By virtue of their favorable properties, rhenium(I) tricarbonyl (Re(CO) 3 ) complexes have arisen as novel therapeutic agents and cellular imaging probes for addressing problems of biomedical relevance. Although great success has been found in monometallic complexes of this type, there has been recent interest in developing multimetallic compounds containing Re(CO) 3 moieties to capitalize on the potential synergistic effects of different metal centers. This Minireview provides an overview of multimetallic Re(CO) 3 complexes that have been developed specifically for biomedical applications. The promising therapeutic and diagnostic potential of such complexes and future needs in this field are discussed.

The mitochondrial calcium uniporter (MCU) is a transmembrane protein that resides on the inner membrane of the mitochondria and mediates calcium uptake into this organelle. Given the critical role of mitochondrial calcium trafficking in cellular function, inhibitors of this channel have arisen as tools for studying the biological relevance of this process and as potential therapeutic agents. In this study, four new analogues of the previously reported Ru-based MCU inhibitor [ClRu(NH 3 ) 4 (μ-N)Ru(NH 3 ) 4 Cl]Cl 3 (Ru265) are reported. These compounds, which bear axial carboxylate ligands, are of the general formula [(RCO 2 )Ru(NH 3 ) 4 (μ-N)Ru(NH 3 ) 4 (O 2 CR)]X 3 , where X = NO 3 − or CF 3 SO 3 − and R = H (1), CH 3 (2), CH 2 CH 3 (3), and (CH 2 ) 2 CH 3 (4). These complexes were fully characterized by IR spectroscopy, NMR spectroscopy, and elemental analysis. X-ray crystal structures of 1 and 3 were obtained, revealing the expected presence of both the linear Ru(μ-N)Ru core and axial formate and propionate ligands. The axial carboxylate ligands of complexes 1− 4 are displaced by water in buffered aqueous solution to give the aquated compound Ru265′. The kinetics of these processes were measured by 1 H NMR spectroscopy, revealing half-lives that span 5.9−9.9 h at 37 °C. Complex 1 with axial formate ligands underwent aquation approximately twice as fast as the other compounds. In vitro cytotoxicity and mitochondrial membrane potential measurements carried out in HeLa and HEK293T cells demonstrated that none of these four complexes negatively affects cell viability or mitochondrial function. The abilities of 1−4 to inhibit mitochondrial calcium uptake in permeabilized HEK293T cells were assessed and compared to that of Ru265. Fresh solutions of 1−4 are approximately 2-fold less potent than Ru265 with IC 50 values in the range of 14.7−19.1 nM. Preincubating 1−4 in aqueous buffers for longer time periods to allow for the aquation reactions to proceed increases their potency of mitochondrial uptake inhibition to match that of Ru265. This result indicates that 1− 4 are aquation-activated prodrugs of Ru265′. Finally, 1−4 were shown to inhibit mitochondrial calcium uptake in intact, nonpermeabilized cells, revealing their value as tools and potential therapeutic agents for mitochondrial calcium-related disorders.

Increasing the lipophilicity of rhenium-based anticancer agents increases the rate at which they induce their biological effects.