title: Substrate-guided optimization of the syringolins yields potent proteasome inhibitors with activity against leukemia cell lines.
abstract: Natural products that inhibit the proteasome have been fruitful starting points for the development of drug candidates. Those of the syringolin family have been underexploited in this context. Using the published model for substrate mimicry by the syringolins and knowledge about the substrate preferences of the proteolytic subunits of the human proteasome, we have designed, synthesized, and evaluated syringolin analogs. As some of our analogs inhibit the activity of the proteasome with second-order rate constants 5-fold greater than that of the methyl ester of syringolin B, we conclude that the substrate mimicry model for the syringolins is valid. The improvements in in vitro potency and the activities of particular analogs against leukemia cell lines are strong bases for further development of the syringolins as anti-cancer drugs.
authors: Department of Chemistry, Brown University, 324 Brook Street, Providence, RI 02912, United States.
authors: Kyle A
authors: KA
authors: Totaro
authors: Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States.
authors: Dominik
authors: D
authors: Barthelme
authors: Department of Chemistry, Brown University, 324 Brook Street, Providence, RI 02912, United States.
authors: Peter T
authors: PT
authors: Simpson
authors: Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, United States.
authors: Robert T
authors: RT
authors: Sauer
authors: Department of Chemistry, Brown University, 324 Brook Street, Providence, RI 02912, United States. Electronic address: jason_sello@brown.edu.
authors: Jason K
authors: JK
authors: Sello
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D001688:Biological Products / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; D010456:Peptides, Cyclic; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex
keywords: Inhibitors; Leukemia; Proteasome; Syringolins