Title:

Macrocyclic Chromophores as a Novel Class of Fluorescent Molecules

With recent advances in biological imaging technologies, the ability to observe biological targets and processes has become imperative for all areas of biological research. Small molecule fluorophores, whose optical and structural tunability offer an expansive toolset for biological visualization, have become a popular area of study in recent years. Despite their utility, certain fluorophores are limited by a dependence on restrictive environmental conditions to maintain proficient fluorescent properties. Consequently, these fluorophores are largely unexplored, leaving significant unrealized potential for leveraging their unique optical capabilities. This research proposes macrocyclization of small molecule fluorophores to inhibit free rotation of the molecule and induce fluorescence in non-restrictive environments. A macrocyclic backbone is anticipated to provide a rigid and synthetically tunable structure that enables precise optimization of fluorophore optical properties for diverse biological targets. The increased pi conjugation awarded by the backbone is expected to promote a red-shifted emission and increase the Stokes shift in a small molecule fluorophore, thereby minimizing self-absorption, reducing autofluorescence, improving signal-to-noise ratios, and lowering phototoxicity to dramatically enhance current live-cell imaging capabilities. A key step in this work is incorporating a nitrogen-swapping reaction to install an imidazolidinone core analogous to the GFP chromophore. This enables direct structural comparison to the natural GFP chromophore and is expected to optimize fluorescence relative to the corresponding oxygen-containing analog due to the reduced electronegativity of nitrogen influencing electronic delocalization within the molecule.

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