title: Niphatenones, glycerol ethers from the sponge Niphates digitalis block androgen receptor transcriptional activity in prostate cancer cells: structure elucidation, synthesis, and biological activity.
abstract: Extracts of the marine sponge Niphates digitalis collected in Dominica showed strong activity in a cell-based assay designed to detect antagonists of the androgen receptor (AR) that could act as lead compounds for the development of a new class of drugs to treat castration recurrent prostate cancer (CRPC). Assay-guided fractionation showed that niphatenones A (3) and B (4), two new glycerol ether lipids, were the active components of the extracts. The structures of 3 and 4 were elucidated by analysis of NMR and MS data and confimed via total synthesis. Biological evaluation of synthetic analogues of the niphatenones has shown that the enantiomers 7 and 8 are more potent than the natural products in the screening assay and defined preliminary SAR for the new AR antagonist pharmacophore, including the finding that the Michael acceptor enone functionality is not required for activity. Niphatenone B (4) and its enantiomer 8 blocked androgen-induced proliferation of LNCaP prostate cancer cells but had no effect on the proliferation of PC3 prostate cancer cells that do not express functional AR, consistent with activity as AR antagonists. Use of the propargyl ether 44 and Click chemistry showed that niphatenone B binds covalently to the activation function-1 (AF1) region of the AR N-terminus domain (NTD).
authors.affiliation: Department of Chemistry and Earth, University of British Columbia, 2036 Main Mall, Vancouver, B.C., Canada V6T 1Z1.
authors.forename: Labros G
authors.initials: LG
authors.lastname: Meimetis
authors.forename: David E
authors.initials: DE
authors.lastname: Williams
authors.forename: Nasrin R
authors.initials: NR
authors.lastname: Mawji
authors.forename: Carmen A
authors.initials: CA
authors.lastname: Banuelos
authors.forename: Aaron A
authors.initials: AA
authors.lastname: Lal
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Park
authors.forename: Amy H
authors.initials: AH
authors.lastname: Tien
authors.forename: Javier Garcia
authors.initials: JG
authors.lastname: Fernandez
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: de Voogd
authors.forename: Marianne D
authors.initials: MD
authors.lastname: Sadar
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Andersen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005995:Glyceryl Ethers / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008968:Molecular Conformation; D011161:Porifera / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D005995:Glyceryl Ethers; D011944:Receptors, Androgen; C570920:niphatenone A; C570921:niphatenone B