Muccio D D, Brouillette W J, Alam M, Vaezi M F, Sani B P, Venepally P, Reddy L, Li E, Norris A W, Simpson-Herren L, Hill D L
Department of Chemistry, University of Alabama at Birmingham 35294, USA.
J Med Chem. 1996 Sep 13;39(19):3625-35. doi: 10.1021/jm9603126.
We recently demonstrated that conformationally defined 6-s-trans-retinoic acid (RA) analogs were effective in the prevention of skin papillomas (Vaezi et al. J. Med. Chem. 1994, 37, 4499-4507) and selective agonists for nuclear receptor binding and activation (Alam et al. J. Med. Chem. 1995, 38, 2302-2310). In order to probe important structure-activity relationships, we evaluated a homologous series of four 6-s-trans-retinoids that are 8-(2'-cyclohexen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acids with different substituents at 2' (R2) and 3' (R1) positions on the cyclohexene ring. UAB1 (R1 = R2 = H), UAB4 (R1 = R2 = Me), UAB7 (R1 = Me, R2 = iPr), and UAB8 (R1 = Et, R2 = iPr) contain alkyl R groups that mimic, to different extents, portions of the trimethylcyclohexenyl ring of RA. Both 9Z- and all-E-isomers of these retinoids were evaluated in binding assays for cellular retinoic acid-binding proteins (CRABP-I and CRABP-II), a nuclear retinoic acid receptor (RAR alpha), and a nuclear retinoid X receptor (RXR alpha). The all-E-isomers of UAB retinoids bound tightly to CRABPs and RAR alpha, the binding affinity of the all-E-isomer increased systematically from UAB1 to UAB8, and binding for the latter was comparable to that of all-E-RA. In contrast to RA, the (9Z)-UAB retinoids were at least 200-fold less active than the all-E-isomers in binding to RAR alpha. The (9Z)-UAB isomers exhibited increasingly stronger binding to RXR alpha, and (9Z)-UAB8 was nearly as effective as (9Z)-RA in binding affinity. The retinoids were also evaluated in gene expression assays mediated by RAR alpha and RXR alpha homodimers or RAR alpha/RXR alpha heterodimers. Consistent with the binding affinities, the (all-E)-UAB retinoids activated gene transciption mediated by RAR alpha homodimers or RAR alpha/RXR alpha heterodimers, while the (9Z)-UAB isomers activated only the RXR alpha homodimer-mediated transcription. The all-E- and 9Z-isomers of the UAB retinoids were further evaluated for their capacity to prevent the induction of mouse skin papillomas. When compared to RA, only the (all-E)-UAB retinoids containing bulky R1 and R2 groups were effective in this chemoprevention assay. (9Z)-RA displayed equal capacity as RA to prevent papillomas, while the 9Z-isomers of the UAB retinoids were much less effective. Taken together, these studies demonstrate that the cyclohexenyl ring substituents of 6-s-trans-UAB retinoids are important for their biological activities and that the chemopreventive effect of the all-E-isomers of these retinoids correlates well with their capacity to bind to RARs and activate RAR/RXR-mediated transcription.
我们最近证明，构象明确的6-s-反式视黄酸（RA）类似物在预防皮肤乳头瘤方面有效（Vaezi等人，《药物化学杂志》，1994年，37卷，4499 - 4507页），并且是核受体结合和激活的选择性激动剂（Alam等人，《药物化学杂志》，1995年，38卷，2302 - 2310页）。为了探究重要的构效关系，我们评估了一系列同源的四种6-s-反式视黄酸类化合物，它们是8-(2'-环己烯-1'-亚基)-3,7-二甲基-2,4,6-辛三烯酸，在环己烯环的2'（R2）和3'（R1）位置有不同的取代基。UAB1（R1 = R2 = H）、UAB4（R1 = R2 = Me）、UAB7（R1 = Me，R2 = iPr）和UAB8（R1 = Et，R2 = iPr）含有烷基R基团，它们在不同程度上模拟了RA的三甲基环己烯基环的部分结构。这些视黄酸类化合物的9Z-和全反式异构体都在细胞视黄酸结合蛋白（CRABP-I和CRABP-II）、核视黄酸受体（RARα）和核类视黄醇X受体（RXRα）的结合试验中进行了评估。UAB视黄酸类化合物的全反式异构体与CRABPs和RARα紧密结合，全反式异构体的结合亲和力从UAB1到UAB8系统性增加，并且后者与全反式RA的结合相当。与RA相反，(9Z)-UAB视黄酸类化合物与RARα结合的活性比全反式异构体至少低200倍。(9Z)-UAB异构体与RXRα的结合越来越强，并且(9Z)-UAB8在结合亲和力方面几乎与(9Z)-RA一样有效。这些视黄酸类化合物还在由RARα和RXRα同二聚体或RARα/RXRα异二聚体介导的基因表达试验中进行了评估。与结合亲和力一致(全反式)-UAB视黄酸类化合物激活由RARα同二聚体或RARα/RXRα异二聚体介导的基因转录，而(9Z)-UAB异构体仅激活RXRα同二聚体介导的转录。UAB视黄酸类化合物的全反式和9Z-异构体进一步评估了它们预防小鼠皮肤乳头瘤诱导的能力。与RA相比，在这种化学预防试验中，只有含有庞大R1和R2基团的(全反式)-UAB视黄酸类化合物有效。(9Z)-RA在预防乳头瘤方面与RA具有相同的能力，而UAB视黄酸类化合物的9Z-异构体效果要差得多。综上所述，这些研究表明6-s-反式-UAB视黄酸类化合物的环己烯基环取代基对其生物活性很重要，并且这些视黄酸类化合物全反式异构体的化学预防效果与其结合RARs和激活RAR/RXR介导的转录的能力密切相关。
