title: Fluorinated isatin derivatives. Part 1: synthesis of new N-substituted (S)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatins as potent caspase-3 and -7 inhibitors.
abstract: 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.
authors.affiliation: Organisch-Chemisches Institut and International NRW Graduate School of Chemistry, Westfälische Wilhelms-Universität, Corrensstrasse 40, D-48149 Münster, Germany.
authors.forename: Anil Kumar
authors.initials: AK
authors.lastname: Podichetty
authors.forename: Andreas
authors.initials: A
authors.lastname: Faust
authors.forename: Klaus
authors.initials: K
authors.lastname: Kopka
authors.forename: Stefan
authors.initials: S
authors.lastname: Wagner
authors.forename: Otmar
authors.initials: O
authors.lastname: Schober
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.forename: Günter
authors.initials: G
authors.lastname: Haufe
mesh_terms: D000478:Alkylation; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D061945:Caspase Inhibitors; D054879:Halogenation; D007510:Isatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D061945:Caspase Inhibitors; D011480:Protease Inhibitors; D007510:Isatin; D053148:Caspase 3; D053179:Caspase 7