Nanjing University of Chinese Medicine, Nanjing 210046, China.
Nanjing University of Chinese Medicine, Nanjing 210046, China.
Bioorg Med Chem. 2018 Aug 7;26(14):3992-4000. doi: 10.1016/j.bmc.2018.06.025. Epub 2018 Jun 18.
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 IC 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，设计并合成了 13 种不同 C2 位取代基的吡啶并[2,3-D]嘧啶衍生物，旨在寻找新型的 PI3Kα/mTOR 双重抑制剂。大多数目标化合物对 mTOR 表现出很强的抑制活性，IC 值范围在单位数到两位数纳摩尔之间。其中 5 种目标化合物对 PI3Kα 表现出明显的抑制活性。体外细胞实验表明，大多数目标化合物表现出优异的抗增殖活性，特别是化合物 3j，其对 SKOV3 的活性比阳性对照药 AZD8055 高 8 倍。体外代谢稳定性研究发现，化合物 3j 的稳定性与 AZD8055 相当。更重要的是，与 AZD8055 相比，3j 在体内表现出更好的抗肿瘤活性和药代动力学特性。
