Cysteine proteases as targets for metal-based drugs

Abstract

The discovery of the platinum anticancer drug cisplatin provided a major stimulus for research into metal-based drugs. The molecular target for the platinum agents is DNA; however recent developments in inorganic medicinal chemistry have identified several alternative novel targets for metal-based drugs. Biological molecules with essential thiol groups are attractive targets. Thiol-containing molecular targets include the redox enzymes thioredoxin reductase and glutathione reductase, transcription factors, and cysteine proteases such as caspases and cathepsins. Inorganic chemistry offers many opportunities for medicinal chemistry, and alternative targets for metal-based drugs are reviewed, with a focus on cysteine proteases. The cathepsin cysteine proteases have numerous physiological functions, and have been implicated in diseases including cancer, autoimmune and inflammatory, and parasitic diseases. The catalytic mechanism of these enzymes is dependent upon a cysteine at the active site. We postulate that metal complexes can inhibit these enzymes via a ligand substitution with the thiol of the active site cysteine. We have investigated several classes of metal complexes including cyclometalated organo gold(iii) and Pd(ii) complexes, and a series of rhenium(v) mixed ligand oxorhenium complexes as inhibitors of cathepsin cysteine proteases. Mechanistic studies were conducted on the latter supporting the hypothesis of active site-directed inhibition. These data are reviewed below and discussed in the context of possible therapeutic applications including cancer and parasitic disease.

Inhibition of the cathepsin cysteine proteases B and K by square-planar cycloaurated gold(III) compounds and investigation of their anti-cancer activity

“…This results in a completely ionic thiolate group thus favoring the interaction of thiophilic metals such as gold, which have a high affinity for thiolates with a low pKa. We therefore hypothesized that a metal complex could inhibit a cysteine protease by ligand exchange with the thiol of the active site cysteine [43]. We have subsequently described a series of rhenium(V) oxorhenium complexes with inhibitory activity against cathepsin B which interacts with the thiol of the active site cysteine [44,45].…”

Platinum(II) and palladium(II) complexes with (N,N′) and (C,N,N′)− ligands derived from pyrazole as anticancer and antimalarial agents: Synthesis, characterization and in vitro activities

“…Cyclometallated complexes derived from N-donor ligands have attracted great interest during the last decade due to their properties and applications in a wide variety of fields [10,[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] and compounds of this kind containing Pd(II), Pt(II), Ru(II), Ir(III) Rh(III) and Au have shown promising cytotoxic activities [10,20,[27][28][29][30][31][32][33][34][35][36]. Few cyclopalladated complexes derived from pyrazole are known [37][38][39][40][41] and, to the best of our knowledge, their cytotoxicity has only been reported once [41].…”

Affinity-Enhanced Luminescent Re(I)- and Ru(II)-Based Inhibitors of the Cysteine Protease Cathepsin L

“…27 In these cases, the rhenium metal center undergoes direct ligation to the nucleophilic thiolate in the cysteine protease active site. To gain further insight into the mode of inhibition of CTSL by 7 , several more experiments were carried out.…”