title: The carmaphycins: new proteasome inhibitors exhibiting an α,β-epoxyketone warhead from a marine cyanobacterium.
abstract: Two new peptidic proteasome inhibitors were isolated as trace components from a Curaçao collection of the marine cyanobacterium Symploca sp. Carmaphycin A (1) and carmaphycin B (2) feature a leucine-derived α,β-epoxyketone warhead directly connected to either methionine sulfoxide or methionine sulfone. Their structures were elucidated on the basis of extensive NMR and MS analyses and confirmed by total synthesis, which in turn provided more material for further biological evaluations. Pure carmaphycins A and B were found to inhibit the β5 subunit (chymotrypsin-like activity) of the S. cerevisiae 20S proteasome in the low nanomolar range. Additionally, they exhibited strong cytotoxicity to lung and colon cancer cell lines, as well as exquisite antiproliferative effects in the NCI60 cell-line panel. These assay results as well as initial structural biology studies suggest a distinctive binding mode for these new inhibitors.
authors.affiliation: Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, La Jolla, CA 92093-0212, USA.
authors.forename: Alban R
authors.initials: AR
authors.lastname: Pereira
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Kale
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Fenley
authors.forename: Tara
authors.initials: T
authors.lastname: Byrum
authors.forename: Hosana M
authors.initials: HM
authors.lastname: Debonsi
authors.forename: Michael K
authors.initials: MK
authors.lastname: Gilson
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Valeriote
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Moore
authors.forename: William H
authors.initials: WH
authors.lastname: Gerwick
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism; D045744:Cell Line, Tumor; D000458:Cyanobacteria / Q000737:chemistry* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry* / Q000378:metabolism; D061988:Proteasome Inhibitors; D012623:Seawater / Q000382:microbiology; D013329:Structure-Activity Relationship
chemical_list: D001426:Bacterial Proteins; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex