Discoipyrroles A–D: Isolation, Structure Determination, and Synthesis of Potent Migration Inhibitors from Bacillus hunanensis

• Published in: Journal of the American Chemical Society Vol. 135; no. 36; pp. 13387 - 13392
• Main Authors: Hu, Youcai, Potts, Malia B., Colosimo, Dominic, Herrera-Herrera, Mireya L., Legako, Aaron G., Yousufuddin, Muhammed, White, Michael A., MacMillan, John B.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.09.2013; Amer Chemical Soc
• Subjects: Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - isolation & purification; Antineoplastic Agents, Phytogenic - pharmacology; Bacillus - chemistry; Biological Products - chemistry; Biological Products - isolation & purification; Biological Products - pharmacology; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemistry; Chemistry, Multidisciplinary; Discoidin Domain Receptors; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Fibroblasts - cytology; Fibroblasts - drug effects; Heterocyclic Compounds, 3-Ring - chemistry; Heterocyclic Compounds, 3-Ring - isolation & purification; Heterocyclic Compounds, 3-Ring - pharmacology; Humans; Models, Molecular; Molecular Structure; Physical Sciences; Pyrrolidinones - chemistry; Pyrrolidinones - isolation & purification; Pyrrolidinones - pharmacology; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Receptors, Mitogen - antagonists & inhibitors; Receptors, Mitogen - genetics; Receptors, Mitogen - metabolism; Science & Technology; Signal Transduction - drug effects; Stereoisomerism; Structure-Activity Relationship; CELL LUNG-CANCER; DISCOIDIN; COLLAGEN MATRICES; BIOSYNTHESIS; KINASE; DOMAIN RECEPTOR 2; GENE-EXPRESSION; CHITINOPHAGA-SANCTI; ERYTHROBACTER SP; DDR2
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/ja403412y

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.