含四氢吡啶并[4,3-d]嘧啶环的双芳基脲类化合物的合成及抗肿瘤细胞增殖活性研究

Synthesis and antiproliferative activity of diaryl ureas possessing tetrahydropyride [4,3-d]pyrimidine

目的设计合成2-氨基-7,8-二氢吡啶并[4,3-d]嘧啶-6(5H)烷氧基双芳基脲类化合物,并测定其体外抗肿瘤细胞增殖活性。方法以对硝基苯酚为原料,经O-烷基化、N-烷基化、缩合、环合、还原、加成共6步反应合成目标化合物。采用MTT法,以索拉菲尼(sorafenib)为阳性对照药,测定了目标化合物对人乳腺癌细胞株(MDA-MB-231)的抗增殖活性。结果与结论合成了16个新化合物,其结构经1H-NMR、MS谱确证;初步药理试验结果表明,5个化合物(7a^7c、7l和7n)表现出良好的抗肿瘤细胞增殖活性,以2,4-二氯苯基取代的化合物7c活性最好,IC50值为0.46μmol·L-1,是对照药的5.4倍。初步构效关系研究表明,引入乙氧基侧链对化合物的活性提高有利,R取代基的活性顺序为:Cl>F>CH3>OCH3。

To design and synthesize 2-amino-7,8-dihydropyrido [ 4,3-d ] pyrimidine-6 （5H） -ylalkoxyldiaryl urea derivatives, and evaluate their antiproliferative activities in vitro preliminarily, with p-nitrophenol as the starting material, the target compounds were synthesized by six steps, including O-alkylation, N-alkylation, condensation, cyclization ,reduction and addition. Their antiproliferative activities against MDA-MB-231 can- cer cell lines were tested by MTT assay with sorafenib as the positive control. Sixteen new compounds were synthesized, and their structures were confirmed by ^1H-NMR and MS. The pharmacological data indicated that five compounds （7a - 7c,71 and 7n） showed potent antiproliferative activities, and 2,4-dichlorophenyl substituted compound 7c displayed prominent activity with IC50 value of 0. 46 μmol·L^-1 which was 5.4 folds more active than sorafenib. The preliminary structure-activity relationships indicated that the ethoxyl group is better than propoxyl group and the R substituent affected the activity dramatically with the descen- ding order of C1 〉 F 〉 CH3 〉 OCH3.