Sue Berners-Price

Biological relevance of interaction of platinum drugs with O-donor ligands

Publisher: Elsevier BV

Date: 09-2019

DOI: 10.1016/J.ICA.2019.118974

Influence of geometric isomerism on the binding of platinum anticancer agents with phospholipids

Publisher: Royal Society of Chemistry (RSC)

Date: 2019

DOI: 10.1039/C9DT00753A

Abstract: A holistic approach to the molecular mechanism of platinum anti-cancer agents extends DNA interactions to membrane phospholipids relevant to cellular accumulation and delivery.

Luminescence Studies of the Intracellular Distribution of a Dinuclear gold(I) N-Heterocyclic Carbene Complex

Publisher: Wiley

Date: 05-09-2006

DOI: 10.1002/ANIE.200601526

Gold(i) phosphine compounds as parasite attenuating agents for malaria vaccine and drug development.

Publisher: Oxford University Press (OUP)

Date: 2018

DOI: 10.1039/C7MT00311K

Abstract: Here, the anti-malarial activity of two gold(i) phosphine compounds auranofin and [Au(d2pype)

Cationic, linear Au(I) N-heterocyclic carbene complexes: synthesis, structure and anti-mitochondrial activity

Publisher: Royal Society of Chemistry (RSC)

Date: 2006

DOI: 10.1039/B602560A

Abstract: Six linear, two-coordinate cationic Au(I) N-heterocyclic carbene complexes of the form [(R2Im)2Au]+ (R = Me 1, Me, Et 2, i-Pr 3, n-Bu 4, t-Bu 5 and Cy 6) have been prepared by the reaction of two equivalents of the appropriate dialkylimidazol-2-ylidene (R2Im) with (Me2S)AuCl in dmf. Single crystal structural studies for 1.PF6, 2.PF6), 3.Cl and 4-6.PF6 show that for all six complexes the gold(I) centres have quasi-linear C-Au-C coordination, with quasi-parallel pairs of aromatic imidazole planes, except in 5.PF6 where they are quasi-normal in the latter, Au-C are 2.038(3), 2.033(3) A, cf. (e.g.) 2.027(2) A. Inter-cation Au...Au are close at 3.487(2), 3.525(2) A in 1PF6 and 2.PF6. The structural studies and low temperature NMR experiments provide no supportive evidence for the presence of pi back-bonding within this series of complexes. The lipophilicities of the six compounds, as estimated from the logarithm of the n-octanol-water partition coefficients (log P), varied across the series within the range -1.09 to 1.73. To investigate their potential as possible anti-mitochondrial anti-tumour agents, five of the compounds have been evaluated for their propensities to induce mitochondrial membrane permeabilization (MMP) in isolated rat liver mitochondria. At concentrations between 1-10 microM compounds 1.Br and 3-6.Cl induced dose-dependent, Ca2+-sensitive mitochondrial swelling at rates that increased with the lipophilicities of the complexes, with the most lipophilic compounds inducing the most rapid onset of swelling. The swelling was completely inhibited by cyclosporin A, the specific inhibitor of the mitochondrial permeability transition pore.

Metalloglycomics

Publisher: De Gruyter

Date: 05-02-2018

DOI: 10.1515/9783110470734-004

Antiangiogenic platinum through glycan targeting

Publisher: American Association for Cancer Research (AACR)

Date: 08-2015

DOI: 10.1158/1538-7445.AM2015-4486

Abstract: Heparanase is an endo-β-D-glucuronidase that cleaves heparan sulfate glycosaminoglycans (HS-GAGs) in the extracellular matrix and basement membrane. Cancer cells that aberrantly express heparanase potentiate tumor progression, invasion and metastasis in two distinct ways (1) cleavage of HS-GAGs releases growth-factors to directly activate growth receptors and (2) degradation of the heparan sulfate structural component of the extracellular matrix (ECM) allows metastatic spread of cancer cells. Recently, we determined that accumulation and cytotoxicity of polynuclear platinum compounds (PPCs), including the Phase II clinical trial compound, BBR3464 (+4), are dependent on the presence of cell-surface GAGs. Here, we demonstrate that high affinity PPC-GAG binding provides a new approach to glycan-based targeting by protection against enzymatic cleavage by heparanase. It was determined by NMR spectroscopy, that PPCs, especially the higher charged compound, TriplatinNC (+8), inhibit heparanase cleavage of the oligosaccharide, Fondaparineaux. Further, using the human umbilical primary cell line, HUVEC, it was determined that PPCs reduce heparanase cleavage of the GAG-bound growth factor, bFGF, from ECM. The end result of inhibition of heparanase cleavage is a reduction in tumor invasion and angiogenesis. Using the matrigel invasion assay, we show that sub-cytotoxic doses of PPCs, but not cisplatin, reduces serum-induced invasion of HCT116 cells through basement membrane. In an ex vivo rat aorta model, PPCs exhibit antiangiogenesis activity, measured by the inhibition of new blood vessel growth sprouting from the original aortic ring. Together, these encouraging results support the potential to combine anti-metastatic and cytotoxic activity in the development of dual-function platinum-based drugs. Citation Format: Erica J. Peterson, Susan J. Berners-Price, Anna Bezos, Lisa Bohlman, Samantha J. Katner, A. Gerard Daniel, Chih-Wei Chang, Mark von Itzstein, Christopher R. Parish, Nicholas P. Farrell. Antiangiogenic platinum through glycan targeting. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research 2015 Apr 18-22 Philadelphia, PA. Philadelphia (PA): AACR Cancer Res 2015 (15 Suppl):Abstract nr 4486. doi:10.1158/1538-7445.AM2015-4486

A Comparison of the Potentin vitroAntitumor Activity of Triphenyltin Benzoates with that of Related Tin Compounds

Publisher: IOS Press

Date: 09-1995

DOI: 10.1080/13583149512331338375

Antiangiogenic platinum through glycan targeting

Publisher: Royal Society of Chemistry (RSC)

Date: 2017

DOI: 10.1039/C6SC02515C

Abstract: The high affinity of highly charged polynuclear platinum complexes for glycans such as heparan sulfate results in modulation of the biomolecule signaling functions leading to inhibition of angiogenesis.

