3H-吡喃并[2,3-d]嘧啶-4,7-二酮类MEK激酶抑制剂的设计、合成及初步活性评价  

Design,synthesis and biological evaluation of 3H-pyrano[2,3-d]pyrimidine-4,7-dionederivatives as MEK inhibitors

作　　者：孙静[1] 牛彦[1] 许凤荣[1] 梁磊[1] 王超[1] 徐萍[1] 

机构地区：[1]北京大学医学部药学院,北京100191

出　　处：《中国科技论文》2015年第24期2823-2829,共7页China Sciencepaper

基　　金：国家自然科学基金资助项目(21172012);高等学校博士学科点专项科研基金资助项目(20120001110010)

摘　　要：Ras/Raf/MEK/ERK通路在许多人类肿瘤中均为异常活化,通过抑制MEK激酶阻断此信号通路成为小分子抗癌药物开发的良好靶标。将前期研究工作发现的嘧啶-4(3H)-酮骨架结构与香豆素骨架进行拼合,设计了3H-吡喃并[2,3-d]嘧啶-4,7-二酮骨架,并对骨架的4个位点进行结构修饰,根据5-位和6-位取代基的不同,采用2条路线分别合成了16个目标物。经活性初筛发现,2个化合物能较强地抑制非磷酸化MEK1的活性,具有进一步优化的潜力。Ras/Raf/MEK/ERK signaling pathway is upregulated in many human cancer cells.Blocking of this cascade by MEK inhibition is an attractive target for small molecular anti-tumor drug development.The pyrimidin-4（3H）-one skeleton which was found in a prelimary study was integrated with coumarin skeleton into 3H-pyrano[2,3-d]pyrimidine-4,7-dione skeleton,with four sites on the scaffold remained suitable for further substitutions and modifications.Two different synthetic routes were used for different substitution at 5-and 6-position and 16 target compounds were obtained.Two compounds show significant potency to inhibitunphosphorylatedMEK1（npMEK1）.These two compounds have the potential of further structural optimization.

关 键 词：药物化学 MEK抑制剂 抗肿瘤 3H-吡喃并[2 3-d]嘧啶-4 7-二酮 

分 类 号：R914[医药卫生—药物化学]