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目的在蛋氨酸合成酶抑制剂先导化合物的基础上设计合成4-氨基-8,10-二去氮杂-N~5-取代四氢叶酸类似物和4-氨基-8-去氮杂-N~5,N10-二取代四氢叶酸类似物,并对其蛋氨酸合成酶(MS)抑制活性进行评价,以考察N~5位和N10位酰基取代基对活性的影响,寻找新的活性更高的蛋氨酸合成酶抑制剂。方法以2,4-二氨基-6-溴甲基吡啶并[3,2-d]嘧啶为原料,经Wittig反应、还原反应、酰胺化及水解反应合成目标化合物;采用分光光度法对目标化合物的蛋氨酸合成酶抑制活性进行考察。结果与结论合成了10个未见文献报道的目标化合物,其结构均经~1H-NMR、MS谱确证。生物活性结果表明,目标化合物Ⅰc和Ⅱa对蛋氨酸合成酶的抑制活性优于先导化合物7a。
Objective To design and synthesize 4-amino-8,10-dideaza-N ~ 5-substituted tetrahydrofolate analogs and 4-amino-8-deaza-N ~ 5, N10-disubstituted tetrahydrofolate analogues, and its methionine synthase (MS) inhibitory activity was evaluated in order to investigate the N ~ 5 and N10 acyl substituents on the activity of looking for new higher activity Methionine synthase inhibitor. Methods The target compounds were synthesized from 2,4-diamino-6-bromomethylpyrido [3,2-d] pyrimidine by Wittig reaction, reduction reaction, amidation and hydrolysis. The target compounds Methionine synthase inhibitory activity was investigated. RESULTS AND CONCLUSION Ten target compounds were synthesized. Their structures were confirmed by ~ 1H-NMR and MS spectra. The biological activity results show that the target compounds Ic and IIa have better inhibitory activity on methionine synthase than the lead compound 7a.