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Development of novel anticancer therapeutic candidates is one of the key challenges in medicinal chemistry. Podophyllotoxin and its derivatives, as a potent cytotoxic agent, have been at the center of extensive chemical amendment and pharmacological investigation. Herein, a new series of podophyllotoxin-<i>N</i>-sulfonyl amidine hybrids (<b>4a</b>–<b>4v</b>, <b>5a</b>–<b>5f</b>) were synthesized by a CuAAC/ring-opening procedure. All the synthesized podophyllotoxins derivatives were evaluated for in vitro cytotoxic activity against a panel of human lung (A-549) cancer cell lines. Different substituents’, or functional groups’ antiproliferative activities were discussed. The –CF₃ group performed best (IC₅₀: 1.65 μM) and exhibited more potent activity than etoposide. Furthermore, molecular docking and dynamics studies were also conducted for active compounds and the results were in good agreement with the observed IC₅₀ values.