Glycans as Ligands in Bioinorganic Chemistry. Probing the Interaction of a Trinuclear Platinum Anticancer Complex with Defined Monosaccharide Fragments of Heparan Sulfate

Publisher: American Chemical Society (ACS)

Date: 11-01-2019

DOI: 10.1021/ACS.INORGCHEM.8B03035

Abstract: We report herein a detailed NMR study of the aquation and subsequent covalent binding of the trinuclear clinical agent [{ trans-PtCl(

Gold(I) chloride adducts of 1,3-bis(di-2-pyridylphosphino)propane: Synthesis, structural studies and antitumour activity

Publisher: Royal Society of Chemistry (RSC)

Date: 2007

DOI: 10.1039/B705008A

Abstract: The novel water soluble bidentate phosphine ligand 1,3-bis(di-2-pyridylphosphino)propane (d2pypp) has been synthesized by a convenient route involving treatment of 2-pyridyllithium with Cl(2)P(CH(2))(3)PCl(2) and isolation in crystalline form as the hydrochloride salt. The synthesis of the precursor Cl(2)P(CH(2))(3)PCl(2) has been optimized by the use of triphosgene as the chlorinating agent. The 2 : 1 and 1 : 2 AuCl : d2pypp adducts have been synthesized and characterized by NMR spectroscopy and single crystal X-ray studies, and shown to be of the form (AuCl)(2)(mu-d2pypp-P,P') and [Au(d2pypp-P,P')(2)]Cl(.3.75H(2)O), respectively. The latter is more lipophilic than analogous 1 : 2 adducts of gold(I) chloride with the diphosphine ligands 1,2-bis(di-n-pyridylphosphino)ethane (dnpype) for n = 2, 3 and 4, based on measurement of the n-octanol-water partition coefficient (log P = -0.46). A single crystal structure determination of the 1 : 2 Au(I) complex of the 3-pyridyl ethane ligand shows it to be of the form [Au(d3pype-P,P')(2)]Cl.5H(2)O. The in vitro cytotoxic activity of [Au(d2pypp)(2)]Cl was assessed in human normal and cancer breast cells and selective toxicity to the cancer cells found. The significance of these results to the antitumour properties of chelated 1 : 2 Au(I) diphosphine complexes is discussed.

The Design of Gold-Based, Mitochondria-Targeted Chemotherapeutics

Publisher: CSIRO Publishing

Date: 2008

DOI: 10.1071/CH08175

Abstract: Recent developments in understanding the central place of mitochondria as regulators of programmed cell death have stimulated enormous interest in using them as targets for cancer chemotherapy. To overcome drug resistance and the lack of selectivity of cancer drugs in differentiating between normal and tumour cells, many strategies have been described in recent literature, including the use of delocalized lipophilic cations that selectively accumulate in tumour-cell mitochondria. Thioredoxin reductase, an enzyme involved in redox regulation and cell growth, has also emerged recently as an attractive drug target. Here we discuss the rationale for the design of lipophilic, cationic Au(i) phosphine complexes that are targeted to mitochondria of tumour cells and have potent and selective anticancer activity for cancer cells but not for normal cells. Our discovery that the thioredoxin system may be a critical target responsible for the selective toxicity provides a new strategy in the development of mitochondria-targeted chemotherapeutics.

Recent advances in the application of 13C and 15N NMR spectroscopy to soil organic matter studies

Publisher: CSIRO Publishing

Date: 2000

DOI: 10.1071/SR99074

Abstract: Nuclear magnetic resonance (NMR) spectroscopy has been applied to many studies in soil science, geochemistry, and environmental science. In recent years, the study of soil organic matter (SOM) using NMR techniques has progressed rapidly. NMR spectroscopy has been used to study chemical changes of SOM during decomposition, and also of soil extract fractions such as humic acid and fulvic acid. NMR spectroscopy of soils has improved rapidly in recent years with the introduction of pre-treatment and particle-size fractionation. In addition to routine liquid- and solid-state 13C NMR applications, 15N NMR spectra of natural abundant s les have been reported, but 15N-enriched material is more convenient to use due to the low natural abundance of 15N. Some newly developed NMR techniques have also been utilised, such as 2-dimensional NMR spectroscopy and improved 1H NMR techniques. These are reviewed and commented on in this paper.

