Wnendt S, Finkam M, Winter W, Ossig J, Raabe G, Zwingenberger K
Department of Molecular Pharmacology, Gruenenthal Centre of Research, Aachen, Germany.
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.
通过合成和分离在不对称碳原子上带有甲基从而防止消旋的沙利度胺类似物的纯对映体，研究了消旋沙利度胺的免疫调节活性是存在于（-）-（S）-对映体还是（+）-（R）-对映体中。通过使用刺激的外周血单个核细胞在体外测试了沙利度胺类似物的纯对映体以及沙利度胺对映体对TNF-α释放的影响。沙利度胺的两种对映体在低浓度（5和12.5微克/毫升）时对TNF-α释放的抑制效果相同，但在较高浓度（25和50微克/毫升）时，对（-）-（S）-对映体有微弱但具有统计学意义的选择性。对于构型稳定的沙利度胺类似物，即使在较低浓度（≥5微克/毫升）时，对（S）-型也有非常明显且具有统计学意义的对映体选择性。沙利度胺类似物中的（S）-对映体在抑制效力上与（-）-（S）-沙利度胺不同，这表明甲基的引入增加了TNF-α抑制活性，而戊二酰亚胺部分中的一个羰基功能还原为亚甲基则降低了活性。这些小分子改变对活性和对（S）-对映体的对映体选择性的影响可能表明沙利度胺及其类似物与一种或几种细胞靶蛋白直接相互作用。
