Derivatives of grindelic acid: From a non-active natural diterpene to synthetic antitumor derivatives

• Syntheses of grindelic acid derivatives.
• Oxy-nitrogenated and nitrogenated groups are key for the cytotoxic activity.
• The more active derivative showed a GI50 values in the range 0.95–1.8 μM.
• Labdanes-type diterpenes represent a potential source for new anticancer drug candidates.

Using several reactions that include homologations and asymmetric epoxidations as well as Ugi and Huisgen couplings, we generated a small focused library of new derivatives from the labdane-type diterpene grindelic acid. These compounds were evaluated as cytotoxic agents against a panel of five human solid tumor cell lines (HBL-100, HeLa, SW1573, T-47D, and WiDr). The presence of the diamide functionalizations enhanced the cytotoxic effect. N-Benzyl-