Modular Chemoenzymatic Synthesis of GE81112 B1 and Related Analogues Enables Elucidation of Its Key Pharmacophores
- 8 January 2021
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 143 (3), 1673-1679
- https://doi.org/10.1021/jacs.0c13424
Abstract
The GE81112 complex has garnered much interest due to its broad antimicrobial properties and unique ability to inhibit bacterial translation initiation. Herein we report the use of a chemoenzymatic strategy to complete the first total synthesis of GE81112 B1. By pairing iron and α-ketoglutarate dependent hydroxylases found in GE81112 biosynthesis with traditional synthetic methodology, we were able to access the natural product in 11 steps (longest linear sequence). Following this strategy, 10 GE81112 B1 analogues were synthesized, allowing for identification of its key pharmacophores. A key feature of our medicinal chemistry effort is the incorporation of additional biocatalytic hydroxylations in modular analogue synthesis to rapidly enable exploration of relevant chemical space.Keywords
Funding Information
- National Institute of General Medical Sciences (GM128895)
This publication has 43 references indexed in Scilit:
- Insights into an Unusual Nonribosomal Peptide Synthetase BiosynthesisOnline Journal of Public Health Informatics, 2010
- Characterization of novel 2-oxoglutarate dependent dioxygenases converting l-proline to cis-4-hydroxy-l-prolineBiochemical and Biophysical Research Communications, 2009
- Straightforward Access to Protected syn α‐Amino‐β‐hydroxy Acid DerivativesAngewandte Chemie, 2008
- Dioxirane Oxidations of Compounds other than AlkenesPublished by Wiley ,2008
- Evolution of the Total Syntheses of Ustiloxin Natural Products and Their AnaloguesJournal of the American Chemical Society, 2008
- Novel Tetrapeptide Inhibitors of Bacterial Protein Synthesis Produced by a Streptomyces sp.Biochemistry, 2006
- Synthesis of L-(+)-ErgothioneineThe Journal of Organic Chemistry, 1995
- Synthesis and Properties of a 2-Diazohistidine Derivative: A New Photoactivatable Aromatic Amino-Acid AnalogHelvetica Chimica Acta, 1990
- Novel chlorinatin of the 1,3,4‐thiadiazole ringJournal of Heterocyclic Chemistry, 1980
- The Displacement of Aromatic Substituents by Halogen Atoms1Journal of the American Chemical Society, 1957