Abstract
Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase involved in a variety of cellular response pathways, including regulation of cell growth, proliferation, and motility. Using a newly developed platform to identify the signaling pathway/molecular target of natural products, we identified a family of alkaloid natural products, discoipyrroles A-D (1-4), from Bacillus hunanensis that inhibit the DDR2 signaling pathway. The structure of 1-4, determined by detailed two-dimensional (2D) NMR methods and confirmed by X-ray crystallographic analysis has an unusual 3H-benzo[d]pyrrolo][1,3]oxazine-3,5-dione core. Discoipyrroles A-D potently inhibit DDR2 dependent migration of BR5 fibroblasts and show selective cytotoxicity to DDR2 mutant lung cancer cell lines (IC50 120-400 nM). Examination of the biosynthesis has led to the conclusion that the discoipyrroles are formed through a nonenzymatic process, leading to a one-pot total synthesis of 1.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents, Phytogenic / chemistry
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Antineoplastic Agents, Phytogenic / isolation & purification
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Antineoplastic Agents, Phytogenic / pharmacology*
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Bacillus / chemistry*
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Biological Products / chemistry
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Biological Products / isolation & purification
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Biological Products / pharmacology*
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Discoidin Domain Receptors
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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Fibroblasts / cytology
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Fibroblasts / drug effects*
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Heterocyclic Compounds, 3-Ring / chemistry
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Heterocyclic Compounds, 3-Ring / isolation & purification
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Heterocyclic Compounds, 3-Ring / pharmacology*
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Humans
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Models, Molecular
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Molecular Structure
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Pyrrolidinones / chemistry
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Pyrrolidinones / isolation & purification
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Pyrrolidinones / pharmacology*
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptors, Mitogen / antagonists & inhibitors*
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Receptors, Mitogen / genetics
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Receptors, Mitogen / metabolism
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Signal Transduction / drug effects
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Antineoplastic Agents, Phytogenic
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Biological Products
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Heterocyclic Compounds, 3-Ring
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Pyrrolidinones
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Receptors, Mitogen
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discoipyrrole A
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discoipyrrole B
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discoipyrrole C
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discoipyrrole D
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Discoidin Domain Receptors
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Receptor Protein-Tyrosine Kinases