Design, synthesis and preliminary biological evaluation of brain targeting L-ascorbic acid prodrugs of ibuprofen

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.