title: Optimization of subsite binding to the beta5 subunit of the human 20S proteasome using vinyl sulfones and 2-keto-1,3,4-oxadiazoles: syntheses and cellular properties of potent, selective proteasome inhibitors.
abstract: Beginning with the peptide sequence Cbz-Ile-Glu(OtBu)-Ala-Leu found in PSI (3), a series of vinyl sulfones (VS) were synthesized for evaluation as inhibitors of the chymotrypsin-like activity of the 20S proteasome. Variations at the key P3 position confirmed the importance of a long side chain capped with a hydrophobic group for optimal potency, consistent with a model of binding to the S3 subsite. The tert-butyl glutamic ester initially used at P3 gave plasma unstable, insoluble compounds and was replaced with the better isostere, N-beta-neopentyl asparagine. The inhibitors were shortened by replacing the N-terminal Cbz-isoleucine with a p-tosyl group without loss of potency. Small l-amino acids were used at P2, where d-substitution was not tolerated. The resulting optimized P4-P3-P2 sequence was grafted onto a novel proteasome inhibitor warhead, 2-keto-1,3,4-oxadiazoles (KOD), to produce reversible, subnanomolar proteasome inhibitors that were 1000-fold selective versus cathepsin B (CatB), cathepsin S (CatS), and trypsin-like as well as PGPH-like proteasome activity. A number of compounds in both the VS and the KOD series exhibited growth inhibitory effects against the human prostate cancer cell line PC3 at submicromolar concentrations.
authors: Department of Medicinal Chemistry, 180 Kimball Way, South San Francisco, California 94080, USA. brydzewski@sbcglobal.net
authors: Robert M
authors: RM
authors: Rydzewski
authors: Leland
authors: L
authors: Burrill
authors: Rohan
authors: R
authors: Mendonca
authors: James T
authors: JT
authors: Palmer
authors: Mark
authors: M
authors: Rice
authors: Ram
authors: R
authors: Tahilramani
authors: Kathryn E
authors: KE
authors: Bass
authors: Ling
authors: L
authors: Leung
authors: Erik
authors: E
authors: Gjerstad
authors: James W
authors: JW
authors: Janc
authors: Lin
authors: L
authors: Pan