Photoactivatable protecting groups (PPGs) are useful for a broad range of applications ranging from biology to materials science. In chemical biology, induction of biological processesviaphotoactivation is a powerful strategy for achieving spatiotemporal control. The importance of cysteine, glutathione, and other bioactive thiols in regulating protein structure/activity and cell redox homeostasis makes modulation of thiol activity particularly useful. One major objective for enhancing the utility of photoactivatable protecting groups (PPGs) in living systems is creating PPGs with longer wavelength absorption maxima and efficient two-photon (TP) absorption. Toward these objectives, we developed a carboxyl- and dimethylamine-functionalized nitrodibenzofuran PPG scaffold (cDMA-NDBF) for thiol photoactivation, which has a bathochromic shift in the one-photon absorption maximum fromλmax= 315 nm with the unfunctionalized NDBF scaffold toλmax= 445 nm. While cDMA-NDBF-protected thiols are stable in the presence of UV irradiation, they undergo efficient broad-spectrum TP photolysis at wavelengths as long as 900 nm. To demonstrate the wavelength orthogonality of cDMA-NDBF and NDBF photolysis in a biological setting, caged farnesyltransferase enzyme inhibitors (FTI) were prepared and selectively photoactivated in live cells using 850-900 nm TP light for cDMA-NDBF-FTI and 300 nm UV light for NDBF-FTI. These experiments represent the first demonstration of thiol photoactivation at wavelengths above 800 nm. Consequently, cDMA-NDBF-caged thiols should have broad applicability in a wide range of experiments in chemical biology and materials science.
Bibliographical noteFunding Information:
We thank Dr Guillermo Marques for valuable microscopy insights and support. We thank Dr Viktor Young for solving the X-ray crystal structure of intermediate 6. Microscopy was performed at the University of Minnesota Imaging Center, a Nikon Center of Excellence for confocal microscopy. X-Ray crystallography was performed at the University of Minnesota X-Ray Crystallographic Laboratory supported by The National Science Foundation (CHE-1229400 Mass spectrometry analysis was performed at the University of Minnesota Department of Chemistry Mass Spectrometry Laboratory (MSL), supported by the Office of the Vice President of Research, College of Science and Engineering, and the Department of Chemistry at the University of Minnesota, as well as The National Science Foundation (CHE-1336940). This work was supported by the National Institute of General Medical Sciences, including F32 GM126862 to M. H. and R01 GM084152 and R21 CA185783 to M. D.
© The Royal Society of Chemistry 2020.
PubMed: MeSH publication types
- Journal Article
- Research Support, U.S. Gov't, Non-P.H.S.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't