Hydrofluoric acid pre-treatment for improving 13C CPMAS NMR spectral quality of forest soils in south-east Queensland, Australia

Publisher: CSIRO Publishing

Date: 2002

DOI: 10.1071/SR01073

Abstract: Hydrofluoric acid (HF) was used to pre-treat forest soils of south-east Queensland for assessing the effectiveness of iron (Fe) removal, carbon (C) composition using 13C cross-polarisation (CP) with magic-angle-spinning (MAS) nuclear magnetic resonance (NMR) before and after the HF pre-treatment, and the improvement of 13C CPMAS NMR spectra. Soil s les were collected from 4 experimental sites of different soil types, harvest residue management or prescribed burning, and tree species. More than 86% of Fe was in all soil types removed by the HF treatment. The 13C NMR spectral quality was improved with increased resolution, especially in the alkyl C and O-alkyl C regions, and reduced NMR run-time (1-5�h per s le compared with & �h per s le without the pre-treatment). The C composition appeared to alter slightly after the pre-treatment, but this might be largely due to improved spectrometer conditions and increased resolution leading to more accurate NMR spectral integration. Organic C recovery after HF pre-treatment varied with soil types and forest management, and soluble soil organic matter (SOM) could be lost during the pre-treatment. The Fourier Transform-Infrared (FT-IR) spectra of HF extracts indicated the preferential removal of carboxylic C groups during the pre-treatment, but this could also be due to adsorbed water on the mineral matter. The NMR spectra revealed some changes in C composition and quality due to residue management and decomposition. Overall, the HF treatment was a useful pre-treatment for obtaining semi-quantitative 13C CPMAS NMR spectra of subtropical Australian forest soils.

Bioenergetic differences selectively sensitize tumorigenic liver progenitor cells to a new gold(I) compound

Publisher: Oxford University Press (OUP)

Date: 15-04-2008

DOI: 10.1093/CARCIN/BGN093

Abstract: A hallmark of cancer cells is their ability to evade apoptosis and mitochondria play a critical role in this process. Delineating mitochondrial differences between normal and cancer cells has proven challenging due to the lack of matched cell lines. Here, we compare two matched liver progenitor cell (LPC) lines, one non-tumorigenic [p53-immortalized liver (PIL) 4] and the other tumorigenic (PIL2). Analysis of these cell lines and a p53 wild-type non-tumorigenic cell line [bipotential murine oval liver (BMOL)] revealed an increase in expression of genes encoding the antiapoptotic proteins cellular inhibitor of apoptosis protein (cIAP) 1 and yes associate protein in the PIL2 cells, which resulted in an increase in the protein encoded by these genes. PIL2 cells have higher mitochondrial membrane potential (Deltapsi(m)) compared with PIL4 and BMOL and had greater levels of reactive oxygen species, despite the fact that the mitochondrial antioxidant enzyme, manganese superoxide disumutase, was elevated at transcript and protein levels. Taken together, these results may account for the observed resistance of PIL2 cells to apoptotic stimuli compared with PIL4. We tested a new gold compound to show that hyperpolarized Deltapsi(m) led to its increased accumulation in mitochondria of PIL2 cells. This compound selectively induces apoptosis in PIL2 cells but not in PIL4 or BMOL. The gold compound depolarized the Deltapsi(m), depleted the adenosine triphosphate pool and activated caspase-3 and caspase-9, suggesting that apoptosis was mediated via mitochondria. This investigation shows that the non-tumorigenic and tumorigenic LPCs are useful models to delineate the role of mitochondrial dysfunction in tumorigenesis and for the future development of mitochondria-targeted chemotherapeutics that selectively target tumor cells.

Therapeutic Gold Compounds

Publisher: Wiley

Date: 02-05-2014

DOI: 10.1002/9781118697191.CH9

Conformational Modulation of Iduronic Acid‐Containing Sulfated Glycosaminoglycans by a Polynuclear Platinum Compound and Implications for Development of Antimetastatic Platinum Drugs

Publisher: Wiley

Date: 09-12-2021

DOI: 10.1002/ANGE.202013749

A gold(I) phosphine complex selectively induces apoptosis in breast cancer cells: Implications for anticancer therapeutics targeted to mitochondria

Publisher: Elsevier BV

Date: 10-2007

DOI: 10.1016/J.BCP.2007.07.022

Abstract: Bis-chelated gold(I) phosphine complexes have shown great potential as anticancer agents, however, their efficacy has been limited by their high toxicity and lack of selectivity for cancer cells. Here, we have investigated the anticancer activity of a new bis-chelated Au(I) bidentate phosphine complex of the novel water soluble ligand 1,3-bis(di-2-pyridylphosphino)propane (d2pypp). We show that this gold complex [Au(d2pypp)(2)]Cl, at submicromolar concentrations, selectively induces apoptosis in breast cancer cells but not in normal breast cells. Apoptosis was induced via the mitochondrial pathway, which involved mitochondrial membrane potential depolarisation, depletion of the glutathione pool and caspase-3 and caspase-9 activation. The gold lipophilic complex was accumulated in mitochondria of cells, driven by the high mitochondrial membrane potential. To address the molecular basis of the observed selectivity between the two cell lines we investigated the effect of the gold complex on the thioredoxin/thioredoxin reductase system in normal and cancer breast cells. We show that [Au(d2pypp)(2)]Cl inhibits the activities of both thioredoxin and thioredoxin reductase and that this effect is more pronounced in the breast cancer cells. This difference may account for the selective cell death seen in the breast cancer cells but not in the normal cells. Our investigation has led to new insights into the mechanism of action of bis-chelated gold(I) diphosphine complexes and their future development as mitochondria targeted chemotherapeutics.

