Nitrosopyridine Probe To Detect Polyketide Natural Products with Conjugated Alkenes: Discovery of Novodaryamide and Nocarditriene
Abstract
An optimized nitroso-based probe that facilitates the discovery of conjugated alkene-containing natural products in unprocessed extracts was developed. It chemoselectively reacts with conjugated olefins via a nitroso-Diels-Alder cyclization to yield derivatives with a distinct chromophore and an isotopically unique bromine atom that can be rapidly identified using liquid chromatography/mass spectrometry and a bioinformatics tool called MeHaloCoA (Marine Halogenated Compound Analysis). The probe is ideally employed when genome-mining techniques identify strains containing polyketide gene clusters with two or more repeating KS-AT-DH-KR-ACP domain sequences, which are required for the biosynthesis of conjugated alkenes. Comparing the reactivity and spectral properties of five brominated arylnitroso reagents with model compounds spiramycin, bufalin, rapamycin, and rifampicin led to the identification of 5-bromo-2-nitrosopyridine as the most suitable probe structure. The utility of the dienophile probe was then demonstrated in bacterial extracts. Tylactone, novodaryamide and daryamide A, piperazimycin A, and the saccharamonopyrones A and B were cleanly labeled in extracts from their respective bacterial producers, in high regioselectivity but with varying degrees of diastereoselectivity. Further application of the method led to the discovery of a new natural product called nocarditriene, containing an unprecedented epoxy-2,3,4,5-tetrahydropyridine structure, from marine-derived Nocardiopsis strain CNY-503.
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The practice of labeling functional groups in uncharacterized NP mixtures using a non-targeted metabolomics approach is uncommon in NP discovery, and there are currently only a few existing examples.
“Although these approaches have been in certain cases efficiently applied for NP discovery, the practice of labeling functional groups in uncharacterized NP mixtures using a non-targeted metabolomics approach is uncommon in NP discovery, and there are currently only a few existing examples.124–128”
From Connecting metabolome and phenotype: recent advances in functional metabolomics tools for the identification of bioactive natural products (2024) · cites this paper as [126]
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Self-citation
- Authors
- Castro-Falcón, G., Millán-Aguiñaga, N., Roullier, C., Jensen, P. R., & Hughes, C. C.
- Affiliations
- Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, California 92093, United States
- Université de Nantes (FR)
- Scripps Institution of Oceanography (US)
- Corresponding author
- Hughes, Chambers C.
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-10-01
- Volume
- 13
- Issue
- 11
- Pages
- 3097-3106
- ISSN
- 1554-8929 (ISSN-L)
- 1554-8937
- OpenAlex
- W2894954010
- Cited by
- 29
- References
- 50
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 6 · 2023: 1 · 2022: 7 · 2021: 3 · 2020: 4 · 2019: 5
- FWCI
- 1.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- ACS Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Scripps Institution of Oceanography
- Topics
- Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Marine Sponges and Natural Products
- Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
- Keywords
- nitroso Diels-Alder reaction, conjugated alkenes, polyketide natural products, genome mining, natural product discovery
- MeSH terms
- Actinomycetales, Alkenes, Biological Products, Indicators and Reagents, Nitroso Compounds, Pyridines, Polyketides, Cycloaddition Reaction
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