Toward synthesis of third-generation spin-labeled podophyllotoxin derivatives using isocyanide multicomponent reactions

• New spin-labeled podophyllotoxin analogs were prepared and tested for cytotoxicity.
• The synthesis used an isocyanide multicomponent coupling reaction.
• Potent cytotoxicity was found against A-549, DU-145, KB and KBvin cancer cell lines.
• Two compounds (12e, 12h) showed superior potency to etoposide.

Spin-labeled podophyllotoxins have elicited widespread interest due to their far superior antitumor activity compared to podophyllotoxin. To extend our prior studies in this research area, we synthesized a new generation of spin-labeled podophyllotoxin analogs via isocyanide multicomponent reactions and evaluated their cytotoxicity against four human cancer cell lines (A-549, DU-145, KB and KBvin). Most of the compounds exhibited potent cytotoxic activity against all four cell lines, notably against the drug resistant KBvin cancer cell line. Among the new analogs, compounds 12e (IC50: 0.60–0.75 μM) and 12h (IC50: 1.12–2.03 μM) showed superior potency to etoposide (IC50: 2.03 to >20 μM), a clinically available anticancer drug. With a concise efficient synthesis and potent cytotoxic profiles, compounds 12e and 12h merit further development as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidates.

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