Backbone cyclization: A new method for conferring conformational constraint on peptides

This article describes a new concept of medium‐ and long‐range cyclization of peptides through “backbone cyclization.” In this approach, conformational constraints are conferred on a peptide by linking ω‐substituted alkylidene chains replacing N^α or C^α hydrogens in a peptidic backbone. Backbone cyclization, which is divided into N‐backbone and C‐backbone cyclizations, allow for new modes of cyclization in addition to the classical ones that are limited to cyclization through the side chains and/or the amino or carboxyl terminal groups. The article also describes the application of the N‐backbone cyclization to the active region of substance P. Conformational constraints of this peptide by the classical cyclization modes led to inactive analogues whereas N‐backbone cyclization provided an active, selective, and metabolically stable analogue.