ENANTIOSELECTIVE INHIBITION OF TNF-ALPHA RELEASE BY THALIDOMIDE AND THALIDOMIDE-ANALOGS

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-analog ues which carry a methyl-group at the asymmetric carbon atom and are t hus 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 periph eral mononuclear blood cells. Both enantiomers of thalidomide inhibite d the release of TNF-alpha equally well at low concentrations (5 and 1 2.5 mu g/ml) but at higher concentrations (25 and 50 mu g/ml) there wa s a weak but statistically significant selectivity towards the (-)-(S) -enantiomer. In the case of the configuration-stable thalidomide-analo gues there was a very pronounced and statistically significant enantio selectivity towards the (S)-form even at lower concentrations (greater than or equal to 5 mu g/ml). The (S)-enantiomers of the thalidomide-a nalogues differed in their inhibitory potency from (-)-(S)-thalidomide suggesting that the introduction of the methyl-group increases the TN F-alpha-inhibitory activity while the reduction of one of the carbonyl -functions in the glutarimide-moiety to a methylene-group decreases ac tivity. The effect of these small molecular alterations on activity an d the enantioselectivity towards the (S)-enantiomers may indicate that thalidomide and its analogues directly interact with one or several c ellular target-proteins. (C) 1996 Wiley-Liss, Inc.