Synthesis and Antiproliferative Activity of 2,4,5,6-Tetrasubstituted Pyrimidine Derivatives Containing Anisole

Abstract

,4,5,6-四取代嘧啶衍生物, 并采用噻唑 蓝(MTT)法测定了目标化合物对 PC-3(人前列腺癌细胞)、MGC-803(人胃癌细胞)、MCF-7(人乳腺癌细胞)、HGC-27(人 未分化胃癌细胞)四种人肿瘤细胞的抗增殖活性. 结果显示部分化合物表现出中度至强效的抗增殖活性, 其中 5-乙基-6-((4-甲氧基苯基)硫代)-N 4 -(3,4,5-三甲氧基苯基)嘧啶-2,4-二胺(14t)对 HGC-27 细胞具有最好的抗增殖活性, IC50 值为 (0.98±0.12) μmol•L -1 , 抗增殖活性明显优于阳性对照 5-氟尿嘧啶. 进一步抗肿瘤机制研究表明, 化合物 14t 可以显著 抑制 HGC-27 细胞的克隆形成和迁移, 诱导细胞凋亡. 同时化合物 14t 可以下调抗凋亡蛋白 Bcl-2 的表达, 上调促凋亡 蛋白 Bax 和 P53 的表达.

Synthetic Approaches for Pharmacologically Active Decorated Six-Membered Diazines

“…In a recent study Zhang and colleagues reported the synthesis of anisole containing 2,4,5,6-tetrasubstituted pyrimidines [92]. The team exploited the commercially available reagents like properly substituted malonic acid diesters (124) and guanidine hydrochloride (125) that were condensated in anhydrous methanol under slightly basic conditions (sodium methoxide) to produce the 5-substituted 4,6-dihydroxy-2aminopyrimidine intermediate ( 126).…”

“…The 4,6-dichlorides were sequentially displaced under nucleophilic substitution conditions. The first 4-chloro was substituted by aniline derivatives in refluxing ethanol (see step c in Figure 25) while the second chloride was exchanged for anisole (4-methoxythiophenol) employing sodium tert-butoxide (1.33 mmol), under heating at 82°C (see step d in Figure 25, [92].…”