The Application of Freidinger Lactams and their Analogs in the Design of Conformationally Constrained Peptidomimetics

Abstract

Peptides exist in solution as an equilibrium mixture of conformers. The backbone conformational constraints are of interest as a means of limiting degrees of freedom and thereby constraining a synthetic peptide into the bioactive conformation. This concept plays an important role in the design of peptidomimetics in the drug development process. In the early eighties, Freidinger proposed the concept of protected lactam-bridged dipeptides, which was a milestone in the design of conformationally constrained peptides. These types of compounds, now widely known as Freidinger lactams, have been of interest to many medicinal and peptide chemists. This review seeks to present the various applications that Freidinger lactams and their hetero-, fused- and unsaturated analogs have found in the design of conformationally constrained peptidomimetics in different therapeutic areas.

Turning Peptide Sequences into Ribbon Foldamers by a Straightforward Multicyclization Reaction

“…[6] Herein, we propose as trategy to generate novel folded architectures based on a-amino-g-lactam derivatives (Agl-AA x with AA x = amino acid), so-called Freidingers lactams, [9,10] widely used as type II b-turn inducers in relevant bioactive peptides. [11] This strategy has several advantages. First, only a-amino acids are used as starting material, enabling easy access to these new foldamers and the possibility of using conventional solid-phase peptide synthesis (SPPS) methods.S econd, the structurally constrained blocks are generated in the course of the SPPS,a voiding the preparation of each dipeptide lactam unit prior to the construction of the oligomers.S olid-phase methods for the on-line synthesis of peptides containing as ingle a-amino-glactam unit have been reported.…”

Geometrically Constrained Derivatives of Indolylglyoxylamides as Ligands Binding the GABAA/BzR Complex

“…Derivatives bearing a 9-chloro substituent, (45)(46)(47)(48)(49), generally turned out to be more potent than the 9-unsubstituted ones, (38)(39)(40)(41)(42)(43)(44), showing a 2-to 8-fold affinity improvement. According to the authors' hypothesis, the electronwithdrawing effect of the halogen atom reasonably increased Fig.…”

New isosteres of (R)-2-methylhomoserine and (R)-2-methylaspartic acid by alkylation of a chiral imine leading stereoselectively to a quaternary stereogenic center

“…5 Eventually, incorporation of amino acids isosteres into proteins that carry conformational restrictions due to rigidity elements such as double bonds, carbocyclic, or heterocyclic rings is a versatile technique for affecting or enhancing their biological activity. 7 Therefore, the development of methods for the stereoselective synthesis of 3,3,4-trisubstituted pyrrolidin-2-ones is of growing interest directed toward the preparation of strongly conformationally restricted analogues of naturally occurring amino acids.…”