Novel bridged and caged C4-podophyllotoxin derivatives as microtubule disruptors: synthesis, cytotoxic evaluation and structure–activity relationship

New podophyllotoxin C⁴-derivatives with bridged and cage moieties were synthesized by the Steglich esterification of podophyllotoxin with polycyclic carboxylic acids or by etherication with (adamantan-1-yl)methanol in the presence of BF₃·Et₂O with the following separation of diastereomers. Most of the target compounds inhibited the growth of human lung carcinoma A549 cells, induced apoptosis, stimulated shortening of microtubules or induced their unusual curling and involution. The activity depends on the slightest differences in the structures of alicyclic moieties and the type of the bond between podophyllotoxin and alicyclic group.