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Synthesis

Cyclic peptides with heterocycles are cell membrane-permeable

Oxadiazole-containing peptidomimetic macrocycles have potential as drugs

by Stu Borman
October 31, 2016 | APPEARED IN VOLUME 94, ISSUE 43

Peptides, including cyclic peptides, generally don’t cross cell membranes easily, a property that has limited their use in medicine. Researchers have now boosted the drug potential of cyclic peptides by incorporating a heterocycle into their rings. Andrei Yudin and coworkers at the University of Toronto adapted an existing reaction to convert linear peptides into the heterocycle-containing peptidomimetics (Nat. Chem. 2016, DOI: 10.1038/nchem.2636). The one-step reaction of a linear peptide with a variable aldehyde and (N-isocyanimino)triphenylphosphorane doesn’t require peptide preactivation, as most current peptide cyclization reactions do. Yudin and coworkers demonstrated the reaction by constructing 15-, 18-, 21-, and 24-membered peptidomimetic macrocycles, each containing 1,3,4-oxadiazole and an amine. The high cell-membrane permeability of many of the macrocycles and their conformationally rigid structures are both important prerequisites for bioavailability and therapeutic use. The researchers’ ultimate goal is to develop the peptidomimetics as inhibitors of intracellular protein-protein interactions. The phosphorane reagent “is being commercialized by Sigma-Aldrich, which will make this macrocyclization accessible to the chemistry community,” Yudin says.

This reaction converts linear peptides (left) to cyclic peptidomimetics with an oxadiazole ring and an amine. R is a variable group; Ph is phenyl.
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