2, 4, 5-Trideoxyhexopyranosides Derivatives of 4’-Demethylepipodophyllotoxin: De novo Synthesis and Anticancer Activity

Abstract

Background: Podophyllotoxin is a natural lignan which possesses anticancer and antiviral activities. Etoposide and teniposide are semisynthetic glycoside derivatives of podophyllotoxin and are increasingly used in cancer medicine. Objective: The present work was aimed to design and synthesize a series of 2, 4, 5-trideoxyhexopyranosides derivatives of 4’-demethylepipodophyllotoxin as novel anticancer agents. Methods: A divergent de novo synthesis of 2, 4, 5-trideoxyhexopyranosides derivatives of 4’-demethylepipodophyllotoxin has been established via palladium-catalyzed glycosylation. The abilities of synthesized glycosides to inhibit the growth of A549, HepG2, SH-SY5Y, KB/VCR and HeLa cancer cells were investigated by MTT assay. Flow cytometric analysis of cell cycle with propidium iodide DNA staining was employed to observe the effect of compound 5b on cancer cell cycle. Results: Twelve D and L monosaccharides derivatives 5a-5l have been efficiently synthesized in three steps from various pyranone building blocks employing de novo glycosylation strategy. D-monosaccharide 5b showed highest cytotoxicity on five cancer cell lines with the IC50 values from 0.9 to 6.7 mM. It caused HepG2 cycle arrest at G2/M phase in a concentration-dependent manner. Conclusion: The present work leads to the development of novel 2, 4, 5-trideoxyhexopyranosides derivatives of 4’- demethylepipodophyllotoxin. The biological results suggested that the replacement of the glucosyl moiety of etoposide with 2, 4, 5-trideoxyhexopyranosyl is favorable to their cytotoxicity. D-monosaccharide 5b caused HepG2 cycle arrest at G2/M phase in a concentration-dependent manner.