Modeling, synthesis and biological evaluation of potential retinoid X receptor (RXR) selective agonists: novel analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene).
Modeling, synthesis and biological evaluation of potential retinoid X receptor (RXR) selective agonists: novel analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene).
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DOI：
10.1021/jm900496b
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发表时间：
2009-10-08
影响因子：
7.3
通讯作者：
Hart JW
中科院分区：
文献类型：
--
作者：
Wagner CE;Jurutka PW;Marshall PA;Groy TL;van der Vaart A;Ziller JW;Furmick JK;Graeber ME;Matro E;Miguel BV;Tran IT;Kwon J;Tedeschi JN;Moosavi S;Danishyar A;Philp JS;Khamees RO;Jackson JN;Grupe DK;Badshah SL;Hart JW
本文报道了4-[1-（3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基）乙基]苯甲酸(1)类似物（通常称为贝沙罗汀）的合成及其作为类视黄醇- x受体（RXR）特异性激动剂的分析。化合物1已获FDA批准用于治疗皮肤t细胞淋巴瘤（CTCL）；然而，它的使用可能会引起副作用，如甲状腺功能减退和甘油三酯浓度升高，可能是由于RXR与其他核受体的异二聚化被破坏。本研究中的新型类似物已经在RXR哺乳动物-2杂交实验和RXR介导的转录实验中评估了RXR的激活，以及它们诱导细胞凋亡的能力，以及它们的致突变性和细胞毒性。对11种新化合物的分析显示，发现了3种类似物，它们最能诱导RXR介导的转录活性，刺激细胞凋亡，Ki和EC50值接近1，是选择性RXR激动剂。我们的实验方法表明，合理的药物设计可以开发出具有更好生物学特性的新类维生素a。
This report describes the synthesis of analogs of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), commonly known as bexarotene, and their analysis in acting as retinoid-X-receptor (RXR)-specific agonists. Compound 1 has FDA approval to treat cutaneous T-cell lymphoma (CTCL); however, its use can cause side effects such as hypothyroidism and increased triglyceride concentrations, presumably by disruption of RXR heterodimerization with other nuclear receptors. The novel analogs in the present study have been evaluated for RXR activation in an RXR mammalian-2-hybrid assay as well as an RXRE-mediated transcriptional assay, and for their ability to induce apoptosis, as well as for their mutagenicity and cytotoxicity. Analysis of 11 novel compounds revealed the discovery of 3 analogs that best induce RXR-mediated transcriptional activity, stimulate apoptosis, have comparable Ki and EC50 values to 1, and are selective RXR agonists. Our experimental approach suggests that rational drug design can develop new rexinoids with improved biological properties.
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