Wagner Carl E, Jurutka Peter W
School of Mathematical and Natural Sciences, New College of Interdisciplinary Arts and Sciences, Arizona State University, Glendale, AZ, USA.
Methods Mol Biol. 2019;2019:109-121. doi: 10.1007/978-1-4939-9585-1_8.
The methods described in this chapter concern procedures for the design, synthesis, and in vitro biological evaluation of an array of potent retinoid-X-receptor (RXR) agonists employing 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN), and recently reported NEt-TMN analogs, as a case study. These methods have been extensively applied beyond the present case study to generate several analogs of other potent RXR agonists (rexinoids), particularly the RXR agonist known as bexarotene (Bex), a Food and Drug Administration (FDA) approved drug for cutaneous T-cell lymphoma that is also often prescribed, off-label, for breast, lung, and other human cancers. Common side effects with Bex treatment include hypertriglyceridemia and hypothyroidism, because of off-target activation or inhibition of other nuclear receptor pathways impacted by RXR. Because rexinoids are often selective for RXR, versus the retinoic-acid-receptor (RAR), cutaneous toxicity is often avoided as a side effect for rexinoid treatment. Several other potent RXR agonists, and their analogs, have been reported in the literature and rigorously evaluated (often in comparison to Bex) as potential cancer therapeutics with unique activity and side-effect profiles. Some of the more prominent examples include LGD100268, CD3254, and 9-cis-UAB30, to name only a few. Hence, the methods described herein are more widely applicable to a diverse array of RXR agonists.In terms of design, the structure-activity relationship (SAR) study is usually performed by modifying three distinct areas of the rexinoid base structure, either of the nonpolar or polar sides of the rexinoid and/or the linkage that joins them. For the synthesis of the modified base-structure analogs, often identical synthetic strategies used to access the base-structure are applied; however, reasonable alternative synthetic routes may need to be explored if the modified analog intermediates encounter bottlenecks where yields are negligible for a given step in the base-structure route. In fact, this particular problem was encountered and successfully resolved in our case study for generating an array of NEt-TMN analogs.
本章所述方法涉及一系列高效视黄酸X受体（RXR）激动剂的设计、合成及体外生物学评估程序，以6-(乙基(5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基)氨基)烟酸（NEt-TMN）及近期报道的NEt-TMN类似物作为案例研究。这些方法已广泛应用于当前案例研究之外，以生成其他多种高效RXR激动剂（类视黄醇）的类似物，尤其是被称为贝沙罗汀（Bex）的RXR激动剂，它是一种经美国食品药品监督管理局（FDA）批准用于治疗皮肤T细胞淋巴瘤的药物，也常被超适应症处方用于治疗乳腺癌、肺癌及其他人类癌症。使用Bex治疗的常见副作用包括高甘油三酯血症和甲状腺功能减退，这是由于RXR对其他核受体途径的脱靶激活或抑制所致。由于类视黄醇通常对RXR具有选择性，相对于视黄酸受体（RAR），类视黄醇治疗通常可避免皮肤毒性这一副作用。文献中还报道了其他几种高效RXR激动剂及其类似物，并作为具有独特活性和副作用特征的潜在癌症治疗药物进行了严格评估（通常与Bex进行比较）。其中一些较为突出的例子包括LGD100268、CD3254和9-顺式-UAB30等。因此，本文所述方法更广泛适用于多种RXR激动剂。在设计方面，结构-活性关系（SAR）研究通常通过修饰类视黄醇基础结构的三个不同区域来进行，这些区域可以是类视黄醇的非极性或极性侧以及连接它们的键。对于修饰后的基础结构类似物的合成，通常采用与合成基础结构相同的合成策略；然而，如果修饰后的类似物中间体遇到瓶颈，即在基础结构路线的给定步骤中产量可忽略不计，则可能需要探索合理的替代合成路线。事实上，在我们生成一系列NEt-TMN类似物的案例研究中就遇到并成功解决了这个特殊问题。
