Multicomponent assembly of 4-aza-podophyllotoxins: A fast entry to highly selective and potent anti-leukemic agents

Abstract The aim of this study was the synthesis and lead structure selection of a best anti-leukemic agent from a library of aza-podophyllotoxin analogues (APTs). To this end, we report a scalable, modified multicomponent reaction using a “sacrificial” aniline partner as a more general route to rapidly construct the pivotal library of 50 APT analogues. Our preliminary structure activity relationship studies for anti-leukemic activity also address the innate toxicity of these compounds against non-malignant cells. As a result, we identified 2 novel compounds 2ca′ and 2jc′ more potent than etoposide 1 (25–60 fold) having high selectivity against the human THP-1 leukemia cell line and a minimal toxicity (IC 50 of 9.3 ± 0.8 and 19.6 ± 1.4 nM respectively) which represent the best candidates for further pharmacological optimization.