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.

在我们之前的研究中，我们发现了 ubenimex-氟尿嘧啶 (5FU) 偶联物​​ BC-02，它显示出显着的体内抗肿瘤活性，但是，BC-02 在血浆中的不稳定性限制了其作为候选药物的进一步发展。在此，我们通过优化基于 BC-02 的 ubenimex 和 5FU 之间的接头，设计并合成了四种新型 ubenimex-5FU 偶联物。代表性化合物20在人血浆中比 BC-02 更稳定，并且显示出比阳性对照 ubenimex 高约 100 倍的 CD13 抑制活性。同时，20的体外抗增殖活性与5FU相当。初步机理研究表明，化合物20在体外表现出显着的抗侵袭和抗血管生成活性。此外，化合物20在体内具有明显的抑制肿瘤生长和转移的作用，延长荷瘤小鼠的存活时间。我们的研究可能对设计更多类药性的互药前药具有重要的意义参考，化合物20可作为先导化合物进一步设计开发。