Department of Pharmacy, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China.
Department of Pharmacology, Dalian Medical University, Dalian 116044, China.
Bioorg Chem. 2020 Aug;101:104036. doi: 10.1016/j.bioorg.2020.104036. Epub 2020 Jun 25.
Oleanolic acid (OA) and its semi-synthetic derivatives have been reported to have a wide range of biological activities. The introduction of electrophilic Michael acceptor group can increase the reactivity of OA to cellular targets and thus improve the anti-tumor activity. In this work, a series of novel α,β-unsaturated carbonyl derivatives of OA were designed and synthesized. Their in vitro cytotoxic activity against MCF-7, HepG2 and HeLa cells were tested. Most derivatives exhibited improved cell growth inhibitory activity, especially for 3d with an IC of 0.77 μM in MCF-7 cells. Moreover, 3d inhibited the migration of MCF-7 and HeLa cells at the concentration of 4 μM. Flow cytometric analysis revealed that 3d induced cell apoptosis and S phase arrest in a concentration-dependent manner. Western blotting experiment demonstrated that 3d inhibited the phosphorylation of AKT and mTOR. These results suggest that this series of OA derivatives bearing exocyclic methylene ketone pharmacophore are promising anticancer agents as potential PI3K/AKT/mTOR pathway inhibitors.
齐墩果酸（OA）及其半合成衍生物已被报道具有广泛的生物活性。引入亲电迈克尔受体基团可以增加 OA 对细胞靶标的反应性，从而提高抗肿瘤活性。在这项工作中，设计并合成了一系列新型的 OAα，β-不饱和羰基衍生物。测试了它们对 MCF-7、HepG2 和 HeLa 细胞的体外细胞毒性活性。大多数衍生物表现出增强的细胞生长抑制活性，特别是衍生物 3d 在 MCF-7 细胞中的 IC50 为 0.77μM。此外，衍生物 3d 在 4μM 的浓度下抑制 MCF-7 和 HeLa 细胞的迁移。流式细胞术分析显示，3d 以浓度依赖的方式诱导细胞凋亡和 S 期阻滞。Western blot 实验表明，3d 抑制 AKT 和 mTOR 的磷酸化。这些结果表明，这一系列具有外环亚甲基酮药效团的 OA 衍生物作为潜在的 PI3K/AKT/mTOR 通路抑制剂，是有前途的抗癌药物。
