Carbamates of 4′-demethyl-4-deoxypodophyllotoxin: Synthesis, cytotoxicity and cell cycle effects

In an attempt to generate compounds with superior bioactivity and reduced toxicity, 12 carbamates of 4′-demethyl-4-deoxypodophyllotoxin, N-(1-oxyl-4′-demethyl- 4-deoxypodophyllic)-α-amino acids amides, were synthesized and evaluated for antiproliferative activity and cell cycle effects. These synthesized compounds proved to be more hydrophilic, as well as improved or comparable in vitro cytotoxicities against four cell lines (A-549, HeLa, SiHa, and HL-60) compared with either parent DPT or anti-cancer drug VP-16. Furthermore, flow cytometric analysis exhibited that N-(1-oxyl-4′-demethyl-4-deoxypodophyllic)-d-α-methine amide (15f) induced cell cycle arrest in the G2/M phase in A-549 cells.

Graphical abstractThe novel carbamates of deoxypodophyllotoxin, N-(1-oxyl-4′-demethyl- 4-deoxypodophyllic)-α-amino acids amides (15a–l), showed more hydrophilic, and superior or comparable cytotoxicities in vitro compared with either deoxypodophyllotoxin or VP-16. Furthermore, 15f induces cell cycle arrest in the G2/M phase in A-549 cells.Figure optionsDownload full-size imageDownload as PowerPoint slide