evaluated for their activities against PI3K isoforms, DNA-PK and PDE3. The results showed that this substitution pattern has a deleterious effect on PI3K activities, which may arise from steric hindrance in the active site. PI3Kδ was somewhat more tolerant of this substitution particularly where 8-(4-methoxylphenyl) substituents were present (IC50s ∼ 2–3 μM). Good activities against PDE3 were also
合成了一系列40个7-(O-取代)-2-吗啉代-8-芳基-4H-苯并[ e ] [1,3]恶嗪-4-酮衍
生物。它们是通过合成关键的前体8-
溴7-羟基-2-吗啉代-4H-苯并[ e ] [1,3]恶嗪-4-酮13制备的,该化合物可在7位合成醚。和Suzuki联轴器在8位。7-OCH的2个质子2在化合物18克,18H,18I,18升和18米证明是不可磁当量,旋转对映异构(轴向手性),作为结果的位阻大体积的8 -芳基取代基的旋转。 评价产物对
PI3K同工型,DNA-PK和PDE3的活性。结果表明,该取代模式对
PI3K活性具有有害作用,这可能是由于活性位点的空间位阻引起的。
PI3Kδ对这种取代的耐受性更高,特别是在存在8-(4-
甲氧基苯基)取代基的情况下(IC 50 s〜2-3μM)。与上述类似物相比,化合物对PDE3的活性也很好,其中7-(2-
吡啶基)甲氧基系列19的特定成员显示出良好的抑制作用(IC