- Convergent and Modular Synthesis of Candidate Precolibactins. Structural Revision of Precolibactin A
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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.
- Healy, Alan R.,Vizcaino, Maria I.,Crawford, Jason M.,Herzon, Seth B.
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- DNA ALKYLATION AND CROSS-LINKING AGENTS AS COMPOUNDS AND PAYLOADS FOR TARGETED THERAPIES
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The present invention is directed to compounds related to precolibactin, pharmaceutical compositions based upon these compounds and methods of synthesis which are employed to provide intermediates and final compounds, which are principally alkylating agents and anticancer compounds. The chemical synthetic approach disclosed facilitates the synthesis of numerous precolibactin analogs which can be used in the treatment of cancer.
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Page/Page column 120
(2017/08/22)
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- Synthesis of the cyclo- Isomers of Dolastatin 3
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An all-L configuration reverse order of peptide bonding possibility for the cell growth inhibitory (PS system) cyclic peptide dolastatin 3 was eliminated by synthesis of thiazole amino acid containing peptide 2.By employing a series (Schema I) of mixed ca
- Pettit, George R.,Nelson, Paul S.,Holzapfel, Cedric W.
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p. 2654 - 2659
(2007/10/02)
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