School of Pharmaceutical Sciences, Institute of Drug Discovery and Development, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University, Zhengzhou, 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou, 450001, PR China.
School of Pharmaceutical Sciences, Institute of Drug Discovery and Development, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University, Zhengzhou, 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou, 450001, PR China.
Eur J Med Chem. 2019 Nov 15;182:111645. doi: 10.1016/j.ejmech.2019.111645. Epub 2019 Sep 3.
As our research focus on anticancer drugs, two series of novel derivatives of Flexicaulin A (FA), an ent-kaurene diterpene, condensation with amino acid trifluoroacetate were synthesized, and their anti-proliferative activity against four human cancer cell lines (TE-1, MCF-7, A549 and MGC-803) were evaluated. Compared with FA, the anticancer activity and solubility of most derivatives were significantly improved. Among them, compound 6d had the best activity, and its IC value against Esophageal cancer cells (TE-1) was up to 0.75 μM. Subsequent cellular mechanism studies showed that compound 6d could inhibit the proliferation of cancer cells, the formation of cell colonies, and increase the level of ROS on TE-1 cells. In addition, 6d could up-regulate the expressions of SAPK/JNK pathway-associated proteins (p-ASK1, p-MKK4 and p-JNK) and pro-apoptotic proteins (Bak, Bad and Noxa), remarkably increase the ratio of Bax to Bcl-2 and activate Cleaved Caspase-3/9/PARP. These results indicate that compound 6d induces apoptosis through the ROS/JNK/Bcl-2 pathway and holds promising potential as an anti-proliferative agent.
作为我们的研究重点是抗癌药物，我们合成了两个系列的新型衍生物 Flexicaulin A（FA），一种 ent-贝壳杉烯二萜，与氨基酸三氟乙酸缩合，并评估了它们对四种人类癌细胞系（TE-1、MCF-7、A549 和 MGC-803）的抗增殖活性。与 FA 相比，大多数衍生物的抗癌活性和溶解度都有显著提高。其中，化合物 6d 活性最好，其对食管癌细胞（TE-1）的 IC 值达到了 0.75 μM。随后的细胞机制研究表明，化合物 6d 可以抑制癌细胞的增殖、细胞集落的形成，并增加 TE-1 细胞中的 ROS 水平。此外，6d 可以上调 SAPK/JNK 通路相关蛋白（p-ASK1、p-MKK4 和 p-JNK）和促凋亡蛋白（Bak、Bad 和 Noxa）的表达，显著增加 Bax 与 Bcl-2 的比值，并激活 Cleaved Caspase-3/9/PARP。这些结果表明，化合物 6d 通过 ROS/JNK/Bcl-2 通路诱导细胞凋亡，具有作为增殖抑制剂的潜力。
