Zhang, Xin, et al. Bioorganic Chemistry 123 (2022): 105761.
Podophyllotoxin, a natural lignan isolated from the dried rhizomes and roots of various Podophyllum species, demonstrates potent activity in disrupting tubulin polymerization and inducing cancer cell apoptosis. Structure-activity relationship studies have shown that modifications at the 4-position are tolerated without compromising its biological activity. In this study, we designed and synthesized podophyllotoxin derivatives incorporating piperazinyl-cinnamic amide moieties at the 4-position.
Procedure:
To a solution of podophyllotoxin (828 mg, 2 mmol) and sodium iodide (900 mg, 6 mmol) in dry acetonitrile (100 mL), methyl sulfonic acid (576 mg, 6 mmol) was carefully added dropwise. The mixture was stirred at 0 °C for 1 hour, and the reaction was monitored by thin-layer chromatography to ensure complete conversion of the substrate. Following this, barium carbonate (1.18 g, 6 mmol) and triethylamine (606 mg, 6 mmol) were added to adjust the pH to the range of 7-8. Piperazine (190 mg, 2.2 mmol) was then introduced, and the reaction mixture was stirred at room temperature for an additional 12 hours. The reaction was quenched with water, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and the combined organic layers were washed with water, brine, and dried over Na₂SO₄. After the solvent was removed under reduced pressure, the crude product was purified by column chromatography, yielding the intermediate 5 in 56% yield.
Zhang, Lei, et al. Medicinal Chemistry Research 28 (2019): 81-94.
Cai, De-sheng, et al. Bioorganic Chemistry 128 (2022): 106066.