New β-strand macrocyclic peptidomimetic analogues containing α-(O-, S- or NH-)aryl substituted glycine residues: synthesis, chemical and enzymatic properties

Organic & Biomolecular Chemistry Pub Date: 2003-04-07 DOI: 10.1039/B211644H

Abstract

In so much as bis-macrocyclic peptidomimetics have been recognized as high affinity substrates for HIV-1 protease, we were interested in the design and synthesis of new bis-macrocyclic bioisosteric analogues whose general structure is displayed on Fig. 2. The structures of these new analogues are characterized by the specific replacement of the methylene of the benzyl group directly attached to the N-acyl glycine residue in the original molecule 1, by its main bioisosteres, i.e. O-, S- and NH-aryl groups. Knowing that an intermediate in which an heteroatomic aryl group is directly linked to a free amine glycine residue is not stable, we developed an original synthetic pathway which involved the coupling of a specific side chain to the exocyclic carboxylic acid function, followed by an elegant oxidation–nucleophilic substitution Steglich-type reaction. Analogues 2a–d were then submitted to chemical and enzymatic hydrolysis. We demonstrated that, as expected, the specific cleavage of the exocyclic N-acyl bond led to the release of aryl moieties (phenol, thiophenol and aniline species). These chemical and enzymatic stability studies brought to light the biological potential of such macrocyclic analogues in infected cells.

Graphical abstract: New β-strand macrocyclic peptidomimetic analogues containing α-(O-, S- or NH-)aryl substituted glycine residues: synthesis, chemical and enzymatic properties
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