Synthesis of 4β-triazole-podophyllotoxin derivatives by azide–alkyne cycloaddition and biological evaluation as potential antitumor agents

A representative synthetic process of derivatizing the natural product podophyllotoxin utilizing the copper-catalyzed azide–alkyne cycloaddition (CuAAC) is described including molecular design, reaction optimization and X-ray structure confirmation. Evaluation of cytotoxicity against human cancer cell lines (Hela, K562 and K562/A02) using MTT assay proves that these triazole derivatives have good antitumor activities. High activities toward the drug resistant K562/A02 cell line reveal promising future for these derivatives. The rarely prepared 1,5-disubstituted triazole isomers, which would be omitted by the “click chemistry”, were found to have superior cytotoxicities to that of the 1,4-disubstituted isomers. Some novel 4β-triazole-podophyllotoxin derivatives were synthesized and evaluated against human cancer cell lines. The rarely prepared 1,5-isomers were found to have enhanced activities compared to the 1,4-isomers. [Display omitted] ► Derivatizing the natural product podophyllotoxin utilizing the copper-catalyzed azide–alkyne cycloaddition. ► Single 1,4-disubstituted regioisomer obtained by CuAAC. ► Higher in vitro activity than current drugs. ► 1,5-Disubstituted regioisomers obtained without copper catalysis have higher cytotoxicities.