The Organic and Macromolecular Chemistry Program in the Chemistry Division at the National Science Foundation supports Professor Vladimir V. Popik of the University of Georgia who proposes to develop a new family of photolabile protecting groups (PPGs) based on photochemical elimination of substrates from o-hydroxybenzyl alcohol derivatives. Preliminary results suggest that PPGs based on this reaction, while generally applicable, are especially suitable for the direct caging of alcohols. This new PPG platform will also be investigated for the photolabile protection of glycols, carbohydrates, and carbonyl compounds. PPGs developed in this project are expected to have long shelf-life and good hydrolytic stability in the dark, as well as high quantum and chemical yield of photo-deprotection. Substrate release from the newly-developed PPGs is expected to be fast enough to allow for spatial- and time-resolved biochemical studies. The mechanism and dynamics of the cleavage reaction will be studied in detail to assist us in the design of novel PPGs.
Broader impacts of the proposed research will contribute new caging tools to organic synthesis, biochemistry, and medical technology. PPGs and photochromic systems developed in this work might serve as a basis for the design of new drugs and drug delivery systems that can be photoactivated, as well as open new approaches to photolithography and information recording. This project will provide undergraduate and graduate students with interdisciplinary training on the interface of synthetic, physical organic chemistry, and photochemistry. Students from underrepresented groups will be recruited to work on this project. A photochemical laboratory will be established, which will provide the University of Georgia and local scientists with apparatus and expertise to conduct photochemical experiments. The interdisciplinary nature of the research is expected to produce extensive collaboration with other research groups, both locally and internationally.
We have developed a new family of photolabile protecting groups (PPGs) based on photochemical elimination of substrates from o-hydroxybenzyl alcohol derivatives. The utility of this new PPG platform for the photolabile protection of glycols, carbohydrates, and carbonyl compounds was also demonstrated. We have designed and demonstrated the utility of a fluorescent PPGs that allow for separate fluorescent readout and release of a substrate. Exceptionally fast hetero Diels-Alder addition of o-naphthoquinone methide (oNQM) to vinyl ether was adopted for the light-directed labeling of various substrates and photo-patterning of the surfaces. We have developed a novel strategy for the reversible light-directed surface derivatization and patterning based on a very facile reaction between photochemically generated oNQM and thiols. We have demonstrated the use of this reaction for the selective derivatization of solvent-exposed cysteine residues in peptides and proteins. Attractive features of this labeling approach include an exceptionally fast rate of the reaction and a requirement for low equivalence of the reagent. Irradiation of NQMP-labeled protein in a dilute solution (<40 uM) or in the presence of a vinyl ether results in a traceless release of the substrate. We have also adopted this chemistry for quantitative capture and release of proteins on resin beads. We have effectively used NQMP as a photoremovable protecting group for Fluorescein. The caged fluorophore is weakly fluorescent, however, photolysis of the caged dye releases the fluorophore with a fluorescent quantum yield of 0.75 - 0.93.
