5-pyrrolidinylsulfonyl Isatins as a Potential Tool for the Molecular Imaging of Caspases in Apoptosis

J Med Chem. 2006 Nov 16;49(23):6704-15. doi: 10.1021/jm051217c.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Caspase 3 / chemistry
  • Caspase 7 / chemistry
  • Caspase Inhibitors*
  • Caspases / chemistry
  • Cells, Cultured
  • Humans
  • Iodine Radioisotopes
  • Isatin / analogs & derivatives*
  • Isatin / chemical synthesis*
  • Isatin / chemistry
  • Isatin / pharmacology
  • Isotope Labeling
  • Kinetics
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology
  • Radiopharmaceuticals / chemical synthesis
  • Radiopharmaceuticals / chemistry
  • Stereoisomerism
  • Structure-Activity Relationship
  • Umbilical Veins / cytology

Substances

  • 1-(4-(2-fluoroethoxy)benzyl)-5-(1-(2-methoxymethylpyrrolidinyl)sulfonyl)isatin
  • Caspase Inhibitors
  • Iodine Radioisotopes
  • Pyrrolidines
  • Radiopharmaceuticals
  • Isatin
  • Caspase 3
  • Caspase 7
  • Caspases