Structure-Activity Study of the Inhibition of Microtubule Assembly in Vitro by Podophyllotoxin and Its Congeners

This study investigates the inhibition of microtubule assembly in vitro by podophyllotoxin and its derivatives, which include in part the antitumor compounds 4'demethylepipodophyllotoxin ethylidene β-D-glucoside (VP-16-213) and 4'-demethylepipodophyllotoxin thenylidene β-D-glu-coside (VM-26); the cyclic ethers, cyclic sulfides, and cyclic sulfones of podophyllotoxin and deoxypodophyllotoxin; epipodophyllotoxin; picropodophyllotoxin; and several 4'-demethyl compounds. The inhibitory activity of these derivatives is sensitive to the configuration and size of substituents at position 4 in ring C and to steric features of substituents at position 12 in ring D. Decreasing activity correlates with the increasing size of the substituent at position 12, as indexed by their van der Waals radii. These results suggest that rings C and D of these drugs are involved in their interaction with the podophyllotoxin-binding site in tubulin.