ArticleProceedings of the National Academy of Sciences of the United States of America2016
Structural basis for DNA cleavage by the potent antiproliferative agent (-)-lomaiviticin A.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 35 citations in OpenAlex.
- Discovery of the Azaserine Biosynthetic Pathway Uncovers a Biological Route for α-Diazoester Production.Angewandte Chemie (International ed. in English) · 2023Article
- Delivery, structure, and function of bacterial genotoxins.Virulence · 2022Review
- Activation and Characterization of Lanthomicins A-C by Promoter Engineering inFrontiers in microbiology · 2022Article
- Structure Revision of the Lomaiviticins.Journal of the American Chemical Society · 2021Article
- Synthesis and Biological Evaluation of (2Journal of the American Chemical Society · 2021Article
- Structure and bioactivity of colibactin.Bioorganic & medicinal chemistry letters · 2020Review
- Synthesis of the bis(cyclohexenone) core of (-)-lomaiviticin A.Chemical science · 2020Article
- Biosynthesis of aromatic polyketides in microorganisms using type II polyketide synthases.Microbial cell factories · 2020Review
- Macrocyclic colibactin induces DNA double-strand breaks via copper-mediated oxidative cleavage.Nature chemistry · 2019Article
- Discovery of Stealthin Derivatives and Implication of the Amidotransferase FlsN3 in the Biosynthesis of Nitrogen-Containing Fluostatins.Marine drugs · 2019Article
- A survey of recent unusual high-resolution DNA structures provoked by mismatches, repeats and ligand binding.Nucleic acids research · 2018Review
- Discovery of a Diazo-Forming Enzyme in Cremeomycin Biosynthesis.The Journal of organic chemistry · 2018Article
- Molecular basis of dimer formation during the biosynthesis of benzofluorene-containing atypical angucyclines.Nature communications · 2018Article
- The Mechanism of Action of (-)-Lomaiviticin A.Accounts of chemical research · 2017Article
- Heteroatom-Heteroatom Bond Formation in Natural Product Biosynthesis.Chemical reviews · 2017Review
- Diazo Compounds: Versatile Tools for Chemical Biology.ACS chemical biology · 2016Review
- Mechanism of Nucleophilic Activation of (-)-Lomaiviticin A.Journal of the American Chemical Society · 2016Article
- Synergistic potentiation of (-)-lomaiviticin A cytotoxicity by the ATR inhibitor VE-821.Bioorganic & medicinal chemistry letters · 2016Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
(-)-Lomaiviticin A (1) is a complex antiproliferative metabolite that inhibits the growth of many cultured cancer cell lines at low nanomolar-picomolar concentrations. (-)-Lomaiviticin A (1) possesses a C2-symmetric structure that contains two unusual diazotetrahydrobenzo[b]fluorene (diazofluorene) functional groups. Nucleophilic activation of each diazofluorene within 1 produces vinyl radical intermediates that affect hydrogen atom abstraction from DNA, leading to the formation of DNA double-strand breaks (DSBs). Certain DNA DSB repair-deficient cell lines are sensitized toward 1, and 1 is under evaluation in preclinical models of these tumor types. However, the mode of binding of 1 to DNA had not been determined. Here we elucidate the structure of a 1:1 complex between 1 and the duplex d(GCTATAGC)2 by NMR spectroscopy and computational modeling. Unexpectedly, we show that both diazofluorene residues of 1 penetrate the duplex. This binding disrupts base pairing leading to ejection of the central AT bases, while placing the proreactive centers of 1 in close proximity to each strand. DNA binding may also enhance the reactivity of 1 toward nucleophilic activation through steric compression and conformational restriction (an example of shape-dependent catalysis). This study provides a structural basis for the DNA cleavage activity of 1, will guide the design of synthetic DNA-activated DNA cleavage agents, and underscores the utility of natural products to reveal novel modes of small molecule-DNA association.
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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.