N-Hydroxyethyl-4-aza-didehydropodophyllotoxin derivatives as potential antitumor agents

Three different series of N-hydroxyethyl aza-podophyllotoxin derivatives containing (i) a five-membered methylenedioxy ring (7a–f), (ii) a five-membered ring with no heteroatom (8a–f) or (iii) a six membered ethylenedioxy ring (9a–f) as ring A were synthesized using a convenient one-pot multi-component reaction. Further variation on ring E was done by decorating it with methoxy and hydroxy groups at different positions. Calculation of log P values of these compounds indicates them to be better soluble than corresponding non-hydroxy derivatives. These novel aza-podophyllotoxin derivatives were screened for their cytostatic and cytotoxic activities on National Cancer Institute’s 60 human tumor cell lines to study the structure activity relationship. The overall anticancer activity of these compounds was in the order of 8a–f > 9a–f > 7a–f. Furthermore, the compounds having 3′-methoxy and 3′,4′,5′-trimethoxy substitution at ring E were the most active within the series. The cytotoxicity of all the active compounds was low, while their antiproliferative (or cytostatic) activity was high, providing a wide therapeutic window for their potential application as anticancer drugs.

Graphical abstractA simple and efficient synthesis of N-Hydroxyethyl-4-aza-didehyropodophyllotoxins has been described and their anticancer activity and structure activity relationship have been evaluated using a panel of 60 human tumor cell lines.Figure optionsDownload full-size imageDownload as PowerPoint slide