title: Fluorinated isatin derivatives. Part 3. New side-chain fluoro-functionalized pyrrolidinyl sulfonyl isatins as potent caspase-3 and -7 inhibitors.
abstract: BACKGROUND
  Dysregulation of type I programmed cell death (apoptosis) leads to a variety of diseases, among which cancer, cardiovascular and neurodegenerative disorders are the most prominent and widespread. Effector caspases such as caspases-3 and -7 get activated during the apoptotic signaling cascade and hence represent a biological target for the diagnosis and therapy of apoptosis-associated diseases.
  
  
  METHODS
  Synthesis of potent fluorinated analogs of the lead compound (S)-(+)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin facilitates the aim-oriented identification of precursor candidates for (18)F-radiofluorination resulting in radiolabeled compounds that could be employed as tracers for the specific imaging of apoptosis in vivo, using positron-emission tomography.
  
  
  CONCLUSIONS
  Within a series of new mono-, di- and trifluoromethylated pyrrolidine ring analogs of the lead compound, high inhibition potencies were found for caspases-3 and -7 with IC(50) values up to 30 and 37 nM, respectively. A new oxidative desulfurization-fluorination protocol was shown to be a versatile technique for fluorine incorporation.
authors.affiliation: Organisch-Chemisches Institut, Westfälische Wilhelms-Universität, Corrensstraße 40, D-48149 Münster, Germany.
authors.forename: Anil Kumar
authors.initials: AK
authors.lastname: Podichetty
authors.forename: Stefan
authors.initials: S
authors.lastname: Wagner
authors.forename: Andreas
authors.initials: A
authors.lastname: Faust
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.forename: Otmar
authors.initials: O
authors.lastname: Schober
authors.forename: Klaus
authors.initials: K
authors.lastname: Kopka
authors.forename: Günter
authors.initials: G
authors.lastname: Haufe
mesh_terms: D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry*; D005461:Fluorine / Q000737:chemistry*; D005462:Fluorine Radioisotopes / Q000737:chemistry; D054879:Halogenation; D007510:Isatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D049268:Positron-Emission Tomography; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D005462:Fluorine Radioisotopes; D013449:Sulfonamides; D005461:Fluorine; D007510:Isatin; D053148:Caspase 3; D053179:Caspase 7