title: SAR of Sponge-Inspired Hemibastadin Congeners Inhibiting Blue Mussel PhenolOxidase.
abstract: Hemibastadin derivatives, including the synthetically-derived 5,5'-dibromohemibastadin-1 (DBHB), are potent inhibitors of blue mussel phenoloxidase (PO), which is a key enzyme involved in the firm attachment of this invertebrate to substrates and, thus, a promising molecular target for anti-fouling research. For a systematic investigation of the enzyme inhibitory activity of hemibastadin derivatives, we have synthesized nine new congeners, which feature structural variations of the DBHB core structure. These structural modifications include, e.g., different halogen substituents present at the aromatic rings, different amine moieties linked to the (E)-2-(hydroxyimino)-3-(4-hydroxyphenyl)propionic acid, the presence of free vs. substituted aromatic hydroxyl groups and a free vs. methylated oxime group. All compounds were tested for their inhibitory activity towards the target enzyme in vitro, and IC50 values were calculated. Derivatives, which structurally closely resemble sponge-derived hemibastadins, revealed superior enzyme inhibitory properties vs. congeners featuring structural moieties that are absent in the respective natural products. This study suggests that natural selection has yielded structurally-optimized antifouling compounds.
authors.affiliation: Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, Geb. 26.23, 40225 Düsseldorf, Germany. hendrik.niemann@hhu.de.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Niemann
authors.affiliation: Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, Geb. 26.23, 40225 Düsseldorf, Germany. jens.hagenow@hhu.de.
authors.forename: Jens
authors.initials: J
authors.lastname: Hagenow
authors.affiliation: Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, Geb. 26.23, 40225 Düsseldorf, Germany. mi-young.chung@hhu.de.
authors.forename: Mi-Young
authors.initials: MY
authors.lastname: Chung
authors.affiliation: LEMAR UMR 6539 UBO CNRS Ifremer IRD, European Institute of Marine Studies (IUEM), Université de Bretagne Occidentale (UBO), European University of Brittany (UEB), Technopole Brest-Iroise, 29280 Plouzané, France. Claire.Hellio@univ-brest.fr.|Biodimar, Université de Bretagne Occidentale (UBO), European University of Brittany (UEB), 6 Avenue Victor Le Gorgeu, CS93837, 29238 Brest cedex 3, France. Claire.Hellio@univ-brest.fr.
authors.forename: Claire
authors.initials: C
authors.lastname: Hellio
authors.affiliation: Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, Geb. 26.23, 40225 Düsseldorf, Germany. horst.weber@hhu.de.
authors.forename: Horst
authors.initials: H
authors.lastname: Weber
authors.affiliation: Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, Geb. 26.23, 40225 Düsseldorf, Germany. proksch@hhu.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Proksch
mesh_terms: D000818:Animals; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D049880:Mytilus edulis / Q000187:drug effects* / Q000378:metabolism*; D011161:Porifera / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D001688:Biological Products; D004791:Enzyme Inhibitors; D014442:Monophenol Monooxygenase
keywords: Mytilus edulis; antifouling; copper; hemibastadin; phenoloxidase; sponges