Ligand-Directed Approach to Activity-Based Sensing: Developing Palladacycle Fluorescent Probes That Enable Endogenous Carbon Monoxide Detection

Carbon monoxide (CO)
is an emerging gaso­trans­mitter
and reactive carbon species with broad anti-inflammatory, cytoprotective,
and neurotransmitter functions along with thera­peutic potential
for the treatment of cardio­vascular diseases. The study of CO
chemistry in biology and medicine relative to other prominent gaso­trans­mitters
such as NO and H2S remains challenging, in large part due
to limitations in available tools for the direct visualization of
this transient and freely diffusing small molecule in complex living
systems. Here we report a ligand-directed activity-based sensing (ABS)
approach to CO detection through palladium-mediated carbonylation
chemistry. Specifically, the design and synthesis of a series of ABS
probes with systematic alterations in the palladium-ligand environment
(e.g., sp3-S, sp3-N, sp2-N) establish structure–activity
relationships for pallada­cycles
to confer selective reactivity with CO under physiological conditions.
These fundamental studies led to the development of an optimized probe,
termed Carbon Monoxide Probe-3 Ester Pyridine (COP-3E-Py), which enables
imaging of CO release in live cell and brain settings, including monitoring
of endogenous CO production that triggers presynaptic dopamine release
in fly brains. This work provides a unique tool for studying CO in
living systems and establishes the utility of a synthetic methods
approach to activity-based sensing using principles of organometallic
chemistry.