Thioether Coordination Chemistry for Molecular Imaging of Copper in Biological Systems

Abstract

Copper is an essential element in biological systems. Its potent redox activity renders it necessary for life, but at the same time, misregulation of its cellular pools can lead to oxidative stress implicated in aging and various disease states. Copper is commonly thought of as a static cofactor buried in protein active sites; however, evidence of a more loosely bound, labile pool of copper has emerged. To help identify and understand new roles for dynamic copper pools in biology, we have developed selective molecular imaging agents for this metal, drawing inspiration from both biological binding motifs and synthetic model complexes that reveal thioether coordination as a general design strategy for selective and sensitive copper recognition. In this review, we summarize some contributions, primarily from our own laboratory, on fluorescence- and magnetic resonance-based molecular-imaging probes for studying copper in living systems using thioether coordination chemistry.

In vivo bioluminescence imaging of labile iron accumulation in a murine model of Acinetobacter baumannii infection

“…A modest response is observed with free copper salts, as is similarly observed for the related fluorescence probe FIP-1 (15). However, as a typical eukaryotic cell exhibits a ∼10-fold higher level of iron over copper coupled with the high buffering capacity of copper with glutathione and metallochaperones (picomolar to femtomolar K d values) (55)(56)(57)(58)(59)(60), the modest response to free copper salts suggests that ICL-1 should have sufficient selectivity to detect alterations in biological ferrous iron levels. ICL-1 is also selective for labile Fe 2+ over other biologically relevant forms of iron that are tightly bound to proteins and cofactors, such as transferrin, ferritin, hemin, and hemoglobin, as well as Fe 3+ , along with reductants glutathione, N-acetyl cysteine, β-mercaptoethanol, and ascorbic acid (Fig.…”

Lanthanide‐Based T2ex and CEST Complexes Provide Insights into the Design of pH Sensitive MRI Agents

“…Dynamic contrast enhancement (DCE) measurements during agent clearance are widely used as an index of tissue perfusion. Numerous “responsive” contrast agent designs have been reported that alter image contrast in response to changes in pH, common biological cations (Cu 2+ , Ca 2+ , Zn 2+ ), O 2 tension, temperature, glucose, or enzyme activity but none has been approved for clinical use. A new class of contrast agent based on chemical exchange saturation transfer (CEST) that uses frequency selective radio frequency pulses to initiate image contrast is rapidly gaining in popularity .…”

Copper-based reactions in analyte-responsive fluorescent probes for biological applications

“…In addition to the non-exchangeable copper coordinated tightly in protein active sites, the intracellular labile copper pool which can undergo dynamic ligand exchange has attracted much recent attention [7]. The redox activity of the labile copper has been associated with the generation of reactive oxygen species (ROS), cellular redox balance and immune response.…”

“…Using the BODIPY (borondipyrromethene)-based CS1 and CS3 (Figures 2c and 2d), Chang and co-workers observed an increase in intracellular copper in live human embryonic kidney (HEK) cells upon copper enrichment and a calcium-dependent redistribution of labile copper in neurons respectively [19,20]. Since then, a whole series of copper probes has been developed following a similar Cu(I) binding strategy with individual probes displaying various photophysical and organelle labeling properties [7,[21][22][23][24][25][26][27][28][29]. For example, the ratiometric copper sensor RCS1 can visualize the ascorbate-induced release of endogenous Cu(I) in HEK293T and C6 rat glioma cells through a ratiometric response (Figure 2e) [21].…”