Recent Developments in Gold Drugs

Gold 2003
Renato Skerjl, Beth R Cameron, Renee Mosi, Yongbao Zhu,
Abstract The ability of metals to react with a variety of biological ligands has been exploited by medicinal chemists and there are a variety of metal-based drugs from the simple antacid magnesium and aluminium oxides to the anti-tumour platinum drugs cisplatin and carboplatin. Gold drugs, which have been used for the treatment of rheumatoid arthritis since the mid 20th century, are of the disease-modifying antirheumatic drugs (DMARD) class. Methotrexate is often the preferred DMARD, and with the advent of new agents such as the anti-TNF antibody Infliximab, gold drugs are now used infrequently. Since the introduction of auranofin in 1985 there has been no new clinically approved gold drug for either rheumatoid arthritis or any other disease.

In spite of this apparent lack of progress there has been a great deal of interest in the use of gold compounds for cancer therapy. There were early indications that auranofin had limited anti-tumour activity in in vitro systems and in the P388 leukaemia in vivo, however it was inactive against solid tumours. More promising indications were achieved with a series of digold phosphine complexes. The lead compound [dppe(AuCl)2] was shown to rearrange to give the more stable tetrahedral complex [Au(dppe)2]+. The proposed mechanism of action for [Au(dppe)2]Cl was the formation of DNA-protein cross-links, the lack of affinity for Au(I) for O and N containing ligands resulting in poor reactivity with the bases of DNA . Though this compound had marked activity against P388 it had limited activity against solid tumour models. This compound was not entered for clinical trials, however, due to problems with cardiotoxicity highlighted during pre-clinical toxicology studies.

Gold(III) complexes have not been as thoroughly investigated as gold(I) complexes, primarily because of their reactivity. Gold(III) is isoelectronic (d8) with platinum(II) and likewise forms square planar complexes. It is therefore tempting to speculate that such complexes would have similar antitumour activity to cisplatin. In order to stabilise the gold(III) oxidation state in a reducing biological milieu complexes were synthesised with a single mononegative bidentate ligand, damp, (2-[(dimethylamino)methyl]phenyl), and two monodentate anionic ligands e.g. Cl or acetate (OAc). The damp ligand forms part of a five-membered chelate ring in which the nitrogen of the amine group and the carbon of the aryl ring bond to the metal. The monodentate ligands are readily hydrolysed and are available for substitution. These compounds had limited anti-tumour activity in in vivo models using human tumour xenografts in immune-deprived mice. Other groups have adopted a similar approach. Marcon et al have reported the cytotoxicity of Au(III) complexes such as [Au(phen)Cl2]+ , [Au(en)2]3+, and [Au(terpy)Cl]2+ and Dinger and Henderson have reported on the in vitro biological activity of Au(III) (damp) thiosalicylate and salicylate complexes. In both of these cases in vivo biological activity has still to be demonstrated. Studies in our laboratory however demonstrated that the mechanism of the Au(III)(damp) complexes was different to cisplatin. We hypothesise that an alternative molecular target for these compounds is biologically important thiol-containing molecules.

The cysteine protease cathepsin B has been proposed to play a role in tumour metastasis and progression. Other potential thiol-containing molecular targets include cathepsin K (bone disease), L and S (inflammation), caspases (cancer), thioredoxin reductase (cancer), and transcription factors such as NFk-B and its regulator IKK (cancer and inflammation). Gold compounds have been shown to be inhibitors of enzyme activity and transcription. With this in mind we have adopted two parallel approaches to drug discovery, a mechanism-based approach, and a disease-oriented (cancer) approach.

Mechanistic studies focussed on identifying compounds with activity against cysteine proteases. To this end we cloned and isolated the cathepsins B, K, L, and S, and developed assays for enzyme inhibition. The Au(III)damp complexes were first tested against cathepsin B and were found to be moderate inhibitors. Modifications were made to the Au(III) damp structure to give compounds with a six-membered chelate ring comprised of a phenyl and pyridyl rings linked by a linker X with monodentate ligands L=Cl or acetate. Further modifications were explored including changing the linker (X) and the substituents (R) on the phenyl or pyridine ring. The change from a methylene group to other linkers such as oxygen, sulfur or even a carbonyl group significantly alters the activity against cathepsin B whereas the activity with cathepsin K is influenced by the addition of bulky lipophilic groups on the phenyl ring such as butyl or phenyl. A methyl group at the 6-position on the pyridyl ring increased the potency against all the cysteine proteases. Kinetic analysis with compounds where L=Cl or OAC showed that inhibition was time dependent. In addition, this inhibition could be partially reversed by incubation with cysteine indicating that the compounds are acting as tight binding reversible inhibitors.

