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潜在维甲酸 X 受体选择性激动剂的建模、合成和生物学评价：4-[1-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)乙炔基]苯甲酸（贝沙罗汀）的新型卤代类似物。

Modeling, synthesis and biological evaluation of potential retinoid X receptor-selective agonists: novel halogenated analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene).

机构信息

School of Mathematical and Natural Sciences, New College of Interdisciplinary Arts&Sciences, Arizona State University, 4701 W. Thunderbird Rd., Glendale, AZ 85306, USA.

出版信息

ChemMedChem. 2012 Sep;7(9):1551-66. doi: 10.1002/cmdc.201200319.

DOI:10.1002/cmdc.201200319
PMID:22927238
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3479356/
Abstract

The synthesis of halogenated analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), known commonly as bexarotene, and their evaluation for retinoid X receptor (RXR)-specific agonist performance is described. Compound 1 is FDA approved to treat cutaneous T-cell lymphoma (CTCL); however, bexarotene treatment can induce hypothyroidism and elevated triglyceride levels, presumably by disrupting RXR heterodimer pathways for other nuclear receptors. The novel halogenated analogues in this study were modeled and assessed for their ability to bind to RXR and stimulate RXR homodimerization in an RXRE-mediated transcriptional assay as well as an RXR mammalian-2-hybrid assay. In an array of eight novel compounds, four analogues were discovered to promote RXR-mediated transcription with EC(50) values similar to that of 1 and are selective RXR agonists. Our approach also uncovered a periodic trend of increased binding and homodimerization of RXR when substituting a halogen atom for a proton ortho to the carboxylic acid on 1.

摘要

描述了 4-[1-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)乙炔基]苯甲酸（1）的卤代类似物的合成，该化合物通常被称为贝沙罗汀。评估了它们作为视黄醇 X 受体 (RXR) 特异性激动剂的性能。1 已被 FDA 批准用于治疗皮肤 T 细胞淋巴瘤 (CTCL)；然而，贝沙罗汀治疗会导致甲状腺功能减退和甘油三酯水平升高，这可能是通过破坏 RXR 异二聚体途径干扰其他核受体。本研究中的新型卤代类似物经过建模，并评估了它们在 RXRE 介导的转录测定以及 RXR 哺乳动物-2 杂交测定中与 RXR 结合和刺激 RXR 同源二聚化的能力。在一系列的 8 种新型化合物中，发现有 4 种类似物能够促进 RXR 介导的转录，其 EC(50) 值与 1 相似，并且是选择性的 RXR 激动剂。我们的方法还揭示了当在 1 的羧酸对位上用卤素原子取代质子时，RXR 的结合和同源二聚化呈周期性增加的趋势。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3edb/3479356/49a3a5fe23dc/nihms408650f14.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3edb/3479356/ce3dff630e91/nihms408650f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3edb/3479356/fa6a972b4d98/nihms408650f5a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3edb/3479356/0fccf938aaed/nihms408650f6a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3edb/3479356/dabeb734dc97/nihms408650f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3edb/3479356/2de44dc737a8/nihms408650f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3edb/3479356/99a04057d674/nihms408650f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3edb/3479356/3a502a06cd56/nihms408650f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3edb/3479356/062ebe25fe70/nihms408650f11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3edb/3479356/5c56f57d8a59/nihms408650f12.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3edb/3479356/40e965a6b86d/nihms408650f13.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3edb/3479356/49a3a5fe23dc/nihms408650f14.jpg

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