Syntheses of Peptidomimetics Based on Pyranose and Polyhydroxylated Piperidine Scaffolds

Abstract

There has been significant progress in application of pyranoses and related compounds towards drug discovery and development. This review focuses on strategies for grafting of pharmacophore groups at selected positions on pyranoside and related iminosugar scaffolds. Recent developments in the solid phase synthesis of prospecting combinatorial libraries, syntheses of pyranose based sugar amino acids (SAAs) and other scaffolding for peptidomimetics are included. Although no drug molecule has been developed a number of novel potent ligands for receptors have been identified. It has been shown that these pyranoside derivatives could have improved cellular permeability over peptides. Progress in this area is continually dependant on advances in synthetic carbohydrate chemistry both in solution and on solid phase. These include the development of orthogonal protecting group strategies, strategies for regioselective manipulation of pyranoside hydroxyl groups and strategies that could take increasing advantage of chemoselective reactions. In addition a greater understanding of structural carbohydrate chemistry and the preferred orientations of groups attached to pyranose scaffolds may facilitate synthesis of more potent ligands for receptors.

Iterative Multifunctionalization of Unactivated C−H Bonds in Piperidines by Way of Intramolecular Rh(II)-Catalyzed Aminations

“…Direct application to the total synthesis of iminosugars and related compounds demonstrates the synthetic potential of this strategy which should become a useful tool for the diversity-oriented synthesis of various bioactive azacycloalkanes by iterative and direct heterocyclic scaffold decoration. Recent studies have for example shown the interest of grafting pharmacophore groups at selected positions on piperidine scaffolds . Following these lines, we are currently devising various nitrogen-containing systems (cyclic or acyclic) to further expand the synthetic scope of this chemistry.…”

Synthesis of a Benzomacrolactone-Based Somatostatin Mimetic

“…During the early 1990s, Hirschmann and colleagues at the University of Pennsylvania introduced the use of β- d -glucose, its enantiomers, and a diastereomer (β- d -mannose) as scaffolds for the synthesis of ligands for the somatostatin, the substance P, and the β 2 -adrenergic receptors . Since this contribution, monosaccharides, due to their polyfunctional nature, have been a basis for generating a wide range of compounds for screening. The glucopyranoside 3 (Scheme ) prepared by the Hirschmann group, and containing the lysine, tryptophan, and phenylalanine side chains of 1 , was found to be a ligand for somatostatin receptors, indicating that truncated mimetics are of interest.…”