Practical synthesis of a chromene analog for use as a retinoic acid receptor alpha antagonist lead compound.
Practical synthesis of a chromene analog for use as a retinoic acid receptor alpha antagonist lead compound.
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用作视黄酸受体α拮抗剂先导化合物的色烯类似物的实际合成。
DOI：
10.1016/j.ejmech.2013.02.012
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发表时间：
2013
影响因子：
6.7
通讯作者：
Erhardt,Paul
中科院分区：
文献类型：
--
作者：
Jetson,Rachael;Malik,Neha;Luniwal,Amarjit;Chari,Venkatesh;Ratnam,Manohar;Erhardt,Paul
视黄酸受体α（RARα）选择性化合物可以指导药物的设计，这些药物可以与激素辅助治疗联合用于治疗乳腺癌。本文报道了已知RARα拮抗剂2-氟-4-[8-溴-2，2-二甲基-4-（4-甲基苯基）苯并二氢吡喃-6-基]羰基]氨基]苯甲酸的改进合成及其未知的去氟类似物4-[8-溴-2，2-二甲基-4-（4-甲基苯基）苯并二氢吡喃-6-基]羰基]氨基]苯甲酸的合成。改进的路线允许容易的反应后处理、增加的产率、较低的成本，并且结合了绿色替代步骤。通过基于功能细胞的试验确定的结构-活性关系研究证明了两种化合物对RARα的拮抗作用。RARα结合口袋内的分子建模用于比较去氟类似物与已知RAR拮抗剂的结合相互作用。
Retinoic acid receptor alpha (RARα) selective compounds may guide the design of drugs that can be used in conjunction with hormonal adjuvant therapy in the treatment of breast cancer. Herein we report a modified synthesis of a known RARα antagonist, 2-fluoro-4-[[[8-bromo-2,2-dimethyl-4-(4-methylphenyl)chroman-6-yl]carbonyl]amino]benzoic acid and a synthesis of its unknown, desfluoro analog, 4-[[[8-bromo-2,2-dimethyl-4-(4-methylphenyl)chroman-6-yl]carbonyl]amino]benzoic acid. The modified route allows for facile reaction workups, increased yields, lower cost and incorporates a green alternative step. Structure–activity relationship studies determined through functional cell-based assays, demonstrated antagonism to RARα for both compounds. Molecular modeling within the RARα binding pocket was used to compare binding interactions of the desfluoro analog to a known RAR antagonist.