Reactivity of Pyrrol‐2‐ones

Egorova, A. Yu.; Timofeeva, Z. Yu.

doi:10.1002/chin.200524256

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“…4a ). NMR solution studies demonstrate that 2-hydroxypyrroles with acyl-substituents in the 3-position, such as the proposed alkylated-intermediate, strongly favor their keto-tautomeric forms 36 , as shown boxed in Figure 4a . Intriguingly, this suggests that upon alkylation, colibactin could present a second Michael acceptor, expanding its covalent functional utilities relative to the duocarmycins.…”

Section: Resultsmentioning

confidence: 95%

The colibactin warhead crosslinks DNA

2015

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Members of the human microbiota are increasingly being correlated to human health and disease states, but the majority of the underlying microbial metabolites that regulate host-microbe interactions remain largely unexplored. Select strains of E. coli present in the human colon have been linked to initiating inflammation-induced colorectal cancer through an unknown small molecule-mediated process. The responsible nonribosomal peptide-polyketide hybrid pathway encodes “colibactin,” a largely uncharacterized family of small molecules. Genotoxic small molecules from this pathway capable of initiating cancer formation have remained elusive due to their high instability. Guided by metabolomic analyses, here we employ a combination of NMR spectroscopy and bioinformatics-guided isotopic labeling studies to characterize the colibactin warhead, an unprecedented substituted spirobicyclic structure. The warhead crosslinks duplex DNA in vitro, providing direct experimental evidence for colibactin’s DNA-damaging activity. The data support unexpected models for both colibactin biosynthesis and its mode of action.

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Section: Resultsmentioning

confidence: 95%