Amides, bond replacements

D. E. Benovitz, A. F. Spatola, Enkephalin Pseudopeptides Resistance to in vitro Proteolytic Degradation Afforded by Amide Bond Replacements Extends to Remote Sites , Peptides 1985, 6, 257 - 261. 

Robust peptide-derived approaches aim to identify a small drug-like molecule to mimic the peptide interactions. The primary peptide molecule is considered in these approaches as a tool compound to demonstrate that small molecules can compete with a given interaction. A variety of chemical, 3D structural and molecular modeling approaches are used to validate the essential 3D pharmacophore model which in turn is the basis for the design of the mimics. The chemical approaches include in addition to N- and C-terminal truncations a variety of positional scanning methods. Using alanine scans one can identify the key pharmacophore points D-amino-acid or proline scans allow stabilization of (i-turn structures cyclic scans bias the peptide or portions of the peptide in a particular conformation (a-helix, (i-turn and so on) other scans, like N-methyl-amino-acid scans and amide-bond-replacement (depsi-peptides) scans aim to improve the ADME properties." ... 

Synthesis of funtionalized (Z)-fluoroalkene-type dipeptide isosteres (36) via Sml2-mediated reduction of y,y-difluoro-ot, -enoates 2.3.19. Reductive formation of fluoroolefins and subsequent conversion to diketopiperazine mimics (71). Nonpeptidic amide bond replacement... 

P. Wipf, T.C. Henninger, Solid-phase synthesis of peptide mimetics with ( )-alkene amide bond replacements derived from alkenylaziridines, J. Org. Chem. 62 (1997) 1586-1587. 

Sections 10.5 through 10.8 envisage single or, more commonly, multiple replacements of the peptide bond functionality. In particular, substitutions characterized by single, double, or triple C—C bonds are covered in Section 10.5, while substitutions containing C/O, C/N, and C/N/O amide bond replacements are described in Sections 10.6,10.7, and 10.8, respectively. Sections 10.9 and 10.10 focus on the known types of sulfur- or phosphorus-based peptide bond replacements, 1,2 6 7 including different oxidation states of the heteroatoms. 

Volume E 22 10.6 Synthesis of Peptides Containing C/O Amide Bond Replacements... 

The C/O amide bond replacements include methyleneoxy, 1-hydroxyethylene, 2-hydro-xyethylene, 1,2-dihydroxyethylene, 1-oxoethylene, and epoxide isosteres. This chapter focuses on the synthetic methods of dipeptide building blocks containing these isosteres. 

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