5-[(S)-(-)-2-(METHOXYMETHYL)PYRROLIDINO]SULFONYLISATIN

Caspase-3/7 inhibitor I is a potent, reversible, isatin sulfonamide-based inhibitor of caspase-3 (Ki(app) = 60 nM; IC50 = 120 nM) and caspase-7 (Ki(app) = 170 nM). It is a weaker inhibitor of caspase-9 (Ki(app) = 3.1 μM) and caspase-1, caspase-2, caspase-4, caspase-6, and caspase-8 (Ki(app)s ≥25 μM). Caspase-3/7 inhibitor I inhibits apoptosis in camptothecin-treated Jurkat cells (IC50 = ~50 μM) and in chondrocytes (44% inhibition at 10 μM and 98% inhibition at 50 μM). The basis for the unique selectivity of this compound for caspases 3 and 7 involves the recognition of three distinct hydrophobic residues in the S2 pocket surrounding the catalytic cysteine residue.