title: Marine AChE inhibitors isolated from Geodia barretti: natural compounds and their synthetic analogs.
abstract: Barettin, 8,9-dihydrobarettin, bromoconicamin and a novel brominated marine indole were isolated from the boreal sponge Geodia barretti collected off the Norwegian coast. The compounds were evaluated as inhibitors of electric eel acetylcholinesterase. Barettin and 8,9-dihydrobarettin displayed significant inhibition of the enzyme, with inhibition constants (Ki) of 29 and 19 μM respectively towards acetylcholinesterase via a reversible noncompetitive mechanism. These activities are comparable to those of several other natural acetylcholinesterase inhibitors of marine origin. Bromoconicamin was less potent against acetylcholinesterase, and the novel compound was inactive. Based on the inhibitory activity, a library of 22 simplified synthetic analogs was designed and prepared to probe the role of the brominated indole, common to all the isolated compounds. From the structure-activity investigation it was shown that the brominated indole motif is not sufficient to generate a high acetylcholinesterase inhibitory activity, even when combined with natural cationic ligands for the acetylcholinesterase active site. The four natural compounds were also analysed for their butyrylcholinesterase inhibitory activity in addition and shown to display comparable activities. The study illustrates how both barettin and 8,9-dihydrobarettin display additional bioactivities which may help to explain their biological role in the producing organism. The findings also provide new insights into the structure-activity relationship of both natural and synthetic acetylcholinesterase inhibitors.
authors.affiliation: MabCent-SFI, UiT The Arctic University of Norway, Breivika, N-9037, Tromsø, Norway.
authors.forename: Elisabeth K
authors.initials: EK
authors.lastname: Olsen
authors.affiliation: Marbio, UiT The Arctic University of Norway, Breivika, N-9037, Tromsø, Norway. Jeanette.h.andersen@uit.no.
authors.forename: Espen
authors.initials: E
authors.lastname: Hansen
authors.affiliation: Department of Chemistry, University of Umeå, SE-901 87, Umeå, Sweden.
authors.forename: Lindon
authors.initials: L
authors.lastname: W K Moodie
authors.affiliation: Department of Chemistry, UiT The Arctic University of Norway, Breivika, N-9037 Tromsø, Norway.
authors.forename: Johan
authors.initials: J
authors.lastname: Isaksson
authors.affiliation: Department of Biology, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Kristina
authors.initials: K
authors.lastname: Sepčić
authors.affiliation: Department of Biology, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia and Department of Biotechnology, University of Rijeka, 51000 Rijeka, Croatia.
authors.forename: Marija
authors.initials: M
authors.lastname: Cergolj
authors.affiliation: Department of Chemistry, Materials and Surfaces SP Technical Research Institute of Sweden, Box 857, SE-501 15 Borås, Sweden. Johan.svenson@sp.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Svenson
authors.affiliation: Marbio, UiT The Arctic University of Norway, Breivika, N-9037, Tromsø, Norway. Jeanette.h.andersen@uit.no.
authors.forename: Jeanette H
authors.initials: JH
authors.lastname: Andersen
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D047231:Geodia / Q000737:chemistry*; D006801:Humans; D026121:Indole Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C484473:8,9-dihydrobarettin; D001688:Biological Products; D002800:Cholinesterase Inhibitors; D026121:Indole Alkaloids; D007211:Indoles; D010456:Peptides, Cyclic; C484472:barettin; C488270:conicamin; D000110:Acetylcholinesterase