Directed Crosslinking of RNA by Glutathione‐Triggered PNA‐Quinone‐Methide‐Conjugates

Quinone methide precursors protected with alkyldithiomethyl groups have been synthesized and converted into PNA conjugates. Stable in the absence of reducing agents, the electrophilic quinone methide is released by glutathione in concentrations typical for the cytosol. Self‐alkylation then occurs or...

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Bibliographic Details
Published in:European journal of organic chemistry 2022-09, Vol.2022 (33), p.n/a
Main Authors: Hornung, Jan‐Erik, Weinrich, Timo, Göbel, Michael W.
Format: Article
Language:English
Subjects:
Alkylation
Alkylation of RNA
Antisense agents
Conjugates
Crosslinking
Disulfide bond
Glutathione
Peptide nucleic acids
Quinones
Reducing agents
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Summary:Quinone methide precursors protected with alkyldithiomethyl groups have been synthesized and converted into PNA conjugates. Stable in the absence of reducing agents, the electrophilic quinone methide is released by glutathione in concentrations typical for the cytosol. Self‐alkylation then occurs or crosslinking of RNA when hybridized with complementary strands. Fastest reactions are seen for the sterically least hindered compound. PNA conjugates of redox‐labile quinone methide precursors can be activated by glutathione at concentrations typical for the cytosol. The quinone methide, an electrophilic short‐lived intermediate, then reacts with nucleophiles. When the PNA part is hybridized with a complementary strand of RNA, directed alkylation of the nucleobases can form crosslinks in yields up to 71 %.
ISSN:1434-193X
1099-0690
DOI:10.1002/ejoc.202200318