In vitro antitumour and hepatotoxicity profiles of Au(I) and Ag(I) bidentate pyridyl phosphine complexes and relationships to cellular uptake

Publisher: Elsevier BV

Date: 02-2008

DOI: 10.1016/J.JINORGBIO.2007.09.003

Abstract: In this study we characterised the in vitro antitumour and hepatotoxicity profiles of a series of Au(I) and Ag(I) bidentate phenyl and pyridyl complexes in a panel of cisplatin-resistant human ovarian cancer cell-lines, and in isolated rat hepatocytes. The gold and silver compounds overcame cisplatin-resistance in the CH1-cisR, 41M-cisR and SKOV-3 cell-lines, and showed cytotoxic potencies strongly correlated with their lipophilicity. Complexes with phenyl or 2-pyridyl ligands had high antitumour and hepatotoxic potency and low selectivity between different cell-lines. Their cytotoxicity profiles were similar to classic mitochondrial poisons and an ex le of this type of compound was shown to accumulate preferentially in the mitochondria of cancer cells in a manner that depended upon the mitochondrial membrane potential. In contrast, complexes with 3- or 4-pyridyl ligands had low antitumour and hepatotoxic potency and cytotoxicity profiles similar to 2-deoxy-D-glucose. In addition, they showed high selectivity between different cell-lines that was not attributable to variation in uptake in different cell-types. The in vitro hepatotoxic potency of the series of gold and silver compounds varied by over 61-fold and was closely related to their lipophilicity and hepatocyte uptake. In conclusion, Au(I) and Ag(I) bidendate pyridyl phosphine complexes demonstrate activity against cisplatin-resistant human cancer cells and in vitro cytotoxicity that strongly depends upon their lipophilicity.

Substitution‐Inert Polynuclear Platinum Complexes as Metalloshielding Agents for Heparan Sulfate

Publisher: Wiley

Date: 14-04-2018

DOI: 10.1002/CHEM.201706030

Abstract: Cleavage of heparan sulfate proteoglycans (HSPGs) by the enzyme heparanase modulates tumour-related events including angiogenesis, cell invasion, and metastasis. Metalloshielding of heparan sulfate (HS) by positively charged polynuclear platinum complexes (PPCs) effectively inhibits physiologically critical HS functions. Studies using bacterial P. heparinus heparinase II showed that a library of Pt complexes varying in charge and nuclearity and the presence or absence of a dangling amine inhibits the cleavage activity of the enzyme on the synthetic pentasaccharide, Fondaparinux (FPX). Charge-dependent affinity of PPC for FPX was seen in competition assays with methylene blue and ethidium bromide. The dissociation constant (K

Visualising gold inside tumour cells following treatment with an antitumour gold(I)complex

Publisher: Oxford University Press (OUP)

Date: 2011

DOI: 10.1039/C1MT00053E

Abstract: Gold(I) phosphine complexes, such as [Au(d2pype)(2)]Cl, (1, where d2pype is 1,2-bis(di-2-pyridyl phosphinoethane)), belong to a class of promising chemotherapeutic candidates that have been shown to be selectively toxic to tumourigenic cells, and may act via uptake into tumour cell mitochondria. For a more holistic understanding of their mechanism of action, a deeper knowledge of their subcellular distribution is required, but to date this has been limited by a lack of suitable imaging techniques. In this study the subcellular distribution of gold was visualised in situ in human breast cancer cells treated with 1, using nano-scale secondary ion mass spectrometry. NanoSIMS ion maps of (12)C(14)N(-), (31)P(-), (34)S(-) and (197)Au(-) allowed, for the first time, visualisation of cellular morphology simultaneously with subcellular distribution of gold. Energy filtered transmission electron microscopy (EFTEM) element maps for gold were also obtained, allowing for observation of nuclear and mitochondrial morphology with excellent spatial resolution, and gold element maps comparable to the data obtained with NanoSIMS. Following 2 h treatment with 1, the subcellular distribution of gold was associated with sulfur-rich regions in the nucleus and cytoplasm, supporting the growing evidence for the the mechanism of action of Au(I) compounds based on inhibition of thiol-containing protein families, such as the thioredoxin system. The combination of NanoSIMS and EFTEM has broader applicability for studying the subcellular distribution of other types of metal-based drugs.

Structural Factors Affecting Binding of Platinum Anticancer Agents with Phospholipids: Influence of Charge and Phosphate Clamp Formation

Publisher: Wiley

Date: 28-02-2018

DOI: 10.1002/CHEM.201705822

Abstract: We report a detailed NMR and DFT study of the interaction of polynuclear platinum anticancer agents (PPCs) with negatively charged phospholipids as a mechanism for their cellular uptake. The reactions of fully

Role of lipophilicity in determining cellular uptake and antitumour activity of gold phosphine complexes

