Synthesis and biological characterization of ubenimex-fluorouracil conjugates for anti-cancer therapy
Synthesis and biological characterization of ubenimex-fluorouracil conjugates for anti-cancer therapy
复制标题
用于抗癌治疗的乌苯美克斯-氟尿嘧啶缀合物的合成和生物学表征
DOI：
10.1016/j.ejmech.2017.11.074
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发表时间：
2018-01-01
影响因子：
6.7
通讯作者：
Zhang, Yingjie
中科院分区：
文献类型：
--
作者：
Jiang, Yuqi;Li, Xiaoyang;Zhang, Yingjie
Previously a novel ubenimex-fluorouracil (5-FU) conjugate, BC-01 was identified and validated as a potent CD13 inhibitor with marked in vitro and in vivo antitumor potency. Herein, further structural modifications of the linker part of BC-01 was carried out to get more potent and stable ubenimex -fluorouracil conjugates. It was striking that most of these conjugates showed even more potent CD13 inhibitory activities than BC-01 and the approved CD13 inhibitor ubenimex. One representative compound 12a displayed significant in vitro anti-proliferation, pro-apoptosis, anti-metastasis, anti-angiogenesis and CD13(+) cell elimination effects. In vitro stability and in vivo pharmacokinetic study revealed that compound 12a could release ubenimex and 5-FU slowly, which could act as a mutual prodrug of ubenimex and 5-FU. Compared with 5-FU or 5-FU plus ubenimex, 12a exhibited superior in vivo antitumor growth efficiency, even in our mice model of 5-FU-resistant liver cancer. Moreover, 12a exhibited more potent in vivo anti-metastasis and lifespan extension effects compared to the approved 5-FU prodrug capecitabine. Collectively, these results suggest that further optimization and evaluation of 12a as a promising anticancer candidate are warranted to develop effective therapeutic agents for human liver cancer. (C) 2017 Elsevier Masson SAS. All rights reserved.
