ABSTRACT
The proteasome represents an invaluable target for the treatment of cancer and autoimmune disorders. The application of proteasome inhibitors, however, remains limited to blood cancers because their reactive headgroups and peptidic scaffolds convey unfavorable pharmacodynamic properties. Thus, the discovery of more drug-like lead structures is indispensable. In this study, we present the first structure of the proteasome in complex with an indolo-phakellin that exhibits a unique noncovalent binding mode unparalleled by all hitherto reported inhibitors. The natural product inspired pentacyclic alkaloid binds solely and specificially into the spacious S3â subpocket of the proteasomal ß5 substrate binding channel, gaining major stabilization through halogen bonding with the protein backbone. The presented compound provides an ideal scaffold for the structure-based design of subunit-specific nonpeptidic proteasome-blockers.
Subject(s)
Indoles/pharmacology , Piperazines/pharmacology , Proteasome Endopeptidase Complex/metabolism , Proteasome Inhibitors/pharmacology , Dose-Response Relationship, Drug , Humans , Indoles/chemistry , Models, Molecular , Molecular Conformation , Piperazines/chemistry , Proteasome Inhibitors/chemical synthesis , Proteasome Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
We report herein that the oroidin-derived alkaloids palau'amine (1), dibromophakellin (2), and dibromophakellstatin (3) inhibit the proteolytic activity of the human 20S proteasome as well as the (i)20S immunoproteasome catalytic core. Palau'amine is found to prevent the degradation of ubiquitinylated proteins, including IκBα, in cell culture, which may be indicative of the potential mechanism by which these agents exhibit their exciting cytotoxic and immunosuppressive properties.
Subject(s)
Alkaloids/pharmacology , Guanidines/pharmacology , Heterocyclic Compounds, 4 or More Rings/pharmacology , Imidazoles/pharmacology , Proteasome Inhibitors , Pyrroles/pharmacology , Spiro Compounds/pharmacology , Alkaloids/chemistry , Guanidines/chemistry , HeLa Cells , Heterocyclic Compounds, 4 or More Rings/chemistry , Humans , Imidazoles/chemistry , Microscopy, Confocal , NF-kappa B/metabolism , Proteasome Endopeptidase Complex/chemistry , Pyrroles/chemistry , Spiro Compounds/chemistry , StereoisomerismABSTRACT
(±)-Dibromophakellin has been synthesized in two steps from a known alkene intermediate. The key step in the synthesis is the NBS olefin activation to facilitate the addition of a guanidine molecule across the double bond.
