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

目的 设计合成一系列4,6-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4,6-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-（2,3,4-三甲氧基苯基）-3-氰基吡啶 具有显著的抗肿瘤细胞增殖活性，IC₅₀值达纳摩尔级水平，明显优于阳性对照药MX-58151。

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

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 A549, HT-29, and SMMC-7721 cancer cell lines. Among them, 2-amino-6-(4-fluorophenyl)-4-(2,3,4-trimethoxyphenyl)nicotinonitrile(1) exhibited potent anticancer activity against the three 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.