基于天然产物靶向的核苷磷酰胺酯前药的合成与生物评价

Synthesis and Biological Evaluation of Nucleoside Phosphoramidate Prodrugs Based on Natural Product Targeting

本文运用ProTide技术,成功地将齐墩果酸(OA)与核苷或核苷类似物通过氨基酸酯中间体的连接,构建了3个基于天然产物靶向的核苷磷酰胺酯前药。首先齐墩果酸与Boc-L-丙氨酸发生酯化反应,接着脱去保护基团,获得了OA氨基酸酯盐酸盐。然后采用一锅法与二氯磷酸苯酯、对硝基苯酚反应,合成氨基磷酸酯中间体。最后在叔丁基氯化镁的作用下,与核苷或核苷类似物反应,合成了目标化合物。然后通过MTT法对三个目标化合物进行了体外活性测试,部分化合物的活性较好。

This article uses ProTide technology to successfully link oleanolic acid(OA) with nucleoside or nucleoside analogues through amino acid ester intermediates to construct 3 nucleoside phosphoramidate prodrugs based on natural product targeting. First, oleanolic acid and Boc-L-alanine undergo an esterification reaction, and then the protective group is removed to obtain OA amino acid ester hydrochloride. Then a one-pot method is used to react with phenyl dichlorophosphate and p-nitrophenol to synthesize phosphoramidate intermediates. Finally, under the action of tert-butyl magnesium chloride, it reacts with nucleoside or nucleoside analog to synthesize the target compound. Then the three target compounds were tested for in vitro activity by MTT method, and some of the compounds have better activity.