含有芳基脲结构的4H-吡喃类化合物的设计、合成及抗肿瘤活性研究

Study on Design, Synthesis and Anticancer Activity of 4H-Pyran Derivatives Bearing Arylurea Moiety

关键词:  吡喃  芳基脲  合成  抗肿瘤活性

Key words:  pyran  arylurea  synthesis  anticancer activity

摘要:

目的 设计并合成一系列含有芳基脲结构的4H-吡喃类化合物，评价该类化合物的体外抗肿瘤活性。方法 以间硝基苯甲醛、丙二腈和丙酮二羧酸二甲酯为原料，通过“一锅法”合成含有硝基的吡喃中间体，该中间体的硝基经铁粉还原为氨基，再与取代异氰酸苯酯反应得到一系列目标化合物。以人大细胞肺癌细胞H460、人肺癌细胞A549和人结肠癌细胞HT-29 3种肿瘤细胞为测试细胞株，采用MTT法评价了目标化合物的抗肿瘤活性。结果 合成了11个含有芳基脲结构的4H-吡喃类化合物。体外抗肿瘤活性试验表明，11个化合物对3种肿瘤细胞株均具有很好的抑制活性。其中化合物7c活性突出，对H460和A549细胞的IC₅₀值分别为0.82，0.98 μmol·L^-1, 优于阳性对照药索拉非尼(IC₅₀=3.20， 2.83 μmol·L^-1)。结论 含有芳基脲结构的4H-吡喃类化合物具有很好的抗肿瘤活性，可作为抗肿瘤化合物的结构骨架进一步研究。

Abstract:

OBJECTIVE To design and synthesize a series of 4H-pyran-arylurea derivatives and to evaluate their anticancer activities in vitro. METHODS Nitro-containing pyran intermediates was synthesized by "one-pot" condensation of 3-nitrobenzaldehyde, malononitrile, dimethyl 3-oxopentanedioate. Reduction of the nitro group of above compound with iron powder, and then condensed with isocyanates to afford target compounds. Human large cell lung cancer cells H460, human lung cancer cells A549 and human colon cancer cells HT-29 cell lines were employed to evaluate anticancer activities of these compounds using MTT-based assay. RESULTS Eleven 4H-pyran derivatives bearing arylurea moieties were synthesized. The results of in vitro antiproliferative activity showed 11 compounds had good inhibitory activities against 3 tumor cell lines. Among them, compound 7c exhibited remarkable inhibitory activity against H460 and A549 cell lines with IC₅₀ value of 0.82 and 0.98 μmol·L^-1, respectively, which were more potent than that of the positive control sorafenib(IC₅₀=3.20 and 2.83 μmol·L^-1). CONCLUSION 4H-pyran derivatives bearing arylurea moieties show excellent anticancer activities, and they can be used as the structural skeleton of anticancer compounds for futher study.