Methoxy-Substituted Nitrodibenzofuran-Based Protecting Group with an Improved Two-Photon Action Cross-Section for Thiol Protection in Solid Phase Peptide Synthesis

Taysir K. Bader, Feng Xu, Michael H. Hodny, David A. Blank, Mark D. Distefano

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Photoremovable caging groups are useful for biological applications because the deprotection process can be initiated by illumination with light without the necessity of adding additional reagents such as acids or bases that can perturb biological activity. In solid phase peptide synthesis (SPPS), the most common photoremovable group used for thiol protection is the o-nitrobenzyl group and related analogues. In earlier work, we explored the use of the nitrodibenzofuran (NDBF) group for thiol protection and found it to exhibit a faster rate toward UV photolysis relative to simple nitroveratryl-based protecting groups and a useful two-photon cross-section. Here, we describe the synthesis of a new NDBF-based protecting group bearing a methoxy substituent and use it to prepare a protected form of cysteine suitable for SPPS. This reagent was then used to assemble two biologically relevant peptides and characterize their photolysis kinetics in both UV-and two-photon-mediated reactions; a two-photon action cross-section of 0.71-1.4 GM for the new protecting group was particularly notable. Finally, uncaging of these protected peptides by either UV or two-photon activation was used to initiate their subsequent enzymatic processing by the enzyme farnesyltransferase. These experiments highlight the utility of this new protecting group for SPPS and biological experiments.

Original languageEnglish (US)
Pages (from-to)1614-1625
Number of pages12
JournalJournal of Organic Chemistry
Volume85
Issue number3
DOIs
StatePublished - Feb 7 2020

Bibliographical note

Funding Information:
The authors thank Drs. Matt Hammers and Andrew Healy for valuable consultations. We acknowledge the Mass Spectrometry Core Facility of the Masonic Cancer Center, a comprehensive cancer center designated by the National Cancer Institute, supported by Grant P30 CA77598, where the LC-MS/MS analysis was performed. This work was supported by the National Institute of General Medical Sciences, including Grants R01 GM084152, R21 CA185783, and NSF/CHE 1905204 to M.D.D.

Publisher Copyright:
Copyright © 2019 American Chemical Society.

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