Using pyridino[2,3-D]pyrimidine as the core, total 13 pyridino[2,3-D]pyrimidine derivatives with different alkyl substituents at C2 site have been designed and synthesized to search for novel PI3Kα/mTOR dual inhibitors. Most of the target compounds showed potent mTOR inhibition activity with IC₅₀ values ranging from single to double digit nanomole. Five target compounds exhibited pronounced PI3Kα inhibition activity. In vitro cellular assay indicated that most of the target compounds showed excellent antiproliferative activity, especially 3j whose potency against SKOV3 was 8-fold higher than the positive control AZD8055. In vitro metabolic stability study found that 3j had a comparable stability to that of AZD8055. More importantly, 3j showed better antitumor activity and pharmacokinetic properties in vivo as compared with AZD8055.

以吡啶并[2,3- D ]嘧啶为核心，设计合成了13种在C2位具有不同烷基取代基的吡啶并[2,3- D ]嘧啶衍生物，以寻找新型的PI3Kα/ mTOR双重抑制剂。大多数目标化合物显示出有效的mTOR抑制活性，IC ₅₀值范围从一位至两位数纳摩尔。五个目标化合物表现出明显的PI3Kα抑制活性。体外细胞分析表明，大多数目标化合物均具有出色的抗增殖活性，尤其是3j，其对SKOV3的效力是阳性对照AZD8055的8倍。体外代谢稳定性研究发现3j具有与AZD8055相当的稳定性。更重要的是，与AZD8055相比，3j在体内显示出更好的抗肿瘤活性和药代动力学特性。