Characterization and Synthesis of Eudistidine C, a Bioactive Marine Alkaloid with an Intriguing Molecular Scaffold

Susanna T.S. Chan, Roger R. Nani, Evan A. Schauer, Gary E. Martin, R. Thomas Williamson, Josep Saurí, Alexei V. Buevich, Wes A. Schafer, Leo A. Joyce, Andrew K.L. Goey, William D. Figg, Tanya T. Ransom, Curtis J. Henrich, Tawnya C. McKee, Arvin Moser, Scott A. MacDonald, Shabana Khan, James B. McMahon, Martin J. Schnermann*, Kirk R. Gustafson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)10631-10640
Number of pages10
JournalJournal of Organic Chemistry
Volume81
Issue number22
DOIs
StatePublished - 18 Nov 2016
Externally publishedYes

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