Design, synthesis and biological evaluation of hybrid of ubenimex-fluorouracil for hepatocellular carcinoma therapy

• Published in: Bioorganic chemistry 2021-11, Vol.116, p.105343-105343, Article 105343
• Main Authors: Yue, Kairui, Hou, Xiaohan, Jia, Geng, Zhang, Liang, Zhang, Jian, Tan, Leqiao, Wang, Xuejian, Zhang, Zhaolin, Li, Peixia, Xu, Wenfang, Li, Xiaoyang, Jiang, Yuqi
• Format: Article
• Language: English
• Subjects: Angiogenesis; Anti-cancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; APN/CD13 inhibitor; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Fluorouracil - chemistry; Fluorouracil - pharmacology; Humans; Leucine - analogs & derivatives; Leucine - chemistry; Leucine - pharmacology; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Metastasis; Molecular Structure; Mutual prodrug; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105343

[Display omitted] •Four novel ubenimex-fluorouracil (5FU) conjugates were designed and synthesized.•Compound 20 displays about 100 times higher CD13 inhibitory activity than ubenimex.•Compound 20 obviously inhibits tumor growth, metastasis.•Compound 20 exhibited the significant anti-angiogenesis effects in vitro. In our previous study, we discovered a ubenimex-fluorouracil (5FU) conjugates BC-02, which displays significant in vivo anti-tumor activity, however, the instability of BC-02 in plasma limits its further development as a drug candidate. Herein, we designed and synthesized four novel ubenimex-5FU conjugates by optimizing the linkers between ubenimex and 5FU based on BC-02. Representative compound 20 is more stable than BC-02 in human plasma and displays about 100 times higher CD13 inhibitory activity than the positive control ubenimex. Meanwhile, the antiproliferative activity of 20 was comparable with 5FU in vitro. The preliminary mechanism study indicated that compound 20 exhibited significant anti-invasion and anti-angiogenesis activities in vitro. Furthermore, compound 20 obviously inhibits tumor growth and metastasis in vivo and prolong the survival time of tumor-bearing mice. Our study may have an important implication reference for the design of more druglike mutual prodrug, and compound 20 can be used as a lead compound for further design and development.