Design, Synthesis, and Biological Evaluation of the First Podophyllotoxin Analogues as Potential Vascular-Disrupting Agents

We designed and synthesized two novel series of azapodophyllotoxin analogues as potential antivascular agents. A linker was inserted between the trimethoxyphenyl ring E and the tetracyclic ABCD moiety of the 4‐aza‐1,2‐didehydropodophyllotoxins. In the first series, the linker enables free rotation between the two moieties; in the second series, conformational restriction of the E nucleus was considered. We have identified several new compounds with inhibitory activity toward tubulin polymerization similar to that of CA‐4 and colchicine, while displaying low cytotoxic activity against normal and/or cancer cells. An aminologue and a methylenic analogue were shown to disrupt endothelial cell cords on Matrigel at subtoxic concentrations, and an original assay of drug washout allowed us to demonstrate the rapid reversibility of this effect. These two new analogues are promising leads for the development of vascular‐disrupting agents in the podophyllotoxin series. Low cytotoxicity is the key: Two novel series of azapodophyllotoxins were designed and synthesized. Subsequent biological investigations revealed that an aminologue and a methylenic analogue, both of which display low cytotoxicity toward cancer and/or normal cells, can be considered the first potential vascular‐disrupting agents (VDAs) in the podophyllotoxin series.