4,6-双苯基-2-氨基-3-氰基吡啶类化合物的合成及其抗肿瘤活性研究

Synthesis and antitumor activity of 4,6-diphenyl-2-amino-3-cyanopyridine derivatives

目的设计合成一系列46,-双苯基-2-氨基-3-氰基吡啶类化合物,并对其体外抗肿瘤活性进行初步评价。方法以取代苯甲醛、取代苯乙酮、丙二腈和醋酸铵为原料,经一步反应制得目标化合物。采用MTT法,以MX-58151为阳性对照药,以A549、HT-29和SMMC-7721为测试细胞株对目标化合物进行体外抗肿瘤活性评价。结果与结论合成了13个未见报道的46,-双苯基-2-氨基-3-氰基吡啶类化合物,其结构经1H-NMR、MS和IR谱确证。体外活性测试结果显示,多数化合物能够在较低的浓度下抑制肿瘤细胞增殖。其中,2-氨基-6-(4-氟苯基)-4-(23,,4-三甲氧基苯基)-3-氰基吡啶具有显著的抗肿瘤细胞增殖活性I,C50值达纳摩尔级水平,明显优于阳性对照药MX-58151。

A small molecule with a 4H-chromene core,MX-58151,with potent anticancer activity in vitro was identified by using the cell-and caspase-based high throughput screening assay.On the basis of scaffold hopping,together with an understanding of the SARs relating to 4-aryl-4H-chromenes,thirteen 4,6-diphenyl-2-amino-3-cyanopyridine derivatives were synthesized in attempt to develop active antitumor agents.The target compounds were synthesized via a one-pot reaction and their chemical structures were confirmed by IR,MS,1H-NMR.The cytotoxic activity of these target compounds was evaluated in vitro by MTT assay against A549,HT-29 and SMMC-7721,with MX-58151 as the positive control.Most of the evaluated compounds exhibited moderate cytotoxic activity against three cancer cell lines.Among them,2-amino-6-（4-fluorophenyl）-4-（2,3,4-trimethoxyphenyl）nicotinonitrile（1） exhibited potent anticancer activity against the A549,HF-29,and SMMC-7721 cell lines with IC50 values of 10,0.33 and 0.25 nmol·L-1,respectively.The preliminary SARs analysis showed that introduction of small lipid-soluble groups on phenyl at C-4 position of pyridine and fluoro atom on phenyl at C-6 position of pyridine was benefit for their activity.