State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong, Jia Xiang, Nanjing 210009, PR China.
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong, Jia Xiang, Nanjing 210009, PR China.
Bioorg Med Chem. 2022 Oct 15;72:116977. doi: 10.1016/j.bmc.2022.116977. Epub 2022 Aug 25.
Natural products (NPs) are always the important sources in the field of drug discovery, among which spirolactone-type and enmein-type compounds exhibit a wide range of biological activities, especially anti-tumor activity. Based on previous studies, the spirolactone-type and enmein-type compounds could be derived from natural oridonin (1) by several chemical reactions. Herein, a series of novel spirolactone-type and enmein-type derivatives with different aryl allyl ester substitutions at their C-14 hydroxyl group were designed and synthesized. The anti-tumor activity results showed that most of the compounds exhibited better anti-proliferative activities than parent compound oridonin, and the most potent compound had an IC value of 0.40 μM in K562 cells. Further mechanistic studies revealed that the optimal compound could arrest K562 cells at G2/M phase by inhibiting cdc-2, cdc-25c and cyclin B1 expression. In addition, the optimal compound induced apoptosis in K562 cells through increasing ROS production and depolarizing mitochondrial membrane potential. Collectively, these valuable results suggested that the most potent compound could be an anti-tumor agent candidate and is worthy of further investigation.
天然产物（NPs）一直是药物发现领域的重要来源，其中螺内酯型和恩美宁型化合物具有广泛的生物活性，特别是抗肿瘤活性。基于以往的研究，螺内酯型和恩美宁型化合物可以通过几种化学反应从天然的冬凌草甲素（1）衍生而来。在此，设计并合成了一系列新型的 C-14 位羟基具有不同芳基烯丙酯取代的螺内酯型和恩美宁型衍生物。抗肿瘤活性结果表明，大多数化合物的抗增殖活性均优于母体化合物冬凌草甲素，其中活性最强的化合物在 K562 细胞中的 IC 值为 0.40 μM。进一步的机制研究表明，最佳化合物通过抑制 cdc-2、cdc-25c 和 cyclin B1 的表达，将 K562 细胞阻滞在 G2/M 期。此外，最佳化合物通过增加 ROS 生成和去极化线粒体膜电位诱导 K562 细胞凋亡。总之，这些有价值的结果表明，活性最强的化合物可能是一种抗肿瘤药物候选物，值得进一步研究。
