苯并嘧啶衍生物的合成和抗糖尿病活性评价

Synthesis and antidiabetic activity evaluation of benzopyrimidine derivatives

硫氧还蛋白相互作用蛋白(thioredoxin-interacting protein,TXNIP)主要调节胰岛β细胞中葡萄糖的稳态,是治疗糖尿病的新颖靶点。本研究以4-羟基苯并嘧啶为原料,通过不同长度的碳链,引入吡唑、甲基哌嗪、咪唑、吗啡啉等4种含氮杂环,设计合成靶向TXNIP的苯并嘧啶骨架拼合含氮杂环的衍生物,并考察化合物对棕榈酸(palmitate acid,PA)刺激的胰岛β细胞损伤的保护作用。共设计合成20个苯并嘧啶衍生物,结构经1H NMR、ESI-MS确证;药理活性表明大部分化合物对胰岛β细胞有保护作用,其中化合物C-1、C-2、C-4、D-2保护作用较强,相较PA模型组细胞活力为38.3%,这4个化合物细胞活力高于70%,其中化合物D-2细胞活力最高,达到87.2%;化合物D-2可以作为潜在的抗糖尿病新化学实体。

Thioredoxin-interacting protein(TXNIP),which mainly regulates glucose homeostasis in pancreaticβcells,is a novel target in the treatment of diabetes.In this study,4-hydroxybenzopyrimidine was used as the raw material,four nitrogen-containing rings(imidazole,methylpiperazine,pyrazole,morpholine)were introduced,benzopyrimidine skeleton with nitrogen-containing rings derivatives targeting TXNIP was designed and synthesized,and the protective effect of compounds on palmitic acid-stimulated isletβcells was investigated.A total of 20 benzopyrimidine derivatives were designed and synthesized,and the structures were confirmed by 1H NMR and ESI-MS.Pharmacological studies showed that most of the compounds exhibited protective effects on isletβcells,with better axtivity for compounds C-1,C-2,C-4 and D-2(cell survival rate>70%)compared with PA model group(38.3%),Among the four compounds,D-2 had the highest activity of 87.2%,so it could become a potential new anti-diabetic chemical entity.