3-氟或3-氨基-6-取代-5,6-二氢吡咯[3,4-b]吡啶-7-酮的合成及其初步抗肿瘤活性

Synthesis and Primary Anti-tumor Activities of 3-Fluoro-or 3-Amino-6-substituted-5,6-dihydropyrrolo[3,4-b]pyridin-7-ones

以沙利度胺为先导化合物,对其结构进行改造。以3-甲基-2-氰基吡啶为起始原料,经一系列反应合成得到3-氟-6-取代-5,6-二氢吡咯[3,4-b]吡啶-7-酮(12a^12g)和3-氨基-6-取代-5,6-二氢吡咯[3,4-b]吡啶-7-酮(16a^16g)2个系列共计14个新型沙利度胺类似物,结构经1H NMR与高分辨质谱表征确证。并选取MCF-7、A549、HCT-116、MG-63和HUVEC这5种细胞,采用MTT法对目标化合物的抗肿瘤活性进行初筛。结果表明,3-氨基取代的系列化合物活性总体优于3-氟取代系列,且16a、16b和16f对MCF-7细胞表现出高选择性,其中16a活性最好,其IC_(50)值为34μmol/L。

A series of 3-fluoro- or 3-amino-6-substituted-5,6-dihydropyrrolo [3,4-b]pyridin-7-ones were synthesized as novel thalidomide analogues from 3-methylpicolinonitrile via a series of reactions, and the structures of all target compounds were confirmed by 1H NMR and HRMS. The primary anti-tumor activities of these compounds were evaluated by MTT assay with MCF-7, A549, HCT- 116, MG-63 and HUVEC cells. The results indicated that the 3-amino substituted compounds had better bioactivities than 3-fluoro substituted analogues in general, and compounds 16a, 16b and 16f exhibited high selectivities against MCF-7, among them 16a had the most potent activity with an IC50 value of 34 μmol/L.