title: Characterization and Synthesis of Eudistidine C, a Bioactive Marine Alkaloid with an Intriguing Molecular Scaffold.
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.
authors.forename: Susanna T S
authors.initials: ST
authors.lastname: Chan
authors.forename: Roger R
authors.initials: RR
authors.lastname: Nani
authors.forename: Evan A
authors.initials: EA
authors.lastname: Schauer
authors.affiliation: NMR Structure Elucidation, Process Research and Development, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Martin
authors.affiliation: NMR Structure Elucidation, Process Research and Development, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: R Thomas
authors.initials: RT
authors.lastname: Williamson
authors.affiliation: NMR Structure Elucidation, Process Research and Development, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Josep
authors.initials: J
authors.lastname: Saurí
authors.affiliation: NMR Structure Elucidation, Process Research and Development, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Alexei V
authors.initials: AV
authors.lastname: Buevich
authors.affiliation: NMR Structure Elucidation, Process Research and Development, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Wes A
authors.initials: WA
authors.lastname: Schafer
authors.affiliation: NMR Structure Elucidation, Process Research and Development, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Leo A
authors.initials: LA
authors.lastname: Joyce
authors.affiliation: Medical Oncology Branch, Center for Cancer Research, National Cancer Institute , Bethesda, Maryland 20892, United States.
authors.forename: Andrew K L
authors.initials: AK
authors.lastname: Goey
authors.affiliation: Medical Oncology Branch, Center for Cancer Research, National Cancer Institute , Bethesda, Maryland 20892, United States.
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Tanya T
authors.initials: TT
authors.lastname: Ransom
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland 21702-1201, United States.
authors.forename: Curtis J
authors.initials: CJ
authors.lastname: Henrich
authors.forename: Tawnya C
authors.initials: TC
authors.lastname: McKee
authors.affiliation: Advanced Chemistry Development, Inc. (ACD/Laboratories) , Toronto Department, 8 King Street East Suite 107, Toronto, Ontario M5C 1B5, Canada.
authors.forename: Arvin
authors.initials: A
authors.lastname: Moser
authors.affiliation: Advanced Chemistry Development, Inc. (ACD/Laboratories) , Toronto Department, 8 King Street East Suite 107, Toronto, Ontario M5C 1B5, Canada.
authors.forename: Scott A
authors.initials: SA
authors.lastname: MacDonald
authors.affiliation: National Center for Natural Products Research, School of Pharmacy, University of Mississippi , Mississippi 38677, United States.
authors.forename: Shabana
authors.initials: S
authors.lastname: Khan
authors.forename: James B
authors.initials: JB
authors.lastname: McMahon
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Schnermann
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Gustafson
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D002851:Chromatography, High Pressure Liquid; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry; D008386:Marine Biology; D015394:Molecular Structure; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D014561:Urochordata / Q000737:chemistry*
chemical_list: D000470:Alkaloids; D006576:Heterocyclic Compounds, 4 or More Rings; C000627331:eudistidine C