Recent Developments in Gold Drugs

Gold drugs have been used for the treatment of rheumatoid arthritis since the mid 20th century as disease-modifying antirheumatic drugs (DMARD) class. Methotrexate is often the preferred DMARD, and with the advent of new therapies gold drugs are now used infrequently. Since the introduction of auranofin in 1985 there has been no new clinically approved gold drug. 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 and early promising indications were achieved with a gold phosphine complex [Au(dppe)2]Cl. This compound was not entered for clinical trials, however, due to problems with cardiotoxicity highlighted during pre-clinical toxicology studies. 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 antitumor activity to cisplatin. In order to stabilise the gold(III) oxidation cycloaurated complexes were synthesised with a single mononegative bidentate ligand, damp, (2-[(dimethylamino)methyl]phenyl), and two monodentate anionic ligands e.g. Cl or acetate. The damp ligand forms part of a five-membered chelate ring. The monodentate ligands are readily hydrolysed and are available for substitution. These compounds had limited anti-tumor activity in in vivo against human tumor xenografts. Mechanistic studies indicated that these compounds had a different mechanism of action to cisplatin. An alternative molecular target for these compounds is biologically important thiol-containing molecules such as the cysteine protease cathepsin B. Modifications were made to the Au(III) damp structure to give compounds with a six-membered chelate ring. These compounds were shown to be inhibitors of cathepsin B. Compounds were also tested for cytotoxicity against a panel of human tumor cell lines. Three compounds were selected for further evaluation against a human colon tumor xenograft. The compounds showed modest anti-tumor 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.