Alam M, Zhestkov V, Sani B P, Venepally P, Levin A A, Kazmer S, Li E, Norris A W, Zhang X K, Lee M O
Department of Chemistry, University of Alabama at Birmingham 35294, USA.
J Med Chem. 1995 Jun 23;38(13):2302-10. doi: 10.1021/jm00013a006.
We recently demonstrated in animal models that a new conformationally defined RA isomer (Vaezi et al. J. Med. Chem. 1994, 37, 4499-4507) was as effective as RA in the prevention of skin papillomas but was less toxic. In order to provide more details concerning this improved action, we report here the preparation of a homologous conformationally defined 6-s-trans-retinoid (1) and investigate its ability to interact with proteins and to activate gene expression. Four configurational isomers of 1 were evaluated in binding assays for cellular retinoic acid binding protein, CRABP (isolated from chick skin); CRABP-I and CRABP-II (cloned from mouse); nuclear retinoic acid receptors (RARs); and nuclear retinoid X receptors (RXRs). In each assay the all-E-isomer of this retinoid had an activity that was comparable to that of (all-E)-RA. However, the 9Z-isomer was at least 200-fold less active than (all-E)-RA in binding to different RARs, while it was only 6-20 times less active than (9Z)-RA in binding to different RXRs. In an in vivo transient transfection assay, the all-E-isomer activated a reporter gene containing a retinoic acid response element (RARE) with efficiency similar to (all-E)-RA when expression vectors for either RAR alpha, RAR beta, RAR gamma alone or RAR alpha together with RXR alpha were cotransfected. In contrast, the 9Z-isomer was much less active than (9Z)-RA in the same assay systems. However, (9Z)-1 efficiently enhanced the DNA binding and transactivational activity of RXR alpha homodimers. Taken together, these studies demonstrate that the all-E- and 9Z-isomers of this retinoid are selective and potent agonists of RAR and RXR binding and activation.
我们最近在动物模型中证明，一种新的构象确定的视黄酸异构体（Vaezi等人，《药物化学杂志》，1994年，37卷，4499 - 4507页）在预防皮肤乳头状瘤方面与视黄酸一样有效，但毒性较小。为了提供有关这种改善作用的更多细节，我们在此报告一种同源构象确定的6 - s -反式视黄酸（1）的制备，并研究其与蛋白质相互作用以及激活基因表达的能力。在针对细胞视黄酸结合蛋白CRABP（从鸡皮肤中分离）、CRABP - I和CRABP - II（从小鼠中克隆）、核视黄酸受体（RARs）以及核类视黄醇X受体（RXRs）的结合试验中评估了1的四种构型异构体。在每个试验中，这种视黄酸的全反式异构体的活性与（全反式）视黄酸相当。然而，9Z异构体与不同RARs结合时的活性比（全反式）视黄酸至少低200倍，而与不同RXRs结合时的活性仅比（9Z）视黄酸低6 - 20倍。在体内瞬时转染试验中，当单独转染RARα、RARβ、RARγ的表达载体或RARα与RXRα一起转染时，全反式异构体激活含有视黄酸反应元件（RARE）的报告基因的效率与（全反式）视黄酸相似。相比之下，在相同的试验系统中，9Z异构体的活性比（9Z）视黄酸低得多。然而，（9Z）- 1有效地增强了RXRα同二聚体的DNA结合和反式激活活性。综上所述，这些研究表明这种视黄酸的全反式和9Z异构体是RAR和RXR结合及激活的选择性强效激动剂。