Publisher: Springer Science and Business Media LLC

Date: 06-11-2000

DOI: 10.1007/S002800000166

Abstract: The lipophilic cation [Au(I)(dppe)2]+ [where dppe is 1,2-bis(diphenylphosphino)ethane] has previously demonstrated potent in vitro antitumour activity. We wished to determine the physicochemical basis for the cellular uptake of this drug, as well as of analogues including the 1:2 adducts of Au(I) with 1,2-bis(di-n-pyridylphosphino)ethane (dnpype n = 2, 3 and 4), and to compare in vitro and in vivo antitumour activity. Logarithmic IC50 values for the CH-1 cell line bore a parabolic dependence on drug lipophilicity, as measured either by high-performance liquid chromatography or by n-octanol-water partition. Cellular uptake of drug, as measured by inductively coupled plasma mass spectrometry, varied by over three orders of magnitude over the series. Logarithmic uptake had a parabolic dependence on drug lipophilicity but a linear relationship to logarithmic IC50 values. Free drug concentrations were determined under the culture conditions and logarithmic free drug IC50 values and uptake rates were linearly related to lipophilicity. Uptake of drug in vivo in tissue from murine colon 38 tumours was approximately proportional to the dose administered. Host toxicity varied according to lipophilicity with the most selective compound having an intermediate value. This compound was also the most active of those tested in vivo, giving a growth delay of 9 days following daily intraperitoneal dosing (10 days) at 4 micromol kg(-1) day(-1). It was also significantly more active than another lipophilic cation, MKT-077. Alteration of lipophilicity of aromatic cationic antitumour drugs greatly affects cellular uptake and binding to plasma proteins. Changes in lipophilicity also affect host toxicity, and optimal lipophilicity may be a critical factor in the design of analogues with high antitumour activity.

Probing Disaccharide Binding to Triplatin as Models for Tumor Cell Heparan Sulfate (GAG) Interactions

Publisher: American Chemical Society (ACS)

Date: 08-08-2023

DOI: 10.1021/ACS.INORGCHEM.3C01391

NMR studies of erythrocytes immobilized in agarose and alginate gels

Publisher: Wiley

Date: 06-1992

DOI: 10.1002/MRM.1910250206

Abstract: 31P and 13C NMR were used to study the energy metabolism in perfused, human erythrocytes. The erythrocytes were immobilized in agarose threads, Ca- or Ba-alginate beads, and Ba-alginate-coated agarose threads. Erythrocytes were easily washed out from the agarose threads, but not from alginate-containing gels. Various small molecules, such as hypophosphite, dimethyl methylphosphonate, and methylphosphonate, were taken up from the perfusion medium in a normal manner. In addition, the 2,3-bisphosphoglycerate (2,3-DPG) chemical shifts were sensitive to the oxygen partial pressure suggesting that O2 molecules were diffusing through the gel and modifying the binding of 2,3-DPG to hemoglobin. A combination of inosine and pyruvate stimulated the synthesis of 2,3-DPG, but only if inorganic phosphate was present in the perfusion medium. Inosine only resulted in a dramatic rise in the intracellular sugarphosphate concentrations. Furthermore, [2-13C]glucose was converted to [2-13C]lactate by immobilized cells at a rate which was comparable to that in a control suspension. In summary, immobilization in Ba-alginate-coated agarose threads was an efficient way of trapping human erythrocytes for whole cell NMR investigations.

1 : 2 Adducts of copper(i) halides with 1,2-bis(di-2-pyridylphosphino)ethane: solid state and solution structural studies and antitumour activity

Publisher: Royal Society of Chemistry (RSC)

Date: 2009

DOI: 10.1039/B912281H

Abstract: The 1 : 2 adducts of copper(I) halides with 1,2-bis(2-pyridylphosphino)ethane (d2pype) have been synthesized and solution properties characterized by variable temperature (1)H, (31)P and (65)Cu NMR spectroscopy. Single-crystal structure determinations for the chloride, bromide and iodide complexes show these to crystallize from acetonitrile in the triclinic space group P1 as isostructural centrosymmetric dimers [(d2pype)Cu(mu-d2pype)(2)Cu(d2pype)]X(2).(solvent) with a approximately 12.6, b approximately 12.7, c approximately 15.3 A, alpha approximately 84, beta approximately 67, gamma approximately 84 degrees. In contrast to the analogous AuCl:2(d2pype) and AgNO(3):2(d2pype) adducts, in solution these CuX:2(d2pype) adducts (where X = Cl, Br and I) exist almost exclusively as bis-chelated monomeric [Cu(d2pype)(2)]X evidence for an equilibrium between monomeric and dimeric forms is detected only for the CuCl adduct in methanol. Cytotoxicity studies in two human breast cancer lines and two matched liver progenitor cell lines indicate that [Cu(d2pype)(2)]Cl is non selectively toxic to both non-tumourigenic and tumourigenic cells. However, the analogous Au(I) compound [Au(d2pype)(2)]Cl, is toxic to highly tumourigenic cells and more selective in its toxicity to tumourigenic cells compared to non-tumourigenic cells. The significance of these results to the further development of selective, mitochondria-targeted, Au(I) antitumour complexes is discussed.

Structural and solution chemistry of gold(I) and silver(I) complexes of bidentate pyridyl phosphines: selective antitumour agents

Publisher: Elsevier BV

Date: 05-1999

DOI: 10.1016/S0010-8545(99)00039-9

Determination of the Kinetic Profile of a Dinuclear Platinum Anticancer Complex in the Presence of Sulfate: Introducing a New Tool for the Expedited Analysis of 2D [¹H, ¹⁵N] HSQC

Publisher: American Chemical Society (ACS)

Date: 10-11-2010

DOI: 10.1021/IC100576K

Targeting the mitochondrial cell death pathway with gold compounds

Publisher: Elsevier BV

Date: 07-2007

DOI: 10.1016/J.CCR.2007.04.006

Substrate and inhibitor specificities differ between human cytosolic and mitochondrial thioredoxin reductases: Implications for development of specific inhibitors.

