2-芳基-4-吗啉-6-三氮唑基嘧啶环类衍生物的 合成及抗肿瘤PI3K抑制剂的活性

Synthesis and biological research of 2-aryl-4-morpholino-6-triazolylpyrimidine derivatives as antitumor PI3K inhibitors

摘要:

为筛选到活性更好的抗肿瘤PI3K抑制剂，以2,4-二羟基吡啶为原料，经氯化后和吗啡啉反应、碘代、Sonogashira偶联、脱保护基与叠氮化反应得到三氮唑中间体8~13，最后经Suzuki反应，偶联上芳基得到2-芳基-4-吗啉-6-三氮唑基嘧啶14~27，其结构均经1H NMR和LC-MS确证。用MTT法评价了化合物14~27对PI3K高表达的人卵巢细胞A2780增殖的抑制活性，其中，在化合物测试浓度为10 μmol L-1时，14和25的抑制活性均高于正在临床实验的阳性对照药物GDC-0941和BEZ-235，抑制率分别达到76.7%与77.2%。这两个化合物在小鼠体内代谢良好，其中化合物25更为优异，t1/2为3.2h，药时曲线下面积AUC0-∞为34193 ng•h•mL-1。

Abstract:

In order to find more activity antitumor PI3K inhibitors, pyrimidine-2,4-diol as raw material, after chlorinated by POCl3, coupled with morpholine, then lodine generation, followed with Sonogashira coupling and remove the trimethylsilyl to get the triazolyl intermediate, finally, Suzuki coupling to get 2-aryl-4-morpholino-6-triazolylpyrimidine 14~27, their structures were confirmed by 1H NMR and LC-MS. The in vitro anti-proliferative activity assay against A2780 has been cacacarried out by MTT detection method, the result showed that under the test concentration of 10 μmol L-1, the compounds 14 and 25 were more potent than clinical candidates GDC-0941 and BEZ-235, inhibition rate reached 76.7%, 77.2% respectively. Furthermore, the result of pharmacokinetic study suggested that compounds 25 was desirable.t1/2=3.2 h, AUC0-∞ was 34193 ng•h•mL-1.