Design, Synthesis and Cytotoxicity Evaluation of Novel Indole Derivatives of Panaxadiol

Abstract Based on the well‐known cytotoxicity of indole compounds, we used the ‘Fisher indole synthesis’ method to introduce appropriately substituted indole rings into panaxadiol (PD), generating eighteen novel Panaxadiol indole derivatives. Six human cancer cell lines (A549, HepG‐2, HCT‐116, SGC‐7901, MDA‐MB‐231, PC‐3 cells) and one normal ovarian cell lines (IOSE144) were designed to evaluate the anti‐proliferative activity of the PD derivatives. The results showed that the majority of PD derivatives showed enhanced anti‐proliferative activity, when compared with PD, with P ‐Methylindolo‐PD exhibiting the highest cytotoxicity. In A549 cells, IC 50 value was 5.01±0.87 μM, which is roughly 12 times higher than the activity of PD and 5 times that of 5‐FU. Moreover, cell morphology analysis and Annexin V‐FITC/PI assays exhibited that P ‐Methylindolo‐PD could induce A549 cell apoptosis (55.7 % of apoptotic cells at 20 μM). Moreover, molecular docking experiments were performed to explore the molecular mechanism underlining the binding of P ‐Methylindolo‐PD to the active site of EGFR. The results support that P ‐Methylindolo‐PD might be a promising lead compound for further studies.