Quinone methide - based strategies for reversible modification, protection, and ligation of biological substrates and polymers

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In this project funded by the Chemical Structure, Dynamic & Mechanism B Program of the Chemistry Division, Professor Vladimir Popik of the Department of Chemistry at the University of Georgia is developing new approaches for modifying the structures of biological molecules and materials using light. Methods utilizing light-directed reversible derivatization of biological molecules would allow one to control their properties in time and in space. Technological applications of such chemical methods may include drug delivery materials and protein engineering. This project provides students with an interdisciplinary training at the interface of synthetic chemistry, photochemistry, and biochemistry. High school students are conducting summer internships in the laboratory of Professor Popik through the University of Georgia Young Dawgs Program, and they are experiencing modern scientific research. With previous NSF support Professor Popik developed a new family of photolabile protecting groups and demonstrated the Diels-Alder and Michael reactivity of photo-generated o-quinone methides. The strategy incorporates several desirable features: the very fast release of a substrate, "bleaching" of the initial chromophore, and the generation of a fluorescent marker or a different color. Photochromic moieties add a built-in timer for photolabile protecting groups. Professor Popik and his group are designing and synthesizing new o-quinone methide precursors sensitive to long wavelengths of light. Also, they are further studying the mechanism of o-quinone methide formation and the pH-dependence of the thiol- quinone methide reaction kinetics. The pH-control of cysteine labeling allows for selective derivatization of these residues in multi-cysteine substrates, so they are applying these methods to the selective derivatization of proteins under different conditions (pH, light, competing nucleophiles) and examining the reversibility of the protein modification. Based upon this chemistry, Professor Popik is also exploring the feasibility of using o-quinone methide derivatives as protease inhibitors.