Nitrodibenzofuran

A One-and Two-Photon Sensitive Protecting Group That Is Superior to Brominated Hydroxycoumarin for Thiol Caging in Peptides

M. Mohsen Mahmoodi, Daniel Abate-Pella, Tom J. Pundsack, Charuta C. Palsuledesai, Philip C. Goff, David A. Blank, Mark D. Distefano

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Photoremovable protecting groups are important for a wide range of applications in peptide chemistry. Using Fmoc-Cys(Bhc-MOM)-OH, peptides containing a Bhc-protected cysteine residue can be easily prepared. However, such protected thiols can undergo isomerization to a dead-end product (a 4-methylcoumarin-3-yl thioether) upon photolysis. To circumvent that photoisomerization problem, we explored the use of nitrodibenzofuran (NDBF) for thiol protection by preparing cysteine-containing peptides where the thiol is masked with an NDBF group. This was accomplished by synthesizing Fmoc-Cys(NDBF)-OH and incorporating that residue into peptides by standard solid-phase peptide synthesis procedures. Irradiation with 365 nm light or two-photon excitation with 800 nm light resulted in efficient deprotection. To probe biological utility, thiol group uncaging was carried out using a peptide derived from the protein K-Ras4B to yield a sequence that is a known substrate for protein farnesyltransferase; irradiation of the NDBF-caged peptide in the presence of the enzyme resulted in the formation of the farnesylated product. Additionally, incubation of human ovarian carcinoma (SKOV3) cells with an NDBF-caged version of a farnesylated peptide followed by UV irradiation resulted in migration of the peptide from the cytosol/Golgi to the plasma membrane due to enzymatic palmitoylation. Overall, the high cleavage efficiency devoid of side reactions and significant two-photon cross-section of NDBF render it superior to Bhc for thiol group caging. This protecting group should be useful for a plethora of applications ranging from the development of light-Activatable cysteine-containing peptides to the development of light-sensitive biomaterials.

Original languageEnglish (US)
Pages (from-to)5848-5859
Number of pages12
JournalJournal of the American Chemical Society
Volume138
Issue number18
DOIs
StatePublished - May 11 2016

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Photons
Sulfhydryl Compounds
Peptides
Cysteine
Light
Irradiation
Lipoylation
Solid-Phase Synthesis Techniques
Proteins
Photoisomerization
Photolysis
Biocompatible Materials
Sulfides
Cell membranes
Cytosol
Isomerization
Biomaterials
Cell Membrane
Enzymes
Carcinoma

Cite this

Nitrodibenzofuran : A One-and Two-Photon Sensitive Protecting Group That Is Superior to Brominated Hydroxycoumarin for Thiol Caging in Peptides. / Mahmoodi, M. Mohsen; Abate-Pella, Daniel; Pundsack, Tom J.; Palsuledesai, Charuta C.; Goff, Philip C.; Blank, David A.; Distefano, Mark D.

In: Journal of the American Chemical Society, Vol. 138, No. 18, 11.05.2016, p. 5848-5859.

Research output: Contribution to journalArticle

Mahmoodi, M. Mohsen ; Abate-Pella, Daniel ; Pundsack, Tom J. ; Palsuledesai, Charuta C. ; Goff, Philip C. ; Blank, David A. ; Distefano, Mark D. / Nitrodibenzofuran : A One-and Two-Photon Sensitive Protecting Group That Is Superior to Brominated Hydroxycoumarin for Thiol Caging in Peptides. In: Journal of the American Chemical Society. 2016 ; Vol. 138, No. 18. pp. 5848-5859.
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abstract = "Photoremovable protecting groups are important for a wide range of applications in peptide chemistry. Using Fmoc-Cys(Bhc-MOM)-OH, peptides containing a Bhc-protected cysteine residue can be easily prepared. However, such protected thiols can undergo isomerization to a dead-end product (a 4-methylcoumarin-3-yl thioether) upon photolysis. To circumvent that photoisomerization problem, we explored the use of nitrodibenzofuran (NDBF) for thiol protection by preparing cysteine-containing peptides where the thiol is masked with an NDBF group. This was accomplished by synthesizing Fmoc-Cys(NDBF)-OH and incorporating that residue into peptides by standard solid-phase peptide synthesis procedures. Irradiation with 365 nm light or two-photon excitation with 800 nm light resulted in efficient deprotection. To probe biological utility, thiol group uncaging was carried out using a peptide derived from the protein K-Ras4B to yield a sequence that is a known substrate for protein farnesyltransferase; irradiation of the NDBF-caged peptide in the presence of the enzyme resulted in the formation of the farnesylated product. Additionally, incubation of human ovarian carcinoma (SKOV3) cells with an NDBF-caged version of a farnesylated peptide followed by UV irradiation resulted in migration of the peptide from the cytosol/Golgi to the plasma membrane due to enzymatic palmitoylation. Overall, the high cleavage efficiency devoid of side reactions and significant two-photon cross-section of NDBF render it superior to Bhc for thiol group caging. This protecting group should be useful for a plethora of applications ranging from the development of light-Activatable cysteine-containing peptides to the development of light-sensitive biomaterials.",
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AU - Abate-Pella, Daniel

AU - Pundsack, Tom J.

AU - Palsuledesai, Charuta C.

AU - Goff, Philip C.

AU - Blank, David A.

AU - Distefano, Mark D.

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