Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China; Polymers and Composites Division, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, 1219 Zhongguan West Rd, Zhenhai District, Ningbo 315201, People's Republic of China.
Bioorg Chem. 2019 Nov;92:103238. doi: 10.1016/j.bioorg.2019.103238. Epub 2019 Aug 30.
PI3K pathway has been heavily studied and is one of the most potential targets for various cancer treatment. Herein, we designed and synthesized a series of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates contained piperazine based on our previous research. They were evaluated for their PI3Kα wild-type and H1047R mutant inhibitory activities and anticancer effects in vitro. Most of these compounds displayed the potential antiproliferative activities against four cancer cell lines (HCT-116, A549, Huh7 and HL60). Among them, Compound 4p revealed the remarkable antiproliferative activity and was selected for further biological evaluation. Compound 4p displayed the potent activity against both PI3Kα wild-type and H1047R mutant, and a certain degree of selectivity for PI3Kα over PI3Kβ, γ and δ, and meanwhile it can remarkable down-regulate the phosphorylation of Akt. In addition, compound 4p was found to induce cell apoptosis via upregulation of Bax and cleaved-caspase 3/9, and downregulation of Bcl-2. The above results suggested that compound 4p could be considered as a promising PI3Kα inhibitor.
PI3K 通路已被深入研究，是各种癌症治疗的最有潜力的靶点之一。在此，我们基于前期研究，设计并合成了一系列新型含哌嗪的色烯并[4,3-c]吡唑-4(2H)-酮衍生物。评估了它们对 PI3Kα 野生型和 H1047R 突变体的抑制活性以及体外抗癌作用。这些化合物大多数对四种癌细胞系（HCT-116、A549、Huh7 和 HL60）具有潜在的抗增殖活性。其中，化合物 4p 显示出显著的抗增殖活性，并被选择用于进一步的生物学评价。化合物 4p 对 PI3Kα 野生型和 H1047R 突变体均具有很强的活性，对 PI3Kα 相对于 PI3Kβ、γ 和 δ 具有一定的选择性，同时它可以显著下调 Akt 的磷酸化。此外，化合物 4p 被发现通过上调 Bax 和 cleaved-caspase 3/9 以及下调 Bcl-2 来诱导细胞凋亡。上述结果表明，化合物 4p 可以被认为是一种有前途的 PI3Kα 抑制剂。
