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Enantioselective inhibition of TNF‐α release by thalidomide and thalidomide‐analogues
Author(s) -
Wnendt Stephan,
Finkam Michael,
Winter Werner,
Ossig Joachim,
Raabe Gerd,
Zwingenberger Kai
Publication year - 1996
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/(sici)1520-636x(1996)8:5<390::aid-chir6>3.0.co;2-i
Subject(s) - chemistry , thalidomide , enantiomer , racemization , stereochemistry , moiety , enantioselective synthesis , biological activity , in vitro , biochemistry , medicine , multiple myeloma , catalysis
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 relapse of TNF‐α was tested in vitro by using stimulated peripheral mononuclear blood cells. Both enantiomers of thalidomide inhibited the release of TNF‐α equally well at low concentrations (5 and 12.5 μg/ml) but at higher concentrations (25 and 50 μg/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 (≥5 μg/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‐α‐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. © 1996 Wiley‐Liss, Inc.