Publisher: Elsevier BV

Date: 03-2010

DOI: 10.1016/J.FREERADBIOMED.2010.12.015

Abstract: The cytosolic and mitochondrial thioredoxin reductases (TrxR1 and TrxR2) and thioredoxins (Trx1 and Trx2) are key components of the mammalian thioredoxin system, which is important for antioxidant defense and redox regulation of cell function. TrxR1 and TrxR2 are selenoproteins generally considered to have comparable properties, but to be functionally separated by their different compartments. To compare their properties we expressed recombinant human TrxR1 and TrxR2 and determined their substrate specificities and inhibition by metal compounds. TrxR2 preferred its endogenous substrate Trx2 over Trx1, whereas TrxR1 efficiently reduced both Trx1 and Trx2. TrxR2 displayed strikingly lower activity with dithionitrobenzoic acid (DTNB), lipoamide, and the quinone substrate juglone compared to TrxR1, and TrxR2 could not reduce lipoic acid. However, Sec-deficient two-amino-acid-truncated TrxR2 was almost as efficient as full-length TrxR2 in the reduction of DTNB. We found that the gold(I) compound auranofin efficiently inhibited both full-length TrxR1 and TrxR2 and truncated TrxR2. In contrast, some newly synthesized gold(I) compounds and cisplatin inhibited only full-length TrxR1 or TrxR2 and not truncated TrxR2. Surprisingly, one gold(I) compound, [Au(d2pype)(2)]Cl, was a better inhibitor of TrxR1, whereas another, [(iPr(2)Im)(2)Au]Cl, mainly inhibited TrxR2. These compounds also inhibited TrxR activity in the cytoplasm and mitochondria of cells, but their cytotoxicity was not always dependent on the proapoptotic proteins Bax and Bak. In conclusion, this study reveals significant differences between human TrxR1 and TrxR2 in substrate specificity and metal compound inhibition in vitro and in cells, which may be exploited for development of specific TrxR1- or TrxR2-targeting drugs.

Dinuclear Au(I) N-heterocyclic carbene complexes derived from unsymmetrical azolium cyclophane salts: Potential probes for live cell imaging applications

Publisher: Royal Society of Chemistry (RSC)

Date: 2016

DOI: 10.1039/C6DT01409G

Abstract: Dinuclear Au–NHC complexes engineered to have short Au⋯Au distances are strongly luminescent and can be used as probes for live cell imaging applications.

1H and31P NMR and HPLC studies of mouse L1210 Leukemia cell extracts: The effect of Au(I) and Cu(I) diphosphine complexes on the cell metabolism

Publisher: Wiley

Date: 03-1991

DOI: 10.1002/MRM.1910180115

Abstract: The effect of the antitumor complex [Au(dppe)2]Cl (where dppe is Ph2P(CH2)2PPh2) on the overall metabolism of cultured mouse L1210 leukemia cells was investigated by comparing 1H and 31P NMR spectra of perchloric acid extracts of cells incubated for 1 h in the presence and absence of 2 microM [Au(dppe)2]Cl. There were marked (ca. two-fold) increases in the levels of lactate and almost all detectable amino acids suggesting a drug-induced increase in the rate of glycolysis and inhibition of protein synthesis. The levels of taurine and phosphorylcholine were significantly decreased and 31P NMR spectra revealed a depletion of nucleoside triphosphates (NTP). The effect on nucleotide metabolism was investigated further by separating purine and pyrimidine nucleotides and precursors by anion-exchange HPLC. NTP levels were depleted by ca. 70-90% and there was a ca. three- to four-fold increase in nucleoside di- and monophosphates. The effect is postulated to be the result of uncoupling of mitochondrial oxidative phosphorylation. The Cu(I) complex [Cu(Ph2PCH = CHPPh2)2]Cl produced a similar effect on the cellular metabolism but was more potent. The water-soluble complex [Cu(Ph2P(CH2)PEt2)2]Cl caused the accumulation of cellular amino acids at a concentration that did not significantly deplete ATP levels.

Bromide ion binding by a dinuclear gold(i) N-heterocyclic carbene complex: a spectrofluorescence and X-ray absorption spectroscopic study

Publisher: Royal Society of Chemistry (RSC)

Date: 2013

DOI: 10.1039/C2DT31817B

Abstract: Fluorescence and X-ray absorption spectroscopy were used to investigate the anion binding properties of a luminescent, dinuclear Au(I) N-heterocyclic carbene (NHC) complex ([1](2+)) with a short Au(I)···Au(I) contact. The addition of Br(-) ions to a DMSO solution of [1](PF(6))(2) caused a red-shift in the fluorescence emission band from 396 nm to 496 nm. Similarly, the addition of Br(-) ions to [1](PF(6))(2) caused a decrease in the energy of the Au L(3)-edge in the X-ray absorption spectrum, consistent with the formation of an association complex between the cation [1](2+) and Br(-) ions. Solution-based structural studies of the association complex were carried out using extended X-ray absorption fine structure (EXAFS) modelling of the Au(I)···Au(I) core of the cation. These studies indicate that the association complex results from Au(I)···Br(-) interactions, with the Br(-) ions occupying two partially occupied sites at ~2.9 and 3.9 Å from the Au(I) atoms.

