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Chemists have overlooked sulfonamides when designing glowing probes

Multiple bioluminescent and fluorescent scaffolds light up with the right sulfonamide groups attached

by Carmen Drahl, special to C&EN
March 26, 2019


When it comes to expanding the palette of fluorescent and bioluminescent reporters for tracking biological processes, the tactic of using a sulfonamide group hasn’t gotten a fair shake, a new study suggests (Org. Lett. 2019, DOI: 10.1021/acs.orglett.9b00173).

Chemical structure of a sulfonamide-containing luciferin analog.
Credit: Org. Lett.
An analog of the bioluminescent molecule luciferin contains a sulfonamide group.

To report on a wider variety of enzyme and gene activities in cells and live animals, scientists continually seek analogs for firefly D-luciferin, which glows when the luciferase enzyme oxidizes it. But chemists designing dyes tend to stick to familiar territory, says Stephen C. Miller of the University of Massachusetts Medical School, and as a result, they focus on including hydroxyl, amine, or alkylamine functional groups that donate electrons and influence bioluminescence and fluorescence.

Photo of three glass vials, glowing (from left) blue, green, and yellow.
Credit: Stephen C. Miller
Sulfonamide-containing (from left) coumarin, rhodol, and rhodamine dyes fluoresce brightly in water.

Prior studies suggested sulfonamide dyes barely glimmer. But Miller’s team suspected that negatively charged sulfonamides might also be good electron donors and could create a glow. So they made several analogs of D-luciferin containing a sulfonamide group. Not only did nearly all of the team’s new sulfonamide-containing luciferins glow, so did analogs of three common non-natural dye scaffolds with sulfonamides attached. Miller notes that the probes work best in water where the pH is high enough so that the sulfonamide groups are negatively charged. Although all the sulfonamide dyes are dimmer than their parent compounds, Miller thinks they will have other benefits, such as the potential to interact with cellular metal ions and to complement positively charged probes that primarily localize to certain organelles.


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