title: Synthesis of a novel suppressor of beta-cell apoptosis via diversity-oriented synthesis.
abstract: The synthesis of a stereochemically diverse library of medium-sized rings accessible via a 'build/couple/pair' strategy is described. Key aspects of the synthesis include S(N)Ar cycloetherification of a linear amine template to afford eight stereoisomeric 8-membered lactams and subsequent solid-phase diversification of these scaffolds to yield a 6488-membered library. Screening of this compound collection in a cell-based assay for the suppression of cytokine-induced beta-cell apoptosis resulted in the identification of a small-molecule suppressor capable of restoring glucose-stimulated insulin secretion in a rat beta-cell line. The presence of all stereoisomers in the screening collection enabled preliminary determination of the structural and stereochemical requirements for cellular activity, while efficient follow-up chemistry afforded BRD-0476 (probe ML187), which had an approximately three-fold increase in activity. These results demonstrate the utility of diversity-oriented synthesis to probe discovery using cell-based screening, and the importance of including stereochemical diversity in screening collections for the development of stereo/structure-activity relationships.
authors.affiliation: Chemical Biology Program and Chemical Biology Platform, The Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Danny Hung-Chieh
authors.initials: DH
authors.lastname: Chou
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Duvall
authors.forename: Baudouin
authors.initials: B
authors.lastname: Gerard
authors.forename: Haibo
authors.initials: H
authors.lastname: Liu
authors.forename: Bhaumik A
authors.initials: BA
authors.lastname: Pandya
authors.forename: Byung-Chul
authors.initials: BC
authors.lastname: Suh
authors.forename: Erin M
authors.initials: EM
authors.lastname: Forbeck
authors.forename: Patrick
authors.initials: P
authors.lastname: Faloon
authors.forename: Bridget K
authors.initials: BK
authors.lastname: Wagner
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Marcaurelle