Mitochondria-targeted chemotherapeutics : the rational design of gold(I) N-Heterocyclic Carbene complexes that are selectively toxic to cancer cells and target protein selenols in preference to thiols

Publisher: American Chemical Society (ACS)

Date: 26-08-2008

DOI: 10.1021/JA804027J

Abstract: A family of lipophilic, cationic Au(I) complexes of N-heterocyclic carbenes (NHCs) have been designed as new mitochondria-targeted antitumor agents that combine both selective mitochondrial accumulation and selective thioredoxin reductase inhibition properties within a single molecule. Two-step ligand exchange reactions with cysteine (Cys) and selenocysteine (Sec) occur with release of the NHC ligands. At physiological pH the rate constants for the reactions with Sec are 20- to 80-fold higher than those with Cys. The complexes are selectively toxic to two highly tumorigenic breast cancer cell lines and not to normal breast cells, and the degree of selectivity and potency are optimized by modification of the substituent on the simple imidazolium salt precursor. The lead compound is shown to accumulate in mitochondria of cancer cells, to cause cell death through a mitochondrial apoptotic pathway and to inhibit the activity of thioredoxin reductase (TrxR) but not the closely related and Se-free enzyme glutathione reductase.

Copper(I) and gold(I) complexes with cis-bis(diphenylphosphino)ethylene. Crystal structures and 31P cross-polarization magic angle spinning nuclear magnetic resonance studies

Publisher: Royal Society of Chemistry (RSC)

Date: 1992

DOI: 10.1039/DT9920003357

Platinum complexes act as shielding agents against virus infection

Publisher: Royal Society of Chemistry (RSC)

Date: 2021

DOI: 10.1039/D1CC01593A

Abstract: An interdisciplinary approach determines that TriplatinNC binds to cell–surface heparan sulfate to protect cells from virus infection.

NanoSIMS multi-element imaging reveals internalisation and nucleolar targeting for a highly-charged polynuclear platinum compound

Publisher: Royal Society of Chemistry (RSC)

Date: 2013

DOI: 10.1039/C3CC42098A

Reactions of cisplatin hydrolytes with methionine, cysteine, and plasma ultrafiltrate studied by a combination of HPLC and NMR techniques

Publisher: Elsevier BV

Date: 10-1999

DOI: 10.1016/S0162-0134(99)00146-4

Abstract: The reactions of cis-[PtCl(NH3)2(H2O)]+ with L-methionine have been studied by 1D 195Pt and 15N NMR, and by 2D[1H, 15N] NMR. When the platinum complex is in excess, the initial product, cis-[PtCl(NH3)2(Hmet-S)]+ undergoes slow ring closure to [Pt(NH3)2(Hmet-N,S)]2+. Slow ammine loss then occurs to give the isomer of [PtCl(NH3)(Hmet-N,S)]+ with chloride trans to sulfur. When methionine is in excess, a reaction sequence is proposed in which trans-[PtCl(NH3)(Hmet-S)2]+ isomerises to the cis-isomer, with subsequent ring closure reactions leading to cis-[Pt(Hmet-N,S)2]2+. Near pH 7, methionine is unreactive toward cis-[PtCl(OH)(NH3)2]. By contrast, L-cysteine reacts readily with cis-[PtCl(OH)(NH3)2] at pH 7, but there were many reaction products, including bridged species. Cis-[PtCl(OH)(NH3)2] reacts with reduced thiols in ultrafiltered plasma but these are oxidized if the plasma is not fresh or appropriately stored. With very low concentrations of the platinum complexes (35.5 microM), HPLC experiments (UV detection at 305 nm) indicate that the thiolate (probably cysteine) reactions become simpler as bridging becomes less important.

Dinuclear gold(I) complexes of bridging bidentate carbene ligands: synthesis, structure and spectroscopic characterisation

Publisher: Royal Society of Chemistry (RSC)

Date: 2004

DOI: 10.1039/B316804B

Abstract: Eight dinuclear Au(i)-carbene complexes have been synthesized from various imidazolium-linked cyclophanes and related acyclic bis(imidazolium) salts, by treatment of the imidazolium salts with [Au(i)(SMe(2))Cl] in the presence of a carboxylate base. Single crystal structural studies showed that the Au(i)-carbene compounds contain dinuclear (AuL)(2) cations in which a pair of gold(i) centres are linked by a pair of bridging dicarbenoid ligands. Interestingly, the structural studies revealed short AuAu contacts of 3.0485(3)[Angstrom] and 3.5425(6)[Angstrom] in two of these complexes. NMR studies showed that the (AuL)(2) cations constructed from the cyclophane-based ligands retain a relatively rigid structure in solution, whilst those of the non-cyclophane ligand systems are fluxional in solution. The electronic absorption and emission spectra of the complexes in solution at room temperature were recorded and the complex with the shortest AuAu contact was found to emit intensely at 400 nm and more weakly at 780 nm upon excitation at 260 nm. The compounds with longer AuAu separations were not emissive under these conditions.

