Characterization and Synthesis of Eudistidine C, a Bioactive Marine Alkaloid with an Intriguing Molecular Scaffold
| Autor: | Andrew K. L. Goey, Leo A. Joyce, Arvin Moser, Tawnya C. McKee, James B. McMahon, Kirk R. Gustafson, Josep Saurí, Scott A. MacDonald, Shabana I. Khan, Wes Schafer, R. Thomas Williamson, Roger R. Nani, Tanya T. Ransom, William D. Figg, Susanna T. S. Chan, Evan A. Schauer, Gary E. Martin, Alexei V. Buevich, Martin J. Schnermann, Curtis J. Henrich |
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| Rok vydání: | 2016 |
| Předmět: |
Spectrometry
Mass Electrospray Ionization Stereochemistry Proton Magnetic Resonance Spectroscopy Heteroatom Marine Biology 010402 general chemistry Heterocyclic Compounds 4 or More Rings 01 natural sciences Article chemistry.chemical_compound Alkaloids Animals Phenol Moiety Urochordata Carbon-13 Magnetic Resonance Spectroscopy Chromatography High Pressure Liquid Natural product Molecular Structure 010405 organic chemistry Alkaloid Organic Chemistry Pulse sequence 0104 chemical sciences chemistry Heteronuclear molecule Yield (chemistry) |
| Zdroj: | The Journal of Organic Chemistry. 81:10631-10640 |
| ISSN: | 1520-6904 0022-3263 |
| DOI: | 10.1021/acs.joc.6b02380 |
| Popis: | An extract of Eudistoma sp. provided eudistidine C (1), a heterocyclic alkaloid with a novel molecular framework. Eudistidine C (1) is a racemic natural product composed of a tetracyclic core structure further elaborated with a p-methoxyphenyl group and a phenol-substituted aminoimidazole moiety. This compound presented significant structure elucidation challenges due to the large number of heteroatoms and fully substituted carbons. These issues were mitigated by application of a new NMR pulse sequence (LR-HSQMBC) optimized to detect four- and five-bond heteronuclear correlations and the use of computer-assisted structure elucidation software. Synthesis of eudistidine C (1) was accomplished in high yield by treating eudistidine A (2) with 4(2-amino-1H-imidazol-5-yl)phenol (4) in DMSO. Synthesis of eudistidine C (1) confirmed the proposed structure and provided material for further biological characterization. Treatment of 2 with various nitrogen heterocycles and electron-rich arenes provided a series of analogues (5-10) of eudistidine C. Chiral-phase HPLC resolution of epimeric eudistidine C provided (+)-(R)-eudistidine C (1a) and (-)-(S)-eudistidine C (1b). The absolute configuration of these enantiomers was assigned by ECD analysis. (-)-(S)-Eudistidine C (1b) modestly inhibited interaction between the protein binding domains of HIF-1α and p300. Compounds 1, 2, and 6-10 exhibited significant antimalarial activity against Plasmodium falciparum. |
| Databáze: | OpenAIRE |
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