Synthesis of a new 4-aza-2,3-didehydropodophyllotoxin analogues as potent cytotoxic and antimitotic agents.

Abstract A series of novel conjugates of 4-aza-2,3-didehydropodophyllotoxins ( 11a – w ) were synthesized by a straightforward one-step multicomponent synthesis that demonstrated cytotoxicity against five human cancer cell lines (breast, oral, colon, lung and ovarian). All the twenty three compounds ( 11a – w ) have been examined for the inhibition of tubulin polymerization. Among these compounds, 11a , 11k and 11p exhibited inhibition of polymerization tubulin comparable to podophyllotoxin apart from disruption of microtubule organization within the cells. Flow cytometric analysis showed that these compounds ( 11a , 11k and 11p ) arrested the cell cycle in the G2/M phase of cell cycle leading to caspase-3 dependent apoptotic cell death.