Discovering Podophyllotoxin Derivatives as Potential Anti-Tubulin Agents: Design, Synthesis and Biological Evaluation

Podophyllotoxin is a potent cytotoxic agent and serves as a useful lead compound for development of anticancer agents. Tubulin is known as an attractive target for drug discovery and cancer therapies. There are few studies on the treatment of breast cancer with podophyllotoxin and its derivatives targeting tubulin. Here, a series of novel aryl 1,3,4-oxadiazole/1,3,4-thiadiazole acid podophyllotoxin ester derivatives (D1-D16) were synthesized. Among these compounds, D9 exhibited excellent antiproliferation activity against MCF-7 cells (IC50=2.46 +/- 0.12 mu M). Furthermore, D9 caused cell cycle arrest at the G2/M phase and induced cell apoptosis. Confocal microscopy showed that D9 inhibited microtubule polymerization by causing cancer cell growth inhibition. Molecular docking results suggested D9 could bind to the active binding site of tubulin. In a mouse model, compound D9 suppressed malignant growth without causing significant toxicity to normal tissues. Our findings support the utility of D9 as a novel compound for the development of anticancer agent.