Discovery of BC-01, a novel mutual prodrug (hybrid drug) of ubenimex and fluorouracil as anticancer agent.
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.
Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong, 250012, PR China.
Yuqi
Y
Jiang
Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong, 250012, PR China.
Xiaoyang
X
Li
Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong, 250012, PR China.
Jinning
J
Hou
Weifang Bochuang International Biological Medicinal Institute, Weifang, Shandong, 261061, PR China.
Yongxue
Y
Huang
Shandong Academy of Pharmaceutical Sciences, Ji'nan, Shandong, 250101, PR China.
Yuping
Y
Jia
Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong, 250012, PR China.
Mingming
M
Zou
College of Pharmacy, Weifang Medical University, 261053, Wei'fang, Shandong, PR China.
Jian
J
Zhang
College of Pharmacy, Weifang Medical University, 261053, Wei'fang, Shandong, PR China. Electronic address: wangxuejian@wfmc.edu.cn.
Xuejian
X
Wang
Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong, 250012, PR China. Electronic address: wenfxu@163.com.
Wenfang
W
Xu
Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong, 250012, PR China. Electronic address: zhangyingjie@sdu.edu.cn.
Yingjie
Y
Zhang
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D005472:Fluorouracil / Q000737:chemistry*; D007930:Leucine / Q000031:analogs & derivatives* / Q000737:chemistry; D051379:Mice; D009362:Neoplasm Metastasis; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D011355:Prodrugs; D007930:Leucine; C012211:ubenimex; D005472:Fluorouracil
Anti-metastasis; Antitumor; CD13; Liver cancer; Mutual prodrug; Ubenimex