Synthesis, biological and pharmacokinetic characterization of a novel leucine ureido derivative as a multi-target...

Previously, a novel series of leucine ureido derivatives containing the 1,2,3-triazole moiety were identified and validated as potent aminopeptidase N inhibitors with marked in vitro and in vivo antitumor potencies. Moreover, synergistic anti-proliferation effects against tumor cells were found when used in combination with 5-Fluorouracil (5-FU). Herein, a novel leucine ureido derivative (compound 3) was synthesized by coupling cytotoxic agent 5-FU with leucine ureido derivatives containing the 1,2,3-triazole moiety via esterification. The biological activity evaluation showed that compound 3 exhibited more potent in vitro anti-proliferative, anti-metastatic, anti-angiogenic activities than the positive control bestatin. Furthermore, it was observed that compound 3 was very stable in simulated gastric fluid, while slowly cleaved in simulated intestinal fluid. In vivo pharmacokinetic study displayed that compound 3 was absorbed quickly after oral administration in rats and maintained in vivo for a long time, but exhibited poor oral bioavailability. Generally speaking, compound 3 is a promising lead for further development of more potent analogs as anticancer agents.