Fluorinated isatin derivatives. Part 1: Synthesis of new N-substituted (S)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatins as potent caspase-3 and -7 inhibitors

A series of new N-substituted (S)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin derivatives has been synthesized and tested as inhibitors of caspases-3 and -7, which are known to be downstream enzymes critical in the execution of apoptosis. N-Propyl- and N-butyl isatins, as well as the corresponding terminal alcohols and regioisomeric fluorobutyl derivatives were shown to be excellent inhibitors having different binding potencies for caspases-3 and -7. In contrast, the corresponding fluoroethyl and fluoropropyl compounds were about 100–1000 times less active. Fluorinated N-benzyl isatins as well as trifluoroalkyl and difluoroalkyl derivatives were moderate inhibitors. However, isatins bearing different alkylether groups at N-1 are very weak or not active as inhibitors of caspases-3 and -7.

A series of new (S)-5-[1-(2-methoxymethylpyrrolinyl)sulfonyl]isatins bearing fluorinated and non-fluorinated N-alkyl- and N-benzyl substituents has been synthesized and their inhibition potencies were assayed for recombinant human caspases-3 and -7. Among the most active inhibitors in this series are the n-propyl- and n-butyl derivatives as well as the corresponding terminal alcohols and fluorides.Figure optionsDownload as PowerPoint slide