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Total Synthesis and Antimycobacterial Activity of Ohmyungsamycin A, Deoxyecumicin, and Ecumicin
Author(s) -
Hawkins Paige M. E.,
Tran Wendy,
Nagalingam Gayathri,
Cheung ChenYi,
Giltrap Andrew M.,
Cook Gregory M.,
Britton Warwick J.,
Payne Richard J.
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202002408
Subject(s) - antimycobacterial , natural product , depsipeptide , mycobacterium tuberculosis , chemistry , residue (chemistry) , tuberculosis , total synthesis , biological activity , stereochemistry , microbiology and biotechnology , biology , biochemistry , medicine , in vitro , pathology
Abstract The ohmyungsamycin and ecumicin natural product families are structurally related cyclic depsipeptides that display potent antimycobacterial activity. Herein the total syntheses of ohmyungsamycin A, deoxyecumicin, and ecumicin are reported, together with the direct biological comparison of members of these natural product families against Mycobacterium tuberculosis ( Mtb ), the etiological agent of tuberculosis (TB). The synthesis of each of the natural products employed a solid‐phase strategy to assemble the linear peptide precursor, involving a key on‐resin esterification and an optional on‐resin dimethylation step, before a final solution‐phase macrolactamization between the non‐proteinogenic N ‐methyl‐4‐methoxy‐ l ‐tryptophan amino acid and a bulky N ‐methyl‐ l ‐valine residue. The synthetic natural products possessed potent antimycobacterial activity against Mtb with MIC 90 ’s ranging from 110–360 n m and retained activity against Mtb in Mtb ‐infected macrophages. Deoxyecumicin also exhibited rapid bactericidal killing against Mtb , sterilizing cultures after 21 days.