2,7-二苯基-4H-吡啶并[1,2-a]嘧啶-4-酮类雌激素相关受体α(ERRα)转录功能抑制剂的合成及活性研究

Synthesis and biological evaluation of 2,7-diphenyl-4H-pyrido[1,2-a]-pyrimidin-4-ones as transcriptional function suppressors of estrogenrelated receptor α(ERRα)

雌激素相关受体?(estrogen-related receptorα,ERR?)是调控细胞代谢和命运的孤儿核受体.近年来发现它与许多肿瘤疾病相关,是潜在的抗肿瘤靶点.我们设计合成了2,7-二苯基-4H-吡啶并[1,2-a]嘧啶-4-酮类化合物作为ERR?转录功能抑制剂,并进行了构效关系研究.其中,双荧光素酶报告基因测试显示化合物9a对ERR?转录功能抑制的半数抑制率IC50为0.25μmol/L,进一步实验表明9a能抑制ERR?蛋白的表达,并以剂量依赖的方式抑制578T乳腺癌细胞的迁移,为ERR?的抗肿瘤研究提供了良好的探针分子.

Estrogen-related receptor α （ERRα） is an orphan nuclear receptor regulating the energymetabolism and cell fate. Recently it was associated with many types of cancer and was considered as a potential cancer therapeutic target. Herein, we described the synthesis and structure-activity studies of a series of 2,7-diphenyl-4H-pyrido[1,2-α] pyrimidin-4-ones as novel inhibitors of ERRα transcriptional functions. The most potent compound, 7-（2- hydroxyphenyl）-2-phenyl-4H-pyrido[1,2-α]pyrimidin-4-one （ga）, suppressed the transcriptional functions of ERRα with IC50 of 0.25 μmol/L in a two-hybrid reporter gene assay. Further studies showed that 9a down-regulate the expression of ERRα and dose-dependently inhibit the migration of 578T cells.