The disease-oriented approach involved screening compounds for cytotoxicity against a panel of human tumour cell lines. These cell lines were chosen as being representative of different tissue types. In addition they were tested for intracellular cathepsin B and thioredoxin reductase activity. Compounds with L=Cl were found to be unstable in a biological matrix containing plasma therefore a series of complexes were synthesised where L= dithiolate or thiosalicyate. The more stable dithiolate complexes were less active in the short-term enzyme assays but were cytotoxic towards the tumour cells over a 72 hour incubation period. Three compounds, two dithiolates and one thiosalicylate, were selected for in vivo evaluation against the most sensitive tumour line, HT29 colon carcinoma, grown as a xenograft in immune-deprived mice. All three compounds showed modest anti-tumour activity but with no marked improvement over the parent Au(III)damp complexes.

Initial indications are that Au(III) compounds targeted against disease-specific thiol-containing biological molecules have potential as drugs, particularly for cancer. However, further work is required to produce a target-specific drug with a suitable pharmacological activity and toxicity profile.
Keywords: Gold drugs, Cathepsin B, Cancer
Full Access to Technical Paper
PDF version for $20.00
Other papers from Gold 2003
Search
Sort By:  Relevance
Showing results 1 - 50 of 101
Text
Summary: -
Proceedings: Gold 2003
Author(s): Elma van der Lingen, Madeleine du Toit, Cristian Cretu, Lizelle Glaner
Keywords: hard, gold alloys, Strengthening, age hardening
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Author(s): Inga Tuzovskaya, Alexey Pestryakov, Valery Gurin, Andrey Simakov, Miguel Avalos, Mario Farias
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Year: 2003
Text
Proceedings: Gold 2003
Keywords: gold-platinum alloys, ethylene glycol, Heat treatment, Electro-oxidation, Kirkendall effect, Cyclic Voltammetry
Year: 2003
Text
Proceedings: Gold 2003
Author(s): Nina Bogdanchikova, Bernard E. Nieuwenhuys
Keywords: Oxidation, Methane, oxide, additive, Alkali, Hydrocarbons, propene
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Author(s): Michael Cortie, Herman Schwarzer, Stephen Roberts, Gary Pattrick
Keywords: Gold Catalysis, Intermetallic compounds, AuAl2, CO oxidation
Year: 2003
Text
Proceedings: Gold 2003
Author(s): Andreas Zielonka, Renate Freudenberger
Keywords: electroforming, electrodeposition/electroplating, implant, Gold, medical application
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Author(s): Neil E Izatt, Steven R Izatt, Ronald L Bruening
Year: 2003
Text
Proceedings: Gold 2003
Author(s): Jeanette Hohls, Cristian Cretu, Lesley Cornish, Daven Compton
Keywords: Fecraloy, oxidation resistance, Gold
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Author(s): Elma van der Lingen, Stella Valenzuela, Don Martin
Keywords: mesoporous, nanoporous, ultracapacitor
Year: 2003
Text
Proceedings: Gold 2003
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Author(s): Tim W Ellis
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Author(s): Stephan Roberts, Elma van der Lingen, Herman Schwarzer
Keywords: spongy gold, selective catalytic reduction, NOx
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Year: 2003
Text
Proceedings: Gold 2003
Author(s): Shawn D. Lin, Bernard E. Nieuwenhuys
Keywords: nitrous oxide, Oxidation, Alkali, Ammonia, nitric oxide, Reduction, oxide, selectivity
Year: 2003
Text
Proceedings: Gold 2003
Author(s): Ko-ichi Sugawara
Keywords: electron microscopy, nanoparticle, Morphology, Computer simulation, Image analysis, cluster science, Statistics
Year: 2003
Text
Proceedings: Gold 2003
Author(s): Bob Stewart, Carel Wreesmann, Geoff Smith
Keywords: Plants, Induced hyperaccumulation, Gold, Phytomining, nanoparticles
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Year: 2003
Text
Proceedings: Gold 2003
Author(s): Prati Laura, Rossi Michele
Keywords: gold on carbon, liquid phase oxidation
Year: 2003
Text
Proceedings: Gold 2003
Author(s): Uzi Landman
