Convergent and Modular Synthesis of Candidate Precolibactins. Structural Revision of Precolibactin A

Alan Healy, Maria I. Vizcaino, Jason M. Crawford, Seth B. Herzon

Research output: Contribution to journalArticle

Abstract

The colibactins are hybrid polyketide-nonribosomal peptide natural products produced by certain strains of commensal and extraintestinal pathogenic Escherichia coli. The metabolites are encoded by the clb gene cluster as prodrugs termed precolibactins. clb+ E. coli induce DNA double-strand breaks in mammalian cells in vitro and in vivo and are found in 55-67% of colorectal cancer patients, suggesting that mature colibactins could initiate tumorigenesis. However, elucidation of their structures has been an arduous task as the metabolites are obtained in vanishingly small quantities (μg/L) from bacterial cultures and are believed to be unstable. Herein we describe a flexible and convergent synthetic route to prepare advanced precolibactins and derivatives. The synthesis proceeds by late-stage union of two complex precursors (e.g., 28 + 17 → 29a, 90%) followed by a base-induced double dehydrative cascade reaction to form two rings of the targets (e.g., 29a → 30a, 79%). The sequence has provided quantities of advanced candidate precolibactins that exceed those obtained by fermentation, and is envisioned to be readily scaled. These studies have guided a structural revision of the predicted metabolite precolibactin A (from 5a or 5b to 7) and have confirmed the structures of the isolated metabolites precolibactins B (3) and C (6). Synthetic precolibactin C (6) was converted to N-myristoyl-d-asparagine and its corresponding colibactin by colibactin peptidase ClbP. The synthetic strategy outlined herein will facilitate mechanism of action and structure-function studies of these fascinating metabolites, and is envisioned to accommodate the synthesis of additional (pre)colibactins as they are isolated.

Original languageEnglish (US)
Pages (from-to)5426-5432
Number of pages7
JournalJournal of the American Chemical Society
Volume138
Issue number16
DOIs
StatePublished - Apr 27 2016

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Metabolites
Escherichia coli
Polyketides
Double-Stranded DNA Breaks
Asparagine
Prodrugs
Multigene Family
Biological Products
Fermentation
Peptides
Colorectal Neoplasms
Carcinogenesis
DNA
Peptide Hydrolases
Genes
Cells
colibactin
Derivatives

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Convergent and Modular Synthesis of Candidate Precolibactins. Structural Revision of Precolibactin A. / Healy, Alan; Vizcaino, Maria I.; Crawford, Jason M.; Herzon, Seth B.

In: Journal of the American Chemical Society, Vol. 138, No. 16, 27.04.2016, p. 5426-5432.

Research output: Contribution to journalArticle

Healy, Alan ; Vizcaino, Maria I. ; Crawford, Jason M. ; Herzon, Seth B. / Convergent and Modular Synthesis of Candidate Precolibactins. Structural Revision of Precolibactin A. In: Journal of the American Chemical Society. 2016 ; Vol. 138, No. 16. pp. 5426-5432.
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