-doped with Gd3+, Yb3+ and Er3+ (or Tm3+) were successfully synthesized.180 It was found that through the use of b-NaLuF4:Gd3+,Yb3+,Tm3+ nanocrystals as a luminescent label, the detection limit of o50 nanocrystal-labeled cells was achieved for whole-body photoluminescent imaging of a small animal (mouse), and high-contrast upconversion luminescence imaging of a whole-body black mouse with a penetration depth of B 2 cm was achieved.180 The relaxivity (contrast-enhancing ability) of EuII-containing cryptates was found to be better than a clinically approved GdIII-based agent at 7 T.181 These cryptates were among a few examples of paramagnetic substances that show an increase in longitudinal relaxivity, r1, at ultra-high field strength relative to lower field strengths.181

28. Tungsten Several researchers182 reported that rattle-type hollow nanocapsules were among the most promising candidates as drug carriers owing to their huge inner space and multifunctional material combination, and in such a case, it was reported that rattle-type hollow CaWO4:Tb3+@SiO2 nanocapsules were used as carriers for the drug delivery of doxorubicin hydrochloride.182

29. Rhenium The synthesis and characterisation of ‘‘2 + 1’’ complexes of the [M(CO)3]+ (M = Re 10, 99mTc 11) core with the b-diketones acetylacetone and curcumin as bidentate OO ligands, and imidazole or isocyanocyclohexane as monodentate ligands was reported.8 The curcumin complexes, as well as their intermediate aqua complex, that bear potential for radiopharmaceutical applications due to the wide spectrum of pharmacological activity of curcumin, were successfully tested for selective staining of b-amyloid plaques of Alzheimer’s disease.8 The researchers believe that due to the fact that the complexes maintain the affinity of the mother compound curcumin for b-amyloid plaques prompts for further exploration of their chemistry and biological properties as radioimaging probes.8 In a communication, a novel synthetic pathway was used to prepare a dual imaging agent in a single molecule.183 The binuclear Re/Re complex 12 and its Re/Tc analogue 13 were synthesised and characterised.183 The binuclear Re(I)/Tc(I) complex, [Re(CO)3(bipy))(4-PyrIDA)Tc(CO)3)] 13, was reported as the first example of a Re/Tc-based heterometallic assembly which could act as a potential bimodal Optical/SPECT probe.183 Interestingly, the mononuclear Re(I) complex precursor in that communication exhibited significant photophysical properties for biological applications.183


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30. Osmium It was reported that [(bpy)2Os(dpp)RhCl2(phen)]3+ photobinds and photocleaves DNA under red light in an oxygen independent manner, due to molecular design involving one Os chromophore coupled to a photoactive cis-RhIIICl2 moiety.184

31. Iridium Organometallic cyclometallated IrIII cyclopentadienyl complexes were synthesised and characterised.185 Through in vitro studies, all complexes were shown to possess potent cytotoxicity, with IC50 values ranging from 6.5 to 0.7 mM toward A2780 human ovarian cancer cells.185

32. Platinum Anti-tumour properties of platinum complexes are the most important theme of inorganic pharmaceuticals when judged by the number of the papers published on inhibition of cell growth of cancer cells and interaction with DNA.186–199 Other interesting anti-cancer studies have also been reported with platinum-containing compounds.189,192–194,197 In one of those studies, there was a demonstration of enhanced in vivo pharmacokinetics, biodistribution, tolerability, and efficacy of Pt-PLGA-b-PEG-Apt-NP (150 15 nm encapsulating B 5% wt/wt Pt(IV) prodrug) when compared to cisplatin administered in its conventional form in normal Sprague Dawley rats, Swiss Albino mice, and the PSMA-expressing LNCaP subcutaneous xenograft mouse model of PCa, respectively.189 The ten day maximum tolerated dose following a single i.v. injection of Pt-PLGA-b-PEG-NP in rats and mice was determined at 40 mg kg1 and 5 mg kg1, respectively. Pharmacokinetics studies with Pt-PLGA-b-PEG-NP revealed prolonged Pt persistence in systemic blood circulation and decreased accumulation of Pt in the kidneys, a major target site of cisplatin toxicity. Pt-PLGA-b-PEG-Apt-NPs displayed the significant dose-sparing characteristics of the drug, with equivalent anti-tumour efficacy in LNCaP xenografts at 1/3 the dose of cisplatin administered in its conventional form (0.3 mg kg1 versus 1 mg kg1).189 Sensory peripheral neuropathy has been reported as a dose-limiting and long term side effect for 20–30% of patients who use platinum-based compounds as chemotherapeutic agents.200 A critical question was posed by several researchers on whether the mechanisms of cell death underlying clinical efficacy can be separated from the effects on neurons in order to develop strategies that prevent platinuminduced neuropathy.200 The researchers have mentioned that in rodent dorsal root ganglion neurons (DRG), cisplatin was shown to bind and damage neuronal DNA, inducing apoptosis; however, genetic manipulation in order to study mechanisms of

