Pteridines are an important class of fused heterocycles found in natural products and drug molecules, and have shown diverse biological activities. A focused library of 5,8-dihydropteridine-6,7-dione derivatives were designed and evaluated for their antiproliferative activity against MGC-803, SGC-7901, A549 and PC-3 cancer cell lines. The SARs studies highlighted the importance of the piperazine substituted 5,8-dihydropteridine-6,7-dione frameworks for the activity and revealed essential structural elements. Among these compounds, compound 5n displayed the most potent and broad-spectrum antiproliferative inhibition against the tested cell lines and was sensitive to MGC-803 cell line, slightly more potent than 5-FU. Preliminary mechanistic studies showed that compound 5n could inhibit the colony formation and migration of MGC-803 cells. Besides, flow cytometry analysis showed that compound 5n concentration-dependently induced apoptosis of MGC-803 cells. Our studies suggest that the piperazine substituted 5,8-dihydropteridine-6,7-dione frameworks may be regarded as new chemotypes for designing effective antitumor agents targeting gastric cancer cells.

蝶啶是在天然产物和药物分子中发现的重要一类稠合杂环，并已显示出多种生物活性。设计了5,8-二氢蝶啶-6,7-二酮衍生物的重点文库，并评估了它们对MGC-803，SGC-7901，A549和PC-3癌细胞系的抗增殖活性。SARs研究强调了哌嗪取代的5,8-二氢蝶啶-6,7-二酮构架对于活性的重要性，并揭示了必不可少的结构要素。在这些化合物中，化合物5n对测试的细胞系表现出最有效和广谱的抗增殖抑制作用，并对MGC-803细胞系敏感，效力比5-FU略强。初步的力学研究表明，化合物5n可以抑制MGC-803细胞的集落形成和迁移。此外，流式细胞仪分析表明，化合物5n浓度依赖性地诱导了MGC-803细胞的凋亡。我们的研究表明，哌嗪取代的5,8-二氢蝶啶-6,7-二酮骨架可被视为设计针对胃癌细胞的有效抗肿瘤药物的新化学型。