Synthesis of isopeptide epoxide peptidomimetics

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Biochemistry

Background:

• Enzymes hydrolyzing peptides and isopeptides are vulnerable to inactivation by electrophilic substrate analogs.
• Electrophilic analogs can irreversibly inhibit enzyme activity by forming covalent bonds.

Purpose of the Study:

• To synthesize novel epoxide-containing peptidomimetics of glutamyl-gamma-glutamate.
• To develop a general synthetic route for isopeptide analogs with an oxirane replacing the scissile peptide bond.
• To create potential enzyme inhibitors targeting peptide and isopeptide hydrolysis.

Main Methods:

• Stereospecific synthesis of cyclopentene surrogates for L- and D-glutamate enantiomers.
• Julia-Kocienski olefination to form E-olefin isosteres.
• Peracid-mediated epoxidation and deprotection to yield final epoxide-containing peptidomimetics.

Main Results:

• Successful synthesis of two epoxide-containing peptidomimetics (compounds 4 and 5).
• The synthetic route is adaptable for various isopeptide analogs.
• The synthesized compounds mimic the isopeptide bond with an electrophilic oxirane.

Conclusions:

• The developed synthetic strategy provides access to novel epoxide-containing isopeptide analogs.
• These peptidomimetics serve as electrophilic replacements for scissile isopeptide bonds.
• The findings contribute to the design of enzyme inhibitors for peptide and isopeptide hydrolases.