Discoipyrroles A-D: isolation, structure determination, and synthesis of potent migration inhibitors from Bacillus hunanensis.

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.

[1]  Susana P. Gaudêncio,et al.  Ammosamides A and B target myosin. , 2009, Angewandte Chemie.

[2]  A. Kirschning,et al.  Molecular basis of elansolid biosynthesis: evidence for an unprecedented quinone methide initiated intramolecular Diels-Alder cycloaddition/macrolactonization. , 2011, Angewandte Chemie.

[3]  Kevin W. Eliceiri,et al.  The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis , 2013, Nature Cell Biology.

[4]  T. Pawson,et al.  The discoidin domain receptor tyrosine kinases are activated by collagen. , 1997, Molecular cell.

[5]  E. Yang,et al.  Actinomycin D identified as an inhibitor of discoidin domain receptor 2 interaction with collagen through an insect cell based screening of a drug compound library. , 2009, Biological & pharmaceutical bulletin.

[6]  B. Posner,et al.  Precursor-Directed Generation of Amidine Containing Ammosamide Analogs: Ammosamides E-P. , 2013, Chemical science.

[7]  B. Posner,et al.  Chromomycin SA analogs from a marine-derived Streptomyces sp. , 2011, Bioorganic & medicinal chemistry.

[8]  J. MacMillan,et al.  Erythrolic acids A-E, meroterpenoids from a marine-derived Erythrobacter sp. , 2012, The Journal of organic chemistry.

[9]  J. Helmann,et al.  Metal ion homeostasis in Bacillus subtilis. , 2005, Current opinion in microbiology.

[10]  G. Yancopoulos,et al.  An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors. , 1997, Molecular cell.

[11]  J. MacMillan,et al.  Erythrazoles A-B, cytotoxic benzothiazoles from a marine-derived Erythrobacter sp. , 2011, Organic letters.

[12]  U. Rix,et al.  The dynamic structure of jadomycin B and the amino acid incorporation step of its biosynthesis. , 2004, Journal of the American Chemical Society.

[13]  M. Tsao,et al.  Expression and mutation analysis of the discoidin domain receptors 1 and 2 in non-small cell lung carcinoma , 2007, British Journal of Cancer.

[14]  R. Jove,et al.  Dasatinib inhibits migration and invasion in diverse human sarcoma cell lines and induces apoptosis in bone sarcoma cells dependent on SRC kinase for survival. , 2007, Cancer research.

[15]  Paul A Clemons,et al.  The Connectivity Map: Using Gene-Expression Signatures to Connect Small Molecules, Genes, and Disease , 2006, Science.

[16]  J. Risteli,et al.  Aberrant type I and type III collagen gene expression in human breast cancer in vivo , 1998, The Journal of pathology.

[17]  R. Syvitski,et al.  Synthetic diversification of natural products: semi-synthesis and evaluation of triazole jadomycins , 2012 .

[18]  M. Meyerson,et al.  Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. , 2011, Cancer discovery.

[19]  S. Friedman,et al.  Discoidin Domain Receptor 2 Regulates Fibroblast Proliferation and Migration through the Extracellular Matrix in Association with Transcriptional Activation of Matrix Metalloproteinase-2* , 2002, The Journal of Biological Chemistry.

[20]  Paul Workman,et al.  The contemporary drug development process: advances and challenges in preclinical and clinical development. , 2003, Progress in cell cycle research.

[21]  B. Leitinger.  Molecular Analysis of Collagen Binding by the Human Discoidin Domain Receptors, DDR1 and DDR2 , 2003, The Journal of Biological Chemistry.

[22]  L. B. Rocha,et al.  Nested collagen matrices: a new model to study migration of human fibroblast populations in three dimensions. , 2005, Experimental cell research.

[23]  A. Kirschning,et al.  Precursor‐Directed Syntheses and Biological Evaluation of New Elansolid Derivatives , 2012, Chembiochem : a European journal of chemical biology.

[24]  F. Grinnell,et al.  Oncogenic Ras-transformed human fibroblasts exhibit differential changes in contraction and migration in 3D collagen matrices. , 2008, Experimental cell research.

[25]  A. Kirschning,et al.  Elansolid A, a unique macrolide antibiotic from Chitinophaga sancti isolated as two stable atropisomers. , 2011, Angewandte Chemie.

[26]  A. Kirschning,et al.  Elansolid A3, a unique p-quinone methide antibiotic from Chitinophaga sancti. , 2011, Chemistry.

[27]  J. MacMillan,et al.  Ammosamide D, an oxidatively ring opened ammosamide analog from a marine-derived Streptomyces variabilis. , 2012, Organic letters.

[28]  Moshe Talpaz,et al.  Dasatinib (BMS-354825) Tyrosine Kinase Inhibitor Suppresses Invasion and Induces Cell Cycle Arrest and Apoptosis of Head and Neck Squamous Cell Carcinoma and Non–Small Cell Lung Cancer Cells , 2005, Clinical Cancer Research.

[29]  Lin Xu,et al.  Attenuation of osteoarthritis progression by reduction of discoidin domain receptor 2 in mice. , 2010, Arthritis and rheumatism.

[30]  D. Jakeman,et al.  Diverse DNA-cleaving capacities of the jadomycins through precursor-directed biosynthesis. , 2010, Organic Letters.

[31]  L. Al-Gazali,et al.  Trafficking defects and loss of ligand binding are the underlying causes of all reported DDR2 missense mutations found in SMED-SL patients , 2010, Human molecular genetics.

[32]  Michael Arend,et al.  Modern Variants of the Mannich Reaction. , 1998, Angewandte Chemie.

[33]  J. MacMillan,et al.  Hunanamycin A, an antibiotic from a marine-derived Bacillus hunanensis. , 2013, Organic letters.

[34]  C. E. Dalgliesh,et al.  Intermediary Metabolism of Tryptophan , 1951, Nature.

[35]  R. Pompei,et al.  Sattabacins and sattazolins: new biologically active compounds with antiviral properties extracted from a Bacillus sp. , 1995, The Journal of antibiotics.

[36]  J. Imlay,et al.  Pathways of oxidative damage. , 2003, Annual review of microbiology.

[37]  Muhammed Yousufuddin,et al.  Discoipyrroles A—D: Isolation, Structure Determination, and Synthesis of Potent Migration Inhibitors from Bacillus hunanensis. , 2014 .

[38]  E. Hohenester,et al.  Characterization of High Affinity Binding Motifs for the Discoidin Domain Receptor DDR2 in Collagen*♦ , 2008, Journal of Biological Chemistry.

[39]  Susana P. Gaudêncio,et al.  The ammosamides: structures of cell cycle modulators from a marine-derived Streptomyces species. , 2009, Angewandte Chemie.