Total Synthesis and Conformational Study of Callyaerin A: Anti-Tubercular Cyclic Peptide Bearing a Rare Rigidifying (Z)-2,3- Diaminoacrylamide Moiety

Angew Chem Int Ed Engl. 2018 Mar 26;57(14):3631-3635. doi: 10.1002/anie.201712792. Epub 2018 Feb 14.

Abstract

The first synthesis of the anti-TB cyclic peptide callyaerin A (1), containing a rare (Z)-2,3-diaminoacrylamide bridging motif, is reported. Fmoc-formylglycine-diethylacetal was used as a masked equivalent of formylglycine in the synthesis of the linear precursor to 1. Intramolecular cyclization between the formylglycine residue and the N-terminal amine in the linear peptide precursor afforded the macrocyclic natural product 1. Synthetic 1 possessed potent anti-TB activity (MIC100 =32 μm) while its all-amide congener was inactive. Variable-temperature NMR studies of both the natural product and its all-amide analogue revealed the extraordinary rigidity imposed by this diaminoacrylamide unit on peptide conformation. The work reported herein pinpoints the intrinsic role that the (Z)-2,3-diaminoacrylamide moiety confers on peptide bioactivity.

Keywords: conformation analysis; cyclizations; drug discovery; natural products; peptides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylamide / chemistry
  • Amino Acid Sequence
  • Amino Acids / chemistry
  • Antitubercular Agents / chemical synthesis*
  • Biological Products / chemical synthesis*
  • Catalysis
  • Cyclization
  • Oxidation-Reduction
  • Peptides, Cyclic / chemical synthesis*
  • Protein Conformation

Substances

  • Amino Acids
  • Antitubercular Agents
  • Biological Products
  • Peptides, Cyclic
  • callyaerin A
  • Acrylamide