Beard R L, Colon D F, Song T K, Davies P J, Kochhar D M, Chandraratna R A
Department of Chemistry, Allergan, Incorporated, Irvine, California 92715-1599, USA.
J Med Chem. 1996 Aug 30;39(18):3556-63. doi: 10.1021/jm960386h.
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.
类视黄醇通过与核受体结合并激活核受体来发挥其生物学效应，这些核受体与DNA上的反应元件相互作用以促进基因转录。类视黄醇受体有两个家族，即视黄酸受体（RAR）家族和类视黄醇X受体（RXR）家族，每个家族又进一步分为三个亚类：RARα、β、γ和RXRα、β、γ。在此，我们描述了一系列新的二芳基硫醚类视黄醇类似物的合成及其构效关系，这些类似物能特异性结合并反式激活RXR。此外，这些类似物的亚砜和砜衍生物是部分激动剂，仅在高浓度时激活RXR。因此，这些化合物具有潜在的代谢失活位点，与其他具有类芳维甲酸样结构的化合物相比，其全身效应可能持续时间更短。我们还表明，这些化合物在未转染细胞中具有活性，这可通过它们在HL-60细胞中诱导转谷氨酰胺酶活性的能力来证明。最后，我们证实了我们早期的报告，即与RAR特异性激动剂相比，RXR特异性激动剂可能具有更低的致畸毒性，因为这些化合物作为软骨形成抑制剂的效力远低于RAR特异性激动剂，如TTNPB。
