title: The practice of ring constraint in peptidomimetics using bicyclic and polycyclic amino acids.
abstract: Medicinal chemistry has witnessed major advances with the discovery of small synthetic molecules that mimic natural peptidic substrates. These small synthetic mimics do not undergo proteolytic degradation, an advantage they hold over their natural counterparts. Small synthetic molecules make up a number of life-saving marketed drugs that inhibit certain physiologically relevant proteases. The advent of sophisticated instrumental methods, such as X-ray crystallography and high-field NMR, has played a pivotal role in the design of structure-based enzyme inhibitors. Highly stereocontrolled methods of synthesis have led to a variety of functionally diverse molecules that function as peptidomimetics because they have isosteric subunits not affected by proteolytic enzymes. Further studies to optimize biological activity and achieve desirable pharmacokinetic profiles can eventually lead to drug substances. The practice of constraining natural amino acids like their conformationally rigid counterparts has been highly successful in the design and synthesis of peptidomimetic molecules. With some notable exceptions, structural information gathered from protein X-ray crystallography of therapeutically relevant target enzymes, alone or in complex forms with inhibitor molecules, has been instrumental in the design of peptidomimetics. For example, a significant number have become marketed drugs as antihypertensives and antivirals. Natural products have also been a source of inspiration for the design and synthesis of truncated analogues with the intention of maintaining, or even improving, their biological activities. However, lower molecular weight peptides are not suitable as therapeutic agents because they are subject to rapid amide proteolysis. They are poorly transported to the brain and rapidly excreted through the liver and kidney. Thus, lower molecular weight peptides are eliminated as potential drug substances in clinical practice. A synthetic peptidomimetic is needed that is resistant to cleavage but maintains its biological activity. Conformationally constrained monocyclic and bicyclic unnatural amino acids can be directly incorporated in a potential inhibitor molecule as part of the design element. In this Account, we describe our efforts in the synthesis of constrained azacycles that contain proline or pipecolic acid as an integral part of bicyclic and polycyclic amino acids. We devised syntheses of conformationally biased monocyclic, bicyclic, and polycyclic amino acid analogues, into which pharmacologically or structurally relevant functional groups were incorporated. Stereocontrolled reactions for C-C, C-N, and C-O bond formation had to be implemented on appropriately protected amino acid frameworks. A number of these frameworks provided access to functionally diverse scaffolds for further use as core subunits in more elaborated structures. Specific applications as peptidomimetics of natural substrates for relevant enzymes, such as thrombin, were also pursued, resulting in highly active inhibitors in vitro.
authors.affiliation: Department of Chemistry, Universite de Montreal, P.O. Box 6128, Station Centre-ville, Montreal, Quebec H3C 3J7, Canada. stephen.hanessian@umontreal.ca
authors.forename: Stephen
authors.initials: S
authors.lastname: Hanessian
authors.forename: Luciana
authors.initials: L
authors.lastname: Auzzas
mesh_terms: D000588:Amines / Q000737:chemistry; D000598:Amino Acids, Cyclic / Q000737:chemistry*; D040761:Biomimetic Materials / Q000737:chemistry*; D002264:Carboxylic Acids / Q000737:chemistry; D002384:Catalysis; D008697:Methane / Q000737:chemistry; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D010875:Pipecolic Acids / Q000737:chemistry; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: C520392:4,5-methanoproline; D000588:Amines; D000598:Amino Acids, Cyclic; D002264:Carboxylic Acids; D010455:Peptides; D010875:Pipecolic Acids; D011392:Proline; C031345:pipecolic acid; D008697:Methane