嘧啶并嘧啶酮类化合物作为L3MBTL1选择性络合剂的设计与合成  

Design and Synthesis of Pyrimido[4,5-d]pyrimidin-4(3H)-ones as Selective L3MBTL1 Binders

作　　者：周皓[1] 车鑫[1] 彭丽 王娜[1] 柏旭[1] 

机构地区：[1]吉林大学药学院,吉林大学组合化学与创新药物研究中心,长春130021

出　　处：《高等学校化学学报》2016年第7期1293-1301,共9页Chemical Journal of Chinese Universities

基　　金：国家自然科学基金(批准号:81072526);吉林省科技发展计划重点项目(批准号:20140309010YY)资助

摘　　要：用嘧啶并嘧啶酮替换Lethal 3 malignant brain tumor 1(L3MBTL1)小分子络合剂UNC669分子中的芳香部分,合成了一系列嘧啶并嘧啶酮类化合物.采用同质邻近发光放大法(Alpha Screen)测试了其活性,得到IC50值为1.21μmol/L的化合物8a;通过对其5位基团进行改造,最终获得了3个选择性L3MBTL1络合剂8g,8o与8p,它们仅对L3MBTL1有活性,对其同源蛋白L3MBTL3在内的其它甲基化识别蛋白则无活性.Histone methylation is a key epigenetic mark,and its deregulation is linked to many diseases.Malignant brain tumor（ MBT） domain protein is one of the proteins that could read methylated lysine（ Kme） of histones. Lethal 3 malignant brain tumor 1（ L3MBTL1）,a member of the MBT family,is related to transcriptional repression,erythroid differentiation and tumor formation. Developing a potent and selective inhibitor of L3MBTL1 can help explain the regulatory mechanisms and validate its drugability. UNC669 was reported as the first small molecule ligands for a methyl-lysine binding domain. A series of compounds was synthesized by replacing its aromatic component with pyrimido[4,5-d]pyrimidin-4（ 3H）-ones. Screening these compounds by Alpha Screen  led to a hit compound 8a（ IC50= 1. 21 μmol / L）. Exploring 5-position of compound 8a generated three selective and potent L3MBTL1 binders（ compounds 8g,8o and 8p）,which showed no significant activity against the other Kme reader proteins in the panel,even its closely related MBT containing proteins,L3MBTL3.

关 键 词：嘧啶并嘧啶酮 L3MBTL1 选择性络合剂 

分 类 号：O621[理学—有机化学]