两个α,β-不饱和酮药物的合成及抗肿瘤活性研究

Synthesis and Antitumor Activity of Two Pyridine-Substituted α,β-Unsaturated Ketones Drugs

以3-吡啶甲醛与环己酮或N-甲基-4-哌啶酮进行Claisen-Schmidt缩合反应,经柱层析纯化得到2,6-二(3-吡啶亚甲基)-1-环己酮(L1)和3,5-二(3-吡啶亚甲基)-4-哌啶酮(L2),并通过核磁共振(1H NMR)、傅立叶变换红外光谱(FTIR)、元素分析等进行结构表征。采用CCK-8法评价其对A549(肺癌细胞)、He PG2(肝癌细胞)、MCF-7(乳腺癌细胞)、SGC-7901(胃癌细胞)、OVCA-433(卵巢癌细胞)等细胞系的抗肿瘤活性以及对HUVEC(脐静脉内皮细胞)的细胞毒性。结果显示,L1对SGC-7901和He PG2,L2对A549,SGC-7901,OVCA-433和He PG2均有较好的抑制活性,其半抑制率IC50均小于10μmol/L,但对正常细胞HUVEC的毒性较小。另外,通过共聚焦显微成像技术,实时检测了He PG2肿瘤细胞和正常细胞HUVEC对L2的体外摄取情况,随着药物浓度的增大和作用时间的延长,肿瘤细胞中的荧光强度不断增强,说明肿瘤细胞对药物的摄取量明显增加;但在正常细胞中,细胞的药物量变化不明显,说明药物对正常细胞具有一定的选择性。

Two drugs L1 and L2 were prepared by Claisen- Schmidt condensation reaction of 3-pyr- idinecarboxaldehyde with cyclohexanone or N-methyl-4-piperidinone. They were characterized by FT- IR, ^1H NMR and elemental analysis. Their antitumor activities against human neoplastic cell lines A549, HePG2, MCF - 7, SGC - 7901, OVCA - 433 and their cytotoxicities for HUVEC cell lines by CCK -8 method were subsequently evaluated. Their half maximal inhibitory concentration IC50 values were lower than 10μmol/L, but their cytotoxicities were markedly lower. In addition, cellular uptake of L2 by HePG2 cells and HUVEC lines was carried out by confocal fluorescence images. The result showed that fluorescent enhancement following the change of time and concentration, further demonstrated the increase of cellular uptake amount of I2 by HePG2 cells. But the result showed that fluorescent intensity uniformity following the change of time and concentration, further demonstrated the uniformity of cellular uptake amount of L2 by HUVEC cells.