Influence of 4- or 5-substituents on the pyrrolidine ring of 5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin derivatives on their inhibitory activities towards caspases-3 and -7

Eur J Med Chem. 2013 Jun;64:562-78. doi: 10.1016/j.ejmech.2013.04.011. Epub 2013 Apr 11.

Abstract

A series of new 4- or 5-substituted pyrrolidine derivatives of 5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin bearing additional n-butyl or 4-fluorobutyl groups at the isatin nitrogen were prepared and their inhibitory activities have been tested against caspases-3 and -7, which are known to participate in the execution of the programmed cell death, called apoptosis. Several analogues fluorinated at the 4-position of the pyrrolidine ring were also synthesized since such inhibitors might be developed as (18)F-radiotracers for molecular imaging of activated caspases in vivo by PET. Enantiomerically pure diastereomeric 4-fluoropyrrolidinyl derivatives inhibited the enzymes in the nanomolar scale, i.e.100-1000 times more efficient than the corresponding 4-methoxy analogues. The 4,4-difluorinated compound showed the best result with IC50 = 362 nM and 178 nM for the aforementioned caspases. In contrast, the 4-methoxy and 4-trifluoromethyl analogues exhibited less inhibition potencies for the enzymes in the μM scale, whereas all 4-OPEG4 (PEG4 = tetraethyleneglycol) and 5-methoxymethyl derivatives were inactive.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caspase 3 / metabolism*
  • Caspase 7 / metabolism*
  • Caspase Inhibitors / chemical synthesis
  • Caspase Inhibitors / chemistry
  • Caspase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Humans
  • Isatin / analogs & derivatives*
  • Isatin / chemical synthesis
  • Isatin / chemistry
  • Isatin / pharmacology
  • Molecular Structure
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry*
  • Pyrrolidines / pharmacology*
  • Structure-Activity Relationship

Substances

  • 5-(1-(2-methoxymethylpyrrolidinyl)sulfonyl)isatin
  • Caspase Inhibitors
  • Pyrrolidines
  • Isatin
  • Caspase 3
  • Caspase 7
  • pyrrolidine