Beard R L, Chandraratna R A, Colon D F, Gillett S J, Henry E, Marler D K, Song T, Denys L, Garst M E, Arefieg T
Department of Chemistry, Allergan, Incorporated, Irvine, California 92715-1599, USA.
J Med Chem. 1995 Jul 21;38(15):2820-9. doi: 10.1021/jm00015a004.
Retinoids elicit biological responses by activating a series of nuclear receptors. Six retinoid receptors belonging to two families are currently known: retinoic acid receptors (RAR alpha,beta,and gamma) and retinoid X receptors (RXR alpha,beta,and gamma). Stilbene retinoid analogs of retinoic acid (RA), such as (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)prope n-1- yl]benzoic acid (TTNPB, 1) and (E)-4-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)pro pen-1- yl]benzoic acid (3-methyl-TTNPB, 2), display differential RAR and RXR activities, depending on the substituent at C3 of the naphthalene ring. We report here structural modifications of the benzoate moiety of 2 that result in analogs with greater RXR selectivity as well as those with pan-agonist (activate both RAR and RXR receptors) activities, analyze the structural features that impart receptor selectivity, and describe a stereoselective method for the synthesis of these analogs. The biological activities associated with the RAR and RXR receptors were examined by testing representative examples with different receptor activation profiles for their ability to induce tissue transglutaminase (Tgase) activity in a human promyelocytic leukemia cell line (HL-60 cdm-1) and to inhibit tumor-promoter-induced ornithine decarboxylase (ODC) activity in hairless mouse skin. These results suggest that RAR agonists and RXR agonists may have different therapeutic applications. Finally, we show that RXR agonists are significantly reduced in teratogenic potency relative to RAR agonists and may therefore have significant advantages in clinical practice.
类视黄醇通过激活一系列核受体引发生物学反应。目前已知属于两个家族的六种类视黄醇受体：维甲酸受体（RARα、β和γ）和类视黄醇X受体（RXRα、β和γ）。维甲酸（RA）的芪类视黄醇类似物，如（E）-4-[2-（5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基）丙烯-1-基]苯甲酸（TTNPB，1）和（E）-4-[2-（5,6,7,8-四氢-3,5,5,8,8-五甲基-2-萘基）丙烯-1-基]苯甲酸（3-甲基-TTNPB，2），根据萘环C3位的取代基显示出不同的RAR和RXR活性。我们在此报告对2的苯甲酸酯部分进行的结构修饰，这些修饰产生了具有更高RXR选择性的类似物以及具有泛激动剂（激活RAR和RXR受体）活性的类似物，分析赋予受体选择性的结构特征，并描述了这些类似物的立体选择性合成方法。通过测试具有不同受体激活谱的代表性实例在人早幼粒细胞白血病细胞系（HL-60 cdm-1）中诱导组织转谷氨酰胺酶（Tgase）活性以及在无毛小鼠皮肤中抑制肿瘤促进剂诱导的鸟氨酸脱羧酶（ODC）活性的能力，研究了与RAR和RXR受体相关的生物学活性。这些结果表明RAR激动剂和RXR激动剂可能具有不同的治疗应用。最后，我们表明相对于RAR激动剂，RXR激动剂的致畸效力显著降低，因此在临床实践中可能具有显著优势。
