Design, synthesis and topoisomerase II inhibition activity of 4'-demethylepipodophyllotoxin-lexitropsin conjugates.

The design and synthesis of 4'-demethylepipodophyllotoxin-lexitropsin conjugates capable of inhibiting the actions of topoisomerase II are described. Siteselective topoisomerase II cleavage was observed in the presence of the new inhibitors, as determined by DNA sequencing. Additional topoisomerase II cleavage sites were observed with the new compounds that seem to be characteristic of the minor groove-binding lexitropsin moieties. Compound 17, having three pyrrole units in its binding moiety, exhibited distinct topoisomerase-mediated sites of cleavage at positions 4258, 4257, 4255 and 4247 of the pBR322 DNA fragment. These results demonstrate that conjugation with minor groove-binding moieties can alter or increase the number of topoisomerase II-induced cleavable sites and contribute to our understanding of the cytostatic activity of these compounds against KB cancer cell lines.