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As our research focuses on anticancer drugs, a series of novel derivatives of flexicaulin A (FA), an ent -kaurene diterpene, condensed with an aromatic ring were synthesized, and their antiproliferative activities against four human cancer cell lines (TE-1, EC109, MCF-7, and MGC-803) were evaluated. The activities of most of the new compounds were better than those of FA. Compound 2y exhibited the best activity with an IC50 value reaching 0.13 μM against oesophageal cancer cells (EC109 cells). The IC50 values for 2y in normal cells (GES-1 cells and HUVECs) were 0.52 μM and 0.49 μM, respectively. Subsequent mechanistic investigations found that compound 2y can inhibit the proliferation of cancer cells and cell cloning. In addition, 2y could reduce the mitochondrial membrane potential, increase the apoptosis rate, and increase the ROS level in EC109 cells. Moreover, 2y can upregulate the expression of ROS/JNK pathway-related proteins (p-ASK1, p-MKK4, p-JNK, and p-Cjun (ser63)) and pro-apoptotic proteins (Bax, Bad, and Bim). In vivo experiments showed that 2y can inhibit tumour growth in nude mice. The mechanism involves an increase in protein expression in the ROS pathway, leading to changes in apoptosis-related proteins. In addition, compound 2y shows low toxicity. These results indicate that compound 2y holds promising potential as an antiproliferative agent. The schematic diagram shown the possible pathway for 2y duced apoptosis on EC109. Image 1 • A series of novel derivatives of Flexicaulin A were discovered as potential anti-proliferative agent.. • Most of the derivatives showed enhanced anti-proliferative activity. • Compound 2y exerted the best anti-proliferative activity against EC109 cells. • Compound 2y reduce the mitochondrial membrane potential, increase the apoptosis rate and the level of ROS on EC109. • In vivo experiments, 2y could inhibit tumour growth in nude mice and show low toxicity. [ABSTRACT FROM AUTHOR]

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 50 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. The schematic diagram shown the possible pathway for 6d induced apoptosis on TE-1 cells. Image 1 • Two series of novel derivatives of Flexicaulin A were discovered as potential anti-proliferative agent. • Most of the derivatives showed improved solubility and enhanced anti-proliferative activity. • Compound 6d exerted the best anti-proliferative activity against TE-1 cells. • Compound 6d could inhibit the formation of cell colonies and increase the level of ROS on TE-1 cells. • Compound 6d could induce cell apoptosis of TE-1 cells through the ROS/JNK/Bcl-2 pathway. [ABSTRACT FROM AUTHOR]