3,4‐Disubstituted benzamides protect CD4+ T‐cells from acute apoptotic stimuli
Abstract
Sepsis is a pathologic condition with extensive lymphocyte apoptosis. We screened 32,000 compounds and identified 15 that prevent CD4+ T‐cell apoptosis. Most hits also augmented Th1 cytokine production. A 3,4‐disubstituted benzamide was selected for structure‐activity studies. Derivatives were synthesized in four steps, installing different functional groups at the 1 and 4 positions. Compounds were evaluated in apoptosis, cytokine secretion and protein phosphorylation assays. Apoptosis was induced by lyophilized E. coli and caspase‐3 activity was measured. Cytokine secretion was stimulated using agonistic antibodies to CD3 and CD28. Protein phosphorylation was determined after 15 minute incubation with compound. The average yield of 3,4‐disubstituted benzamides was 43%. The first generation library yielded 2 compounds that: protected cells from apoptosis, promoted Th1 cytokine release, and led to ~30% increase in pAkt and ~21% increase in pIκBα without altering MAP kinase phosphorylation. These compounds modulate CD4+ T‐cell activity by removing the need for a costimulatory signal and may represent a new approach to the treatment of sepsis. Supported by DTRA and WUSM.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 01, 2009
- Source ID
- 10.1096/fasebj.23.1_supplement.533.4
Entities
People
- Andrew Walton
- Jeffrey Nguyen
- Jonathan Mcdunn
- Tom Ellenberger
Organizations
- Defense Threat Reduction Agency
- Washington University in St. Louis