title: Discoipyrroles A-D: isolation, structure determination, and synthesis of potent migration inhibitors from Bacillus hunanensis.
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.
authors.affiliation: Department of Biochemistry, ‡Department of Cell Biology, §Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center , 5323 Harry Hines Blvd, Dallas, Texas 75390, United States.
authors.forename: Youcai
authors.initials: Y
authors.lastname: Hu
authors.forename: Malia B
authors.initials: MB
authors.lastname: Potts
authors.forename: Dominic
authors.initials: D
authors.lastname: Colosimo
authors.forename: Mireya L
authors.initials: ML
authors.lastname: Herrera-Herrera
authors.forename: Aaron G
authors.initials: AG
authors.lastname: Legako
authors.forename: Muhammed
authors.initials: M
authors.lastname: Yousufuddin
authors.forename: Michael A
authors.initials: MA
authors.lastname: White
authors.forename: John B
authors.initials: JB
authors.lastname: MacMillan
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001407:Bacillus / Q000737:chemistry*; D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000070818:Discoidin Domain Receptors; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects*; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011760:Pyrrolidinones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011975:Receptors, Mitogen / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001688:Biological Products; D006575:Heterocyclic Compounds, 3-Ring; D011760:Pyrrolidinones; D011975:Receptors, Mitogen; C587604:discoipyrrole A; C587605:discoipyrrole B; C587606:discoipyrrole C; C587607:discoipyrrole D; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases