Synthesis of 7-halogenated Isatin Sulfonamides: Nonradioactive Counterparts of caspase-3/-7 Inhibitor-Based Potential Radiopharmaceuticals for Molecular Imaging of Apoptosis

J Med Chem. 2014 Nov 26;57(22):9383-95. doi: 10.1021/jm500718e. Epub 2014 Nov 14.

Abstract

N-Alkylated (S)-7-halogen-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatins were developed as a new group of nonradioactive reference compounds for future radiotracers. Inhibitor potency studies of these compounds suggest that the binding pockets readily accommodate both the 7-halogen substituents and aliphatic side chains (methyl to n-butyl) as well as some ω-fluorinated analogues (3-fluoropropyl and 4-fluorobutyl) at the isatin nitrogen. Indeed, compared to the halogen free parent compounds, some 7-halogenated derivatives exhibited slightly improved inhibitory potencies with IC50 values up to 2.6 nM (caspase-3) and 3.3 nM (caspase-7), respectively. Moreover, the 7-position of isatin, a potential cytochrome P450 hydroxylation site, was substituted by I, Br, Cl, and F to potentially enhance the metabolic stability of isatin sulfonamides. As an example, the radiotracer [(18)F]39 that was produced by (19)F/(18)F isotope exchange was shown to be stable in human blood serum after incubation at 37 °C for at least 90 min.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Caspase 3 / chemistry
  • Caspase 7 / chemistry
  • Caspase Inhibitors / chemistry*
  • Chemistry, Pharmaceutical / methods
  • Cytochrome P-450 Enzyme System / chemistry
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Halogens / chemistry
  • Humans
  • Inhibitory Concentration 50
  • Isatin / chemical synthesis*
  • Isatin / chemistry
  • Molecular Imaging / instrumentation
  • Molecular Imaging / methods
  • Radiopharmaceuticals / chemistry*
  • Serum / drug effects
  • Solvents / chemistry
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Temperature
  • Time Factors

Substances

  • Caspase Inhibitors
  • Enzyme Inhibitors
  • Halogens
  • Radiopharmaceuticals
  • Solvents
  • Sulfonamides
  • Isatin
  • Cytochrome P-450 Enzyme System
  • Caspase 3
  • Caspase 7