title: 5-pyrrolidinylsulfonyl isatins as a potential tool for the molecular imaging of caspases in apoptosis.
abstract: Caspases are the unique enzymes responsible for the execution of the cell death program and may represent an exclusive target for the specific molecular imaging of apoptosis in vivo. 5-Pyrrolidinylsulfonyl isatins represent potent nonpeptidyl caspase inhibitors that may be suitable for the development of caspase binding radioligands (CBRs). (S)-5-[1-(2-Methoxymethylpyrrolidinyl)sulfonyl]isatin (7) served as a lead compound for modification of its N-1-position. Corresponding pairs of N-1-substituted 2-methoxymethyl- and 2-phenoxymethylpyrrolidinyl derivatives were examined in vitro by biochemical caspase inhibition assays. All target compounds possess high in vitro caspase inhibition potencies in the nanomolar to subnanomolar range for caspase-3 (Ki=0.2-56.1 nM). As shown for compound (S)-1-(4-(2-fluoroethoxy)benzyl)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin (35), the class of N-1-substituted 5-pyrrolidinylsulfonyl isatins competitively inhibits caspase-3. All caspase inhibitors show selectivity for the effector caspases-3 and -7 in vitro. The 2-methoxymethylpyrrolidinyl versions of the isatins appear to possess superior caspase inhibition potencies in cellular apoptosis inhibition assays compared with the 2-phenoxymethylpyrrolidinyl inhibitors.
authors.affiliation: Department of Nuclear Medicine, University Hospital of the Westfälische Wilhelms-Universität, Münster, Germany. kopka@uni-muenster.de
authors.forename: Klaus
authors.initials: K
authors.lastname: Kopka
authors.forename: Andreas
authors.initials: A
authors.lastname: Faust
authors.forename: Petra
authors.initials: P
authors.lastname: Keul
authors.forename: Stefan
authors.initials: S
authors.lastname: Wagner
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Breyholz
authors.forename: Carsten
authors.initials: C
authors.lastname: Höltke
authors.forename: Otmar
authors.initials: O
authors.lastname: Schober
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.forename: Bodo
authors.initials: B
authors.lastname: Levkau
mesh_terms: D017209:Apoptosis; D053148:Caspase 3 / Q000737:chemistry; D053179:Caspase 7 / Q000737:chemistry; D061945:Caspase Inhibitors; D020169:Caspases / Q000737:chemistry; D002478:Cells, Cultured; D006801:Humans; D007457:Iodine Radioisotopes; D007510:Isatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007553:Isotope Labeling; D007700:Kinetics; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014471:Umbilical Veins / Q000166:cytology
chemical_list: C516218:1-(4-(2-fluoroethoxy)benzyl)-5-(1-(2-methoxymethylpyrrolidinyl)sulfonyl)isatin; D061945:Caspase Inhibitors; D007457:Iodine Radioisotopes; D011759:Pyrrolidines; D019275:Radiopharmaceuticals; D007510:Isatin; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases