Cobalt derivatives as promising therapeutic agents

Abstract

Inorganic complexes are versatile platforms for the development of potent and selective pharmaceutical agents. Cobalt possesses a diverse array of properties that can be manipulated to yield promising drug candidates. Investigations into the mechanism of cobalt therapeutic agents can provide valuable insight into the physicochemical properties that can be harnessed for drug development. This review presents examples of bioactive cobalt complexes with special attention to their mechanisms of action. Specifically, cobalt complexes that elicit biological effects through protein inhibition, modification of drug activity, and bioreductive activation are discussed. Insights gained from these examples reveal features of cobalt that can be rationally tuned to produce therapeutics with high specificity and improved efficacy for the biomolecule or pathway of interest.

Figure 1

Schematic representation of the different modes of action of bioactive cobalt complexes. Three classes of cobalt complexes are discussed: 1) complexes that directly act on biomolecules through ligand exchange, 2) complexes that modify the activity of ligated drugs and 3) complexes that are activated by bioreduction to either (I) yield a cobalt effector species or (II) release a small molecule drug.

Figure 2

A schematic showing the Co(III) Schiff base complex, [Co(acacen)(L)₂]⁺, that undergoes a dissociative exchange of the labile axial ligands and coordinates His residues [8,9]. Attachment of a targeting molecule, R, on the ancillary acacen chelate allows for selective inhibition of the protein of interest [8,11,12].

Figure 3

Cobalt complexes with bioactive ligands. A) Structure of the bioactive molecule aspirin complexed to Co₂(CO)₆ through an alkyne bond [32*,33]. B) Interaction of aspirin-[alkyne]-Co₂(CO)₆ with the human COX-2 enzyme with residues relevant to catalytic activity (green) and acetylation by cobalt complex (orange) is highlighted [32*]. Aspirin induces anti-inflammatory effects through acetylation of Ser-516 in the catalytic site of the COX enzyme. In contrast, conjugation of aspirin to the cobalt scaffold alters the pharmacology of the NSAID, as lysine residues are acetylated throughout the enzyme. In particular, acetylation of Lys166 and Lys432 near the heme prosthetic group and Lys346 near the entrance channel of the active site is suspected to result in potent COX inhibition and antiproliferative effects. Figure adapted from ref [32*] with permission.

Figure 4

Cobalt complexes that undergo bioreductive activation. A) Co(III)(L^NN′O)2 undergoes reduction to the more labile Co(II) counterpart to yield an active proteasome inhibitor [40,41*]. In the presence of the reducing agent ascorbic acid, one of the L^NN′O ligands of Co(III)(L^NN′O)2 is lost and replaced by a solvent (DMF) molecule, as identified by mass spectrometry. The activated complex is thought to bind to the active site of the proteasome to elicit inhibition. Scheme adapted from ref [31] with permission. B) The fluorescence of coumarin-343 (c343) is quenched upon coordination to Co(III)/cyclam. When the complex encounters the reducing environment of a hypoxic spheroid core, the complex undergoes reduction, releasing the fluorophores and restoring fluorescence. The process is monitored by fluorescence confocal microscopy [51*].