ArticleJournal of the American Chemical Society2016
Convergent and Modular Synthesis of Candidate Precolibactins. Structural Revision of Precolibactin A.
Article in Journal of the American Chemical Society, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 47 citations in OpenAlex.
- Stage-Specific carcinogenic mechanisms and intervention strategies for pksArchives of microbiology · 2026Review
- Mass spectrometry-based metabolomics approaches to interrogate host-microbiome interactions in mammalian systems.Natural product reports · 2026Review
- Structure Elucidation of Secondary Metabolites: Current Frontiers and Lingering Pitfalls.Accounts of chemical research · 2023Article
- Screening method toward ClbP-specific inhibitors.Genes and environment : the official journal of the Japanese Environmental Mutagen Society · 2023Article
- The microbiome-product colibactin hits unique cellular targets mediating host-microbe interaction.Frontiers in pharmacology · 2022Review
- On the Stability and Spectroscopic Properties of 5-Hydroxyoxazole-4-carboxylic Acid Derivatives.Organic letters · 2021Article
- Employing chemical synthesis to study the structure and function of colibactin, a "dark matter" metabolite.Natural product reports · 2020Review
- Structure and bioactivity of colibactin.Bioorganic & medicinal chemistry letters · 2020Review
- Colibactin DNA-damage signature indicates mutational impact in colorectal cancer.Nature medicine · 2020Article
- Oral and intestinal bacterial exotoxins: Potential linked to carcinogenesis.Progress in molecular biology and translational science · 2020Review
- Synthesis and reactivity of precolibactin 886.Nature chemistry · 2019Article
- Structure elucidation of colibactin and its DNA cross-links.Science (New York, N.Y.) · 2019Article
- The human gut bacterial genotoxin colibactin alkylates DNA.Science (New York, N.Y.) · 2019Article
- Model Colibactins Exhibit Human Cell Genotoxicity in the Absence of Host Bacteria.ACS chemical biology · 2018Article
- Colibactin: More Than a New Bacterial Toxin.Toxins · 2018Review
- ClbS Is a Cyclopropane Hydrolase That Confers Colibactin Resistance.Journal of the American Chemical Society · 2017Article
- Molecular Basis of Gut Microbiome-Associated Colorectal Cancer: A Synthetic Perspective.Journal of the American Chemical Society · 2017Review
- Structure and Functional Analysis of ClbQ, an Unusual Intermediate-Releasing Thioesterase from the Colibactin Biosynthetic Pathway.ACS chemical biology · 2017Article
- Natural product discovery from the human microbiome.The Journal of biological chemistry · 2017Review
- Domain-Targeted Metabolomics Delineates the Heterocycle Assembly Steps of Colibactin Biosynthesis.Journal of the American Chemical Society · 2017Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.