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J Am Chem Soc. 2016 Apr 27;138(16):5426-32. doi: 10.1021/jacs.6b02276. Epub 2016 Apr 12.

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

Author information

1
Department of Chemistry, Yale University , New Haven, Connecticut 06520, United States.
2
Chemical Biology Institute, Yale University , West Haven, Connecticut 06516, United States.
3
Department of Microbial Pathogenesis, Yale School of Medicine , New Haven, Connecticut 06536, United States.
4
Department of Pharmacology, Yale School of Medicine , New Haven, Connecticut 06520, United States.

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.

PMID:
27025153
PMCID:
PMC5049697
DOI:
10.1021/jacs.6b02276
[Indexed for MEDLINE]
Free PMC Article

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