有机化学 ›› 2016, Vol. 36 ›› Issue (12): 2948-2959.DOI: 10.6023/cjoc201607001 上一篇    下一篇

研究论文

嘧啶并二氮(艹卓)类化合物作为L3MBTL3抑制剂的设计、合成与构效关系研究

周皓, 车鑫, 鲍国臣, 王娜, 柏旭   

  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
  • 收稿日期:2016-07-01 修回日期:2016-08-03 发布日期:2016-08-12
  • 通讯作者: 柏旭 E-mail:xbai@jlu.edu.cn
  • 基金资助:

    国家自然科学基金(No. 81072526)和吉林省科技发展计划重点(No. 20140309010YY)资助项目.

Design, Synthesis and Structure-Activity Relationship Study of Pyri-midine-Fused Diazepine Derivatives as L3MBTL3 Inhibitors

Zhou Hao, Che Xin, Bao Guochen, Wang Na, Bai Xu   

  1. Center for Combinatorial Chemistry and Drug Discovery of Jilin University, School of Pharmaceutical Sciences, Changchun 130021
  • Received:2016-07-01 Revised:2016-08-03 Published:2016-08-12
  • Supported by:

    Project supported by the National Natural Science Foundation of China (No. 81072526) and the Science and Technology Development Plan of Jilin Province (No. 20140309010YY).

组蛋白甲基化是表观遗传学的标志之一,其调节紊乱与许多疾病有联系.恶性脑瘤域(MBT)家族蛋白是一类能够识别组蛋白赖氨酸甲基化信号的蛋白,L3MBTL3是该家族中代表性的蛋白之一,它与染色质转录抑制、造血功能、肿瘤形成等都有关系.开发L3MBTL3小分子抑制剂可以辅助阐明其生物学作用和验证其靶点成药性.首先通过筛选嘧啶并二氮化合物库,得到了L3MBTL3的活性化合物1,接着按照已报道L3MBTL3抑制剂的结构特点进行构效关系研究,最终得到了四个IC50值小于1 μmol·L-1新颖的L3MBTL3抑制剂.

关键词: 嘧啶并二氮, L3MBTL3, 抑制剂, 构效关系研究

Histone methylation is one of epigenetic marks and its deregulation is linked to many diseases. Malignant brain tumor (MBT) domain protein is one of proteins that could read methylated lysine (Kme) of histones. L3MBTL1, a representative member of the MBT family, is related to transcriptional repression, hematopoietic function and tumor formation. Developing a potent and selective inhibitor of L3MBTL1 can help explain the regulatory mechanisms and validate its drugability. Active compound 1 for L3MBTL3 from a library of pyrimidine-fused diazepines was initially obtained. By incorporating the structural features of reported binders, the structure-activity relationship (SAR) studies were conducted, which led to four novel L3MBTL3 inhibitors with IC50 values under 1 μmol·L-1.

Key words: pyrimidine-fused diazepine, L3MBTL3, inhibitor, SAR study