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Photoactivated Colibactin Probes Induce Cellular DNA Damage
Author(s) -
Moodie Lindon W. K.,
Hubert Madlen,
Zhou Xin,
Albers Michael F.,
Lundmark Richard,
Wanrooij Sjoerd,
Hedberg Christian
Publication year - 2019
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201812326
Subject(s) - prodrug , dna , genotoxicity , dna damage , biology , bacteria , biochemistry , small molecule , chemistry , microbiology and biotechnology , genetics , organic chemistry , toxicity
Colibactin is a small molecule produced by certain bacterial species of the human microbiota that harbour the pks genomic island. Pks + bacteria induce a genotoxic phenotype in eukaryotic cells and have been linked with colorectal cancer progression. Colibactin is produced in a benign, prodrug form which, prior to export, is enzymatically matured by the producing bacteria to its active form. Although the complete structure of colibactin has not been determined, key structural features have been described including an electrophilic cyclopropane motif, which is believed to alkylate DNA. To investigate the influence of the putative “warhead” and the prodrug strategy on genotoxicity, a series of photolabile colibactin probes were prepared that upon irradiation induced a pks + like phenotype in HeLa cells. Furthermore, results from DNA cross‐linking and imaging studies of clickable analogues enforce the hypothesis that colibactin effects its genotoxicity by directly targeting DNA.