title: Proteasome inhibitors with photocontrolled activity.
abstract: Proteasome inhibitors are widely used in cancer treatment as chemotherapeutic agents. However, their employment often results in severe side effects, due to their non-specific cytotoxicity towards healthy tissue. This problem might be overcome by using a photopharmacological approach, that is, by attaining external, dynamic, spatiotemporal photocontrol over the activity of a cytotoxic agent, achieved by the introduction of a photoswitchable moiety into its molecular structure. Here we describe the design, synthesis, and activity of photoswitchable proteasome inhibitors. Substantial differences in proteasome inhibitory activity in cell extracts were observed before and after irradiation with light. The presented results show potential for the development of chemotherapeutic agents that can be switched on and off with light, constituting a new strategy for spatiotemporally modulating proteasomal activity.
authors.affiliation: Centre for Systems Chemistry, Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG, Groningen (The Netherlands).
authors.forename: Mickel J
authors.initials: MJ
authors.lastname: Hansen
authors.forename: Willem A
authors.initials: WA
authors.lastname: Velema
authors.forename: Gerjan
authors.initials: G
authors.lastname: de Bruin
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
authors.forename: Wiktor
authors.initials: W
authors.lastname: Szymanski
authors.forename: Ben L
authors.initials: BL
authors.lastname: Feringa
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001391:Azo Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D008027:Light; D009369:Neoplasms / Q000188:drug therapy; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001391:Azo Compounds; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex; C009850:azobenzene
keywords: azobenzenes; cytotoxicity; inhibitors; photocontrol; photopharmacology; proteasome