title: Khellinone derivatives as blockers of the voltage-gated potassium channel Kv1.3: synthesis and immunosuppressive activity.
abstract: The voltage-gated potassium channel Kv1.3 constitutes a promising new target for the treatment of T-cell-mediated autoimmune diseases such as multiple sclerosis. In this study, we report the discovery of two new classes of Kv1.3 blockers based on the naturally occurring compound khellinone, 5-acetyl-4,7-dimethoxy-6-hydroxybenzofuran: (1) khellinone dimers linked via the alkylation of the 6-hydroxy groups and (2) chalcone derivatives of khellinone formed by Claisen-Schmidt condensation of the 5-acetyl group with aryl aldehydes. In particular, the chalcone 3-(4,7-dimethoxy-6-hydroxybenzofuran-5-yl)-1-phenyl-3-oxopropene (16) and several of its derivatives inhibited Kv1.3 with K(d) values of 300-800 nM and a Hill coefficient of 2, displayed moderate selectivity over other Kv1-family K(+) channels, suppressed T-lymphocyte proliferation at submicromolar concentrations, and showed no signs of acute toxicity in mice. Because of their relatively low molecular weight and lipophilicity and their high affinity to Kv1.3, aryl-substituted khellinone derivatives represent attractive lead compounds for the development of more potent and selective Kv1.3 blocking immunosuppressants.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research Biotechnology Centre, 4 Research Avenue, La Trobe R&D Park, Bundoora 3086, Australia. jbaell@wehi.edu.au
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Baell
authors.forename: Robert W
authors.initials: RW
authors.lastname: Gable
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Harvey
authors.forename: Nathan
authors.initials: N
authors.lastname: Toovey
authors.forename: Tanja
authors.initials: T
authors.lastname: Herzog
authors.forename: Wolfram
authors.initials: W
authors.lastname: Hänsel
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division; D002460:Cell Line; D002599:Chalcone / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047188:Chalcones; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015640:Ion Channel Gating; D051664:Kv1.3 Potassium Channel; D051379:Mice; D015394:Molecular Structure; D026902:Potassium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D023382:Toxicity Tests, Acute
chemical_list: C485234:3-(4,7-dimethoxy-6-hydroxybenzofuran-5-yl)-1-phenyl-3-oxopropene; D001572:Benzofurans; D047188:Chalcones; D007166:Immunosuppressive Agents; C496973:KCNA3 protein, human; C496974:Kcna3 protein, mouse; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D002599:Chalcone