Keywords: gold nanoclusters, oxidation reactions, relativistic effects, nanocatalysis
Year: 2003
Text
Proceedings: Gold 2003
Author(s): Masayuki Kanehara, Etsushi Kodzuka, Yasunori Oumi, Tsuneji Sano
Keywords: gold nanoparticle, self-assembly
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Author(s): Suresh Bharagva, Martin Bennett
Keywords: Ab Initio Calculations, Gold Complexes, Cyclometallated, Heterovalent complexes, Carbon-carbon coupling, Binuclear
Year: 2003
Text
Proceedings: Gold 2003
Author(s): Yutaka Okinaka
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Author(s): Sandrine Arrii, Albert Renouprez
Keywords: supported catalysts, CO oxidation, support effects, Gold, laser vaporization
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Author(s): Elena Cerrada, Ana Ade, Maria Contel
Keywords: Dipolar cycloaddition, Gold, nitrones, organometallics
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Author(s): Aalbert Zwijnenburg, Wim G Sloofs, Jacob A Moulijn
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Author(s): Cris Kostmann, Gunter Stephani
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Author(s): Elma Van der Lingen, Michael Cortie
Keywords: Gold Catalysis, zinc oxide, CO oxidation
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Keywords: Cyclic Voltammetry, Surface Active Sites, Electrochemistry, Surface, Metastability, RHE, Electrocatalysis, Gold, Premonolayer Oxidation, Cyclic redox mediators, Active state electrochemistry, Protruding surface atoms, Metastable Surface States
Year: 2003
Text
Proceedings: Gold 2003
Author(s): Peter CLAUS, Herbert HOFMEISTER, Christian MOHR
Keywords: nanoparticles, hydrogenation, indentification of active sites, catalysis by gold, real structure
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Author(s): Uwe Manz
Keywords: Electroless, Plating, Barrel, Electronics
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Author(s): P Centomo, D Ferrari, W Meyer-Zaika, G Schmid
Year: 2003
Text
Summary: The preparation of a vapour compound sensor is reported. It is based on a vapochromic organometallic gold compound and optical fiber. The results are comapred with other reported VO«S sensor
Proceedings: Gold 2003
Author(s): Candido Bariain, Elena Cerrada, Julian Garrido, Ignacio R Matias, Mariano Laguna
Keywords: vapochromic, Gold, organometallic, environmental sensor
Year: 2003
Text
Proceedings: Gold 2003
Author(s): Gilbert P. van Berkel, Bernard E. Nieuwenhuys
Keywords: chemisorption, Au(100), nitric oxide, phase transition
Year: 2003
Text
Proceedings: Gold 2003
Author(s): V. La Parola, B. Pawelec, J. L. G. Fierro
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Author(s): Andrea Beck, Gabor Peto, Csaba Daroczi, Krisztina Frey
Keywords: Au/SiO2/Si(100), Size dependence, UPS, support effect, TEM, AFM, CO oxidation
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Author(s): Fernando Canales, Silvia Canales, Olga Crespo, Antonio Laguna, Carmen Larraz
Keywords: aurophilic interactions, polynuclear, chalcogenide, Gold
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Keywords: plasmon resonance, colour, crystal structure, melting point, band gap, nanotechnology
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Author(s): Christopher Corti
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Author(s): David James, Lucy Millard, Jane Greaves, Jorge Soares
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Author(s): Mihaly Hegedus
Year: 2003
Text
Proceedings: Gold 2003
Author(s): Kageeporn Wongpreedee, Alan M Russell
Keywords: Gold, interconnection wire, transformation, Kinetics, Composite, Dislocation
Year: 2003
Text
Proceedings: Gold 2003
Author(s): Chih-Huey Lin, Hsin-Yen Tsai, Chih-Huey Lin, Hsin-Yen Tsai
Keywords: Au, Al2O3, Au, Al2O3, impregnation, NH4OH treatment, NH4OH treatment, impregnation
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Author(s): Aya Kawamoto, Masakazu Date, Susumu Tsubota, Mitsutaka Okumura, Masatake Haruta
Year: 2003
Text
Summary: -
Proceedings: Gold 2003
Author(s): Matthew Hall, Albert F Carley, Graham John Hutchings,
Keywords: XPS, Au - Fe catalysts, Low temperature CO oxidation
Year: 2003