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this phenomenon in the rodent model system was reported to be costly and timeconsuming. Flies are commonly used to study neurological disorders since they have DNA damage-apoptosis mechanisms homologous to mammalian systems, are readily-available and inexpensive species for rapid genetic manipulation. As such, adult Drosophila melanogaster flies were used as a new model to study cisplatininduced neurotoxicity through exposure to 10, 25, 50, 100, 200 and 400 mg ml1 cisplatin for three days; then observed for fly survival and geotactic climbing behaviour, cisplatin-DNA binding, and cellular apoptosis. On day three, 50 mg ml1 cisplatin was found to reduce the number of flies able to climb above 2 cm to 43%, while fly survival was maintained at 92%. 100% lethality was observed at 400 mg ml1 cisplatin. Whole fly platinum-genomic DNA adducts were measured and found to be comparable to adduct levels previously measured in rat DRG neurons.200 Brain, ovaries, kidney and heart harvested from cisplatin treated flies were stained for active caspase 3. Apoptosis was found in ovaries and brain, but not in the heart and kidney. Brain apoptosis was confirmed by TEM. It was found that expression of the antiapoptotic baculoviral protein, p35, in neurons using the GAL4-UAS system prevented cisplatin-induced apoptosis in the brain and restored climbing behavior. In conclusion, cisplatin-induced behavioral and apoptotic changes in Drosophila melanogaster flies resembled those seen in mammals, and that the use of lethality and climbing assays combined with powerful gene manipulation, make them a suitable model to study mechanisms of cisplatin neurotoxicity.

33. Gold A number of structurally diverse gold compounds were evaluated as possible inhibitors of Falcipain 2 (Fp2), a cysteine protease from P. falciparum that is a validated target for the development of novel anti-malarial drugs.201 A novel strategy was utilised to develop a stable probe based on thiolated poly(ethylene glycol) and polyacrylic acid (PAA) functionalised gold nanorods (GNRs), following the attachment of an anti-cancer drug, doxorubicin (DOX), to obtain PAA-PEG-GNRs@DOX assemblies.202 Importantly, the probe acting as a novel drug-delivery and fluorescent imaging agent for simultaneous imaging of and drug delivery to prostate cancer cells has also been demonstrated.202 In addition to designing PAA-PEG-GNRs that passively target tumour cells for cancer-fighting drug therapy, GNRs were also regarded as hyperthermia agents for photokilling cancer cells, so that the tumour would be attacked on two fronts simultaneously.202 The in vitro anti-malaria activity of mono- and dinuclear gold(I) phosphine complexes containing monoanionic selenoand thiosemicarbazones as ligands was investigated in chloroquine sensitive strains of Plasmodium falciparum.203 The IC50 results showed that the sulphur-containing compounds exhibit activity similar to that of chloroquine, whilst the selenium derivatives displayed only moderate anti-malaria activity.203 Bifunctional gold nanorod-loaded polymeric microcapsules were reported for both contrast-enhanced ultrasound imaging and photothermal therapy;204 while gold nanoparticle-cored poly(propyleneimine) dendrimers were reported as a new platform for mul-tifunctional drug delivery systems.9 Four bis(thiosemicarbazonate)gold(III) complexes with a general formula [Au(L)]Cl (L = glyoxal-bis(N4-methylthiosemicarbazone), glyoxal-bis(N4-ethylthiosemicarbazone), diacetyl-bis(N4-methylthiosemicarbazone), diacetyl-bis(N4-ethylthiosemicarbazone)) were synthesised and screened for activity against the human immunodeficiency virus (HIV).205 There was an interesting report of a monoclonal


