二氢乳清酸脱氢酶抑制剂前药的合成和稳定性及活性评价

Synthesis, stability and activity of the prodrugs of dihydroorotate dehydrogenase inhibitors

本文以课题组前期发现的高活性DHODH抑制剂A为基础,依据前药合成策略,对其羧基进行酯化修饰得到12个前药分子,旨在优化化合物A的稳定性。分子水平抑制活性显示12个前药分子中只有A1~A5有微弱活性,与其作用机制和前药设计相符;随后评价了A1~A12在有机溶剂甲醇和pH为2.0、9.0的缓冲液中的稳定性,结果显示A12在甲醇中能较好的抑制先导分子内成环,A1~A8在酸性条件下易于水解,A9~A12在碱性条件易于水解;最后评价了A1~A12的细胞增殖抑制活性,其中A12表现出很好活性,其IC_(50)值为0.63μmol·L^(-1),与布奎那相当。这些结果为开展进一步体内活性研究奠定了基础。

This study was conducted to improve structural instability of a highly active DHODH inhibitor Afound in our group. Twelve prodrugs were synthesized by modifying the carboxyl group. The enzyme activity test of 12 prodrugs A1-A12 demonstrated that A1-A5 displayed weak inhibitory activity, and A6-A12 displayed no activity, which met the action mechanism of designed prodrug. The structural stability of A1-A12 in methanol and pH 2.0, 9.0 buffers were tested, and the results showed that A12 could avoid intramolecular ring-formation in CH_3OH, A1-A8 were easily hydrolyzed under acidic conditions, and A9-A12 were inclined to hydrolyze under alkaline conditions. The cell proliferation inhibitory activity of 12 prodrugs were evaluated, in which compound A12 displayed excellent activity（IC_（50 ）= 0.63 μmol·L^（-1）） similar to brequinar. These results laid a good foundation for conducting further vivo studies.