Synthesis and structure-activity relationships of retinoid X receptor selective diaryl sulfide analogs of retinoic acid
Synthesis and structure-activity relationships of retinoid X receptor selective diaryl sulfide analogs of retinoic acid
复制标题
DOI：
10.1021/jm960386h
复制
发表时间：
1996-08-30
影响因子：
7.3
通讯作者：
Chandraratna, RAS
中科院分区：
文献类型：
--
作者：
Beard, RL;Colon, DF;Chandraratna, RAS
维甲酸通过结合和激活核受体与DNA上的反应元件相互作用来促进基因转录，从而发挥其生物学效应。维甲酸受体(RAR)家族和维甲酸X受体(RXR)家族又分为三个亚类：RAR(α，β，伽马)和RXR(α，β，伽马)。在这里，我们描述了一系列新的二芳基硫化物维甲酸类似物的合成和构效关系，这些类似物可以特异性地结合和反式激活RXRs。此外，这些类似物的亚砜和砜衍生物是部分激动剂，只有在高浓度时才能激活RXRs。因此，这些化合物具有潜在的代谢失活部位，并且可能比其他具有芳香素类结构的化合物具有较短的持续全身效应。我们还表明，这些化合物在未转基因的细胞中具有活性，这是通过它们诱导HL-60细胞中TGase活性的能力来证明的。最后，我们证实了我们先前的报道，与RAR特异性激动剂相比，RXR特异性激动剂的致畸毒性可能更低，因为这些化合物对软骨形成的抑制作用远低于RAR特异性激动剂，如TTNPB。
Retinoids exert their biological effects by binding to and activating nuclear receptors that interact with responsive elements on DNA to promote gene transcription, There are two families of retinoid receptors, the retinoic acid receptor (RAR) family and the retinoid X receptor (RXR) family, which are each further divided into three subclasses: RAR(alpha,beta,gamma) and RXR(alpha,beta,gamma). Herein we describe the synthesis and structure-activity relationships of a new series of diaryl sulfide retinoid analogs that specifically bind and transactivate the RXRs. Furthermore, the sulfoxide and sulfone derivatives of these analogs are partial agonists which activate the RXRs only at high concentrations. Thus, these compounds possess a potential site of metabolic deactivation and may have less prolonged systemic effects than other compounds with arotinoid-like structures. We show also that these compounds have activity in nontransfected cells as demonstrated by their ability to induce TGase activity in HL-60 Cells. Finally, we corroborate our earlier report that RXR-specific agonists may possess reduced teratogenic toxicity compared to RAR-specific agonists since these compounds are much less potent inhibitors of chondrogenesis than RAR-specific agonists such as TTNPB.