Jiang Yuqi, Li Xiaoyang, Hou Jinning, Huang Yongxue, Jia Yuping, Zou Mingming, Zhang Jian, Wang Xuejian, Xu Wenfang, Zhang Yingjie
Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong, 250012, PR China.
Weifang Bochuang International Biological Medicinal Institute, Weifang, Shandong, 261061, PR China.
Eur J Med Chem. 2016 Oct 4;121:649-657. doi: 10.1016/j.ejmech.2016.05.068. Epub 2016 Jun 1.
We designed and synthesized a novel mutual prodrug, named BC-01 (3), by integrating ubenimex and Fluorouracil (5-FU) into one molecule based on prior research results that showed that a combination of the aminopeptidase N (CD13) inhibitor, ubenimex, and the cytotoxic antitumor agent, 5-FU, exhibited improved in vitro and in vivo antitumor efficiency. 3 showed potent inhibitory activity against CD13 enzymatic activity. Compared with ubenimex, 3 exhibited more potent anti-angiogenesis effects, and compared with the approved 5-FU prodrug, capecitabine, 3 exhibited more potent tumor growth inhibitory and anti-metastasis effects. Additionally, compared with 5-FU or 5-FU plus ubenimex, 3 also exhibited a superior antitumor efficiency even in our 5-FU-resistant mice model. Other antitumor agents could be conjugated with ubenimex using this strategy to obtain novel mutual prodrugs with promising antitumor potency.
基于先前的研究结果，即氨肽酶N（CD13）抑制剂乌苯美司与细胞毒性抗肿瘤药物5-氟尿嘧啶（5-FU）联合使用在体外和体内均表现出更高的抗肿瘤效率，我们将乌苯美司和5-氟尿嘧啶整合到一个分子中，设计并合成了一种新型的相互前药，命名为BC-01（3）。3对CD13酶活性表现出强效抑制活性。与乌苯美司相比，3表现出更强的抗血管生成作用，与已获批的5-FU前药卡培他滨相比，3表现出更强的肿瘤生长抑制和抗转移作用。此外，即使在我们的5-FU耐药小鼠模型中，与5-FU或5-FU加乌苯美司相比，3也表现出更高的抗肿瘤效率。其他抗肿瘤药物也可以使用这种策略与乌苯美司缀合，以获得具有有前景的抗肿瘤效力的新型相互前药。
