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In order to find novel synthetic antitumor agents with superior cytotoxicity and overcoming multidrug resistance, a novel series of 4β-N-substituted podophynotoxin derivatives were synthesized and evaluated as potential antitumor agents. Seven novel podophyllotoxin derivatives were synthesized by linking 4β-amino-4-deoxypodophyllotoxin with N-substituted 5-methylindol-3-yl-glyoxyl chlorides and tested against K562 and K562/A02 using SRB methods in vitro, KB and KBV using MTT methods in vitro.