Design, synthesis and preliminary biological evaluation of brain targeting L-ascorbic acid prodrugs of ibuprofen
Design, synthesis and preliminary biological evaluation of brain targeting L-ascorbic acid prodrugs of ibuprofen
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DOI：
10.1016/j.cclet.2013.01.022
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发表时间：
2013-02-01
影响因子：
9.1
通讯作者：
Hai, Li
中科院分区：
文献类型：
--
作者：
Wu, Xue-Ying;Li, Xiao-Cen;Hai, Li
L-抗坏血酸(AA，维生素C)在大脑中显示出较高的浓度。AA在脑内的转运主要由葡萄糖转运蛋白1(GLUT(1))和NE依赖的维生素C转运蛋白SVCT2介导。虽然L-抗坏血酸C6-O结合物已被研究作为促进脑部给药的工具，但C5-O结合物和C5-O&C6-O结合物作为脑靶向工具尚未见报道。在这封信中，布洛芬直接连接到C5-O，C6-O和C5-O 82个C6-O位置，抗坏血酸与食人键，分别提供前药1，2和3，以提高其在大脑中的靶向能力。前药1、2和3的合成方法简单，产率较高。体内初步评价表明，前药2比前药I具有更好的靶向性，且前药3的C5-O和C6-O位均被修饰，具有良好的脑靶向性，这将为我们进一步研究L抗坏血酸的C5-O和C6-O-二取代物提供重要依据。(C)2013年李海。爱思唯尔公司代表中国化学会出版。版权所有。
L-Ascorbic acid (AA, vitamin C) exhibits a high concentration in the brain. The transportation of AA in brain is mainly mediated by the glucose transporter 1 (GLUT(1)) and the Ne-dependent vitamin C transporter SVCT2. While L-ascorbic acid C6-O conjugation has been investigated as a tool to enhance brain drug delivery, C5-O conjugation and C5-O & C6-O conjugation as brain targeting tools have not been reported. In this letter, ibuprofen was linked directly to C5-O, C6-O and C5-O 82 C6-O positions of ',ascorbic acid with eater bonds, providing prodrug 1, 2 and 3, respectively, to improve their targeting abilities in the brain. Prodrug 1, 2 and 3 were synthesized in facile ways with good yields. And the preliminary evaluation in vivo illustrated that prodrug 2 had a better targeting ability than prodrug I. Moreover, prodrug 3, whose C5-O & C6-O positions were both modified, had good targeting ability for brain which will provide an important evidence for our further study on C5-O & C6-O- di-derivatives of L-ascorbic acid. (C) 2013 Li Hai. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.