Exhaustive Fluorine Scanning toward Potent p53–Mdm2 Antagonists

Fluorine dance: We discovered potent p53–Mdm2 antagonists by systematically varying the fluorine substitution pattern around a benzyl group that undergoes stacking interactions with His 96 of Mdm2. The potency of the optimized enantiomer (S)-7 e is >50-fold better than the worst compound of the series. All compounds were efficiently synthesized by Ugi multicomponent reaction chemistry.