Open AccessSynthesis of a Novel Suppressor of β-Cell Apoptosis via Diversity-Oriented Synthesis
Author(s) -
Danny HungChieh Chou,
Jeremy R. Duvall,
Baudouin Gerard,
Haibo Liu,
Bhaumik A. Pandya,
Beomseok Suh,
Erin M. Forbeck,
Patrick W. Faloon,
Bridget K. Wagner,
Lisa A. Marcaurelle
Publication year - 2011
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml200120m
Subject(s) - apoptosis , small molecule , combinatorial chemistry , suppressor , cell culture , computational biology , drug discovery , in vitro , chemistry , cell , amine gas treating , stereochemistry , biology , biochemistry , genetics , gene , organic chemistry
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.