Enantioselective inhibition of TNF-alpha release by thalidomide and thalidomide-analogues

Chirality. 1996;8(5):390-6. doi: 10.1002/(SICI)1520-636X(1996)8:5<390::AID-CHIR6>3.0.CO;2-I.


The question whether the immunomodulating activity of rac-thalidomide resides in either the (-)-(S)- or the (+)-(R)-enantiomer was addressed by synthesis and separation of pure enantiomers of thalidomide analogues which carry a methyl-group at the asymmetric carbon atom and are thus prevented from racemization. The effect of the pure enantiomers of the thalidomide-analogues and also of the enantiomers of thalidomide on release of TNF-alpha was tested in vitro by using stimulated peripheral mononuclear blood cells. Both enantiomers of thalidomide inhibited the release of TNF-alpha equally well at low concentrations (5 and 12.5 micrograms/ml) but at higher concentrations (25 and 50 micrograms 50 micrograms/ml) there was a weak but statistically significant selectivity towards the (-)-(S)-enantiomer. In the case of the configuration-stable thalidomide-analogues there was a very pronounced and statistically significant enantioselectivity towards the (S)-form even at lower concentrations (> or = 5 micrograms/ml). The (S)-enantiomers of the thalidomide-analogues differed in their inhibitory potency from (-)-(S)-thalidomide suggesting that the introduction of the methyl-group increases the TNF-alpha-inhibitory activity while the reduction of one of the carbonyl-functions in the glutarimide-moiety to a methylene-group decreases activity. The effect of these small molecular alterations on activity and the enantioselectivity towards the (S)-enantiomers may indicate that thalidomide and its analogues directly interact with one or several cellular target-proteins.

MeSH terms

  • Cells, Cultured
  • Humans
  • Immunosuppressive Agents / chemistry
  • Immunosuppressive Agents / pharmacology*
  • Kinetics
  • Molecular Conformation
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thalidomide / analogs & derivatives*
  • Thalidomide / chemistry
  • Thalidomide / pharmacology*
  • Tumor Necrosis Factor-alpha / metabolism*


  • Immunosuppressive Agents
  • Tumor Necrosis Factor-alpha
  • Thalidomide