Anticancer activity of a Gold(I) phosphine thioredoxin reductase inhibitor in multiple myeloma

Publisher: Elsevier BV

Date: 2020

DOI: 10.1016/J.REDOX.2019.101310

Mitochondrial permeability transition induced by dinuclear gold(I)-carbene complexes: potential new antimitochondrial antitumour agents

Publisher: Elsevier BV

Date: 10-2004

DOI: 10.1016/J.JINORGBIO.2004.05.011

Conformational Modulation of Iduronic Acid‐Containing Sulfated Glycosaminoglycans by a Polynuclear Platinum Compound and Implications for Development of Antimetastatic Platinum Drugs

Publisher: Wiley

Date: 23-12-2020

DOI: 10.1002/ANIE.202013749

Serine protease inhibition and mitochondrial dysfunction associated with cisplatin resistance in human tumor cell lines: Targets for therapy

Publisher: Elsevier BV

Date: 06-1997

DOI: 10.1016/S0006-2952(97)00015-4

Composition and quality of harvest residues and soil organic matter under windrow residue management in young hoop pine plantations as revealed by solid-state NMR spectroscopy

Publisher: Elsevier BV

Date: 03-2003

DOI: 10.1016/S0378-1127(02)00182-2

Preface

Publisher: Elsevier BV

Date: 09-2016

DOI: 10.1016/J.JINORGBIO.2016.09.011

Gold compounds as therapeutic agents for human diseases

Publisher: Oxford University Press (OUP)

Date: 2011

DOI: 10.1039/C1MT00062D

Abstract: The application of gold in medicine is traceable for several thousand years and Au(i) compounds have been used clinically to treat rheumatoid arthritis since the last century. Recently research into gold-based drugs for a range of human diseases has seen a renaissance. Old as well as new Au(i) and Au(iii) compounds have been used and designed with an aim of targeting cellular components that are implicated in the onset or progression of cancers, rheumatoid arthiritis, viral and parasitic diseases. In addition, new disease targets have been found for gold compounds that have given insight into the mechanism of action of these compounds, as well as in the molecular pathophysiology of human diseases. Here we discuss the rationale for the design and use of gold compounds that have specific and selective targets in cells to alleviate the symptoms of a range of human diseases. We summarise the most recent findings in this research and our own discoveries to show that gold compounds can be developed to become versatile and powerful drugs for diseases caused by dysfunction of selenol and thiol containing proteins.

Kinetic analysis of the human erythrocyte glyoxalase system using 1H NMR and a computer model

Publisher: Wiley

Date: 10-1990

DOI: 10.1111/J.1432-1033.1990.TB19307.X

Abstract: 1H NMR was used with methylglyoxal, purified by an HPLC technique, to study the kinetics of the human erythrocyte glyoxalase system. 1H NMR enabled the direct measurement of the time-dependent changes in concentrations of the two hydrates of methylglyoxal, which have not previously been directly measurable, as well as measurement of substrates and products of the glyoxalase enzyme system in the human red blood cell. A computer model of the reaction scheme was developed and NMR data numerically analyzed, thus allowing a complete kinetic description of the reactions. The rate constants describing the chemical equilibria between the hydrated species of methylglyoxal were determined by this numerical analysis or by a saturation-transfer technique, and found to be much slower (by several orders of magnitude) than previously determined by other methods. The kinetic parameters describing the enzyme-catalyzed reactions were also determined from experiments using a dilute haemolysate that was added to solutions of methylglyoxal and reduced glutathione (GSH). The maximal velocity of glyoxalase 1 is threefold greater (Vmax = 70.4 +/- 4.7 mmol.min-1.1 packed cells-1) than glyoxalase 2(Vmax = 24 +/- 5 mmol.min-1.1 packed cells-1) and it exhibits threefold-greater affinity for its substrate (Km = 0.46 +/- 0.04 mM) than the second enzyme (Km = 1.5 +/- 0.4 mM). Both enzymes are subject to competitive inhibition glyoxalase 1 by reduced glutathione (KiGSH = 7.88 +/- 0.16 mM) and glyoxalase 2 by the hemithioacetal (HTA) of methylglyoxal and GSH (KiHTA = 0.29 +/- 0.04 mM).

Synthesis and structural characterisation of linear Au(I) N-heterocyclic carbene complexes: New analogues of the Au(I) phosphine drug Auranofin

Publisher: Elsevier BV

Date: 12-2005

DOI: 10.1016/J.JORGANCHEM.2005.07.013

Discovery Projects - Grant ID: DP1095383

Start Date: 2010

End Date: 12-2013

Amount: $270,000.00

Funder: Australian Research Council

Linkage - International - Grant ID: LX0667281

Start Date: 2006

End Date: 2009

Amount: $24,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0208117

Start Date: 04-2002

End Date: 12-2005

Amount: $290,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0986318

Start Date: 2009

End Date: 12-2012

Amount: $330,000.00

Funder: Australian Research Council

Linkage - International - Grant ID: LX0346972

Start Date: 09-2002

End Date: 09-2005

Amount: $32,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0452327

Start Date: 2004

End Date: 12-2007

Amount: $300,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP150100308

Start Date: 2015

End Date: 06-2019

Amount: $473,400.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0560712

Start Date: 04-2005

End Date: 06-2005

Amount: $630,837.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0561233

Start Date: 01-2005

End Date: 08-2006

Amount: $434,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0346892

Start Date: 03-2003

End Date: 06-2005

Amount: $689,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0989351

Start Date: 04-2009

End Date: 04-2010

Amount: $425,000.00

Funder: Australian Research Council

Special Research Initiatives - Grant ID: SR0354751

Start Date: 2004

End Date: 12-2004

Amount: $10,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0775551

Start Date: 2007

End Date: 12-2008

Amount: $550,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0989788

Start Date: 01-2009

End Date: 01-2010

Amount: $108,481.00

Funder: Australian Research Council

Special Research Initiatives - Grant ID: SR0354474

Start Date: 01-2004

End Date: 12-2004

Amount: $30,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0662817

Start Date: 03-2006

End Date: 12-2009

Amount: $270,000.00

Funder: Australian Research Council