Ras／Raf／M EK／ERK通路在许多人类肿瘤中均为异常活化，通过抑制M EK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M EK1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 .
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