A series of analogues of etoposide, the C-4 amino- and alkylamino-substituted 4'-demethyl-epipodophyllotoxins, have been synthesized and studied for their activity to inhibit type II human DNA topoisomerase as well as their activity in causing cellular protein-linked DNA breakage. Substitution of the glycosidic moiety of 1 by a 2"-hydroxyethylamino or 2"-methoxyethylamino chain at the C-4 beta position resulted in potent inhibitors of the human DNA topoisomerase II. This inhibitory activity correlates reasonably well with their activity in causing protein-linked DNA breakage in KB cells. The in vitro cytotoxicity (KB) appears to have no correlation with the inhibitory activity of the human DNA topoisomerase II.
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Lee et al. (1989) studied this question.