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antibody-conjugated popcorn shaped gold nanomaterial driven approach to selectively destroy ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline drug resistant Salmonella typhimurium DT104 bacteria.206 The report proved that when an antibody modified popcorn shaped gold nanoparticle conjugated bacteria sample was exposed to 670 nm laser radiation, almost 100% of the drug resistant bacteria were killed due to photothermal lysis.206 As breast cancer treatment presents one of the greatest challenge in health care in today’s world, the key to an ultimately successful treatment of breast cancer disease is an early and accurate diagnosis. There has been a report of the design of novel hybrid nanomaterial using gold nano popcorn-attached single wall carbon nanotube for targeted diagnosis and selective photothermal treatment of breast cancer.207 In another report, a panel of anticancer gold(I)–phosphine complexes which exhibited significant autophagy-inducing properties in cancer cells were described.208 The gold(III) complex, [(5,6DMP)AuCl2]BF4, was synthesized and fully characterized using standard spectroscopic techniques, as well as X-ray crystallography and elemental analysis. It is stable in phosphate buffer over a 24-hour period, but undergoes rapid reduction in the presence of equimolar amounts of reduced glutathione and L-ascorbic acid. The complex, [(5,6DMP)AuCl2]BF4 was found to undergo weak and reversible binding to calf thymus DNA, and was more cytotoxic towards a panel of human cancer cell lines than cisplatin. Cytotoxicity experiments with the ‘‘free’’ 5,6DMP ligand indicated that the ligand has IC50 values that are slightly lower than those observed for [(5,6DMP)AuCl2]BF4 and, coupled with the fact that the ligand appears to be released from the gold(III) metal centre in reducing environments, this suggests that the ligand itself may play an important role in the anti-tumour activity of the parent gold complex.

34. Bismuth Bismuth(III) complexes of non-steroidal anti-inflammatory drugs and substituted benzoic acids (o-methoxybenzoic acid, m-methoxybenzoic acid, o-nitrobenzoic acid, 3,5-diacetamidobenzoic acid and 5-[(R/S)-2,3-dihydroxypropyl carbamoyl]-2-pyridine carboxylic acid) were synthesised and characterised.209 All compounds were tested against the parasite Leishmania major promastigotes for their anti-Leishmanial activity, and were further assessed for their toxicity to mammalian cells.209

Abbreviations 3,4-HP 5CNU 5,6DMP Asc ATSM bpg DIP dmpp dpp dppz dpq dtc GTSC H2Ac4Ph

362

3-hydroxy-4-pyridinone 5-cyanouracil 5,6-dimethyl-1,10-phenanthroline ascorbate anion biacetylbis(4-methyl-3-thiosemicarbazone) bipyridyl-glycoluril=4b,5,7,7a-tetrahydro-4b,7a-epiminomethanoimino-6H-imidazo[4,5-f][1,10]-phenanthroline-6,13-dione 4,7-diphenyl-1,10-phenanthroline 1,2-dimethyl-3-hydroxy-4(1H)-pyridinonate 2,3-bis(2-pyridyl)pyrazine dipyrido[3,2-a:2 0 ,3 0 -c]phenazine dipyrido[3,2-d:2 0 ,3 0 -f]quinoxaline diethyldithiocarbamate glyoxalbis(4-methyl-4-phenyl-3-thiosemicarbazone) N(4)-phenyl-2-acetylpyridine thiosemicarbazone


H2Bz4Ph H2Fo4Ph MTT Norharman NP PLGA-b-PEG

N(4)-phenyl-2-benzoylpyridine thiosemicarbazone N(4)-phenyl-2-formylpyridine thiosemicarbazone 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (9H-pyrido[3,4-b]indole nanoparticles poly(D,L-lactic-co-glycolic acid)-b-poly(ethylene glycol)

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