title: A search for BACE inhibitors reveals new biosynthetically related pyrrolidones, furanones and pyrroles from a southern Australian marine sponge, Ianthella sp.
abstract: Fractionation of a southern Australian marine sponge, Ianthella sp., yielded sixteen metabolites including a new class of pyrrolidone, ianthellidones A-F (1-6), a new class of furanone, ianthellidones G-H (7-8), new and known lamellarins, lamellarins O1 (9), O2 (10), O (11) and Q (12), plus the known 4-hydroxybenzaldehyde (13), 4-hydroxybenzoic acid (14), 4-methoxybenzoic acid (15) and ethyl 4-hydroxybenzoate (16). Structures for all Ianthella metabolites were determined by detailed spectroscopic analysis, supported by a plausible biosynthetic relationship. The ianthellidones were non-cytotoxic towards two human colon cancer cell lines (SW620 and SW620 Ad300), as well as Gram +ve and Gram -ve bacteria, and a fungus. Ianthellidone F (6) and lamellarins O2 (10) and O (11) displayed modest BACE inhibitory properties (IC(50) > 10 μM), while lamellarin O1 (9) was more potent (IC(50) < 10 μM). Lamellarin O (11) exhibited modest cytotoxicity towards SW620 and SW620 Ad300 cell lines (IC(50) > 22 μM), was an inhibitor of the multi-drug resistance efflux pump P-glycoprotein, and displayed selective growth inhibitory activity against the Gram +ve bacterium Bacillus subtilis (ATCC 6633) (IC(50) 2.5 μM).
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Conte
authors.forename: Xiao-Cong
authors.initials: XC
authors.lastname: Huang
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Khalil
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Capon
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005663:Furans / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D011161:Porifera / Q000737:chemistry*; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology; D011760:Pyrrolidinones / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D005663:Furans; D011480:Protease Inhibitors; D011758:Pyrroles; D011760:Pyrrolidinones; D053829:Amyloid Precursor Protein Secretases; C039281:furan