Bexarotene prodrugs: Targeting through cleavage by NQO1 (DT-diaphorase)
Bexarotene prodrugs: Targeting through cleavage by NQO1 (DT-diaphorase)
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DOI：
10.1016/j.bmcl.2014.03.003
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发表时间：
2014-04-15
影响因子：
2.7
通讯作者：
Olsson, Roger
中科院分区：
文献类型：
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作者：
Schafer, Anja;Burstein, Ethan S.;Olsson, Roger
贝沙罗汀（Bexarotene）是一种类维甲酸X受体（RXR）激动剂，目前正在作为一种潜在的神经退行性疾病治疗药物进行测试。为了限制贝沙罗汀的外周暴露并仅在大脑受影响区域释放，我们设计了一种基于NAD(P) H/醌氧化还原酶（NQO1）酶的前药策略，该酶在神经退行性疾病中升高。合成了一系列吲哚醌（已知的NQO1底物）并偶联到贝沙罗酮上。苯沙罗汀-3（羟甲基）-5-甲氧基-1,2-二甲基- 1h -吲哚-4,7-二酮酯7a的裂解效果最好。前药不能被酯酶裂解。(C) 2014 Elsevier Ltd.版权所有。
Bexarotene, a retinoid X receptor (RXR) agonist, is being tested as a potential disease modifying treatment for neurodegenerative conditions. To limit the peripheral exposure of bexarotene and release it only in the affected areas of the brain, we designed a prodrug strategy based on the enzyme NAD( P) H/quinone oxidoreductase (NQO1) that is elevated in neurodegenerative diseases. A series of indolequinones (known substrates of NQO1) was synthesized and coupled to bexarotene. Bexarotene-3(hydroxymethyl)-5-methoxy-1,2-dimethyl-1H-indole-4,7-dione ester 7a was cleaved best by NQO1. The prodrugs are not cleaved by esterase. (C) 2014 Elsevier Ltd. All rights reserved.