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

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

Author information

1
School of Chemical Sciences, The University of Auckland, 23 Symonds St, Auckland, 1142, New Zealand.
2
Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, 1142, New Zealand.
3
Department of Microbiology and Immunology, University of Otago, Dunedin, 9054, New Zealand.

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

PMID:
29345033
DOI:
10.1002/anie.201712792

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