Cytotoxic activity of several ent-kaurane derivatives of atractyligenin. Synthesis of unreported diterpenic skeleton by chemical rearrangement

Atractyloside, carboxyatractyloside, their aglycon atractyligenin, and several synthetic derivatives were tested and found to be active against a panel of human tumor cell lines. Atractyligenin was subjected to oxidation, bromination, and elimination reactions, obtaining several compounds. A singular skeleton was synthesized by chemical rearrangement starting from 3 beta-bromo-2,15-diketoatractyligenin methyl ester. The synthesized compounds resulted active against all cell lines tested. In particular, 15-ketoatractyligenin methyl ester and 3 beta bromo-2,15-diketoatractyligenin methyl ester resulted the most active with IC50 values of 0.427 and 0.723 mu M against A375 melanoma cell line. Excellent results were also obtained against the colon cancer cell line CaCo2, with slightly lower antiproliferative activity. An interesting extension of the study should be to analyze the atractyligenin derivatives also as target for human melanoma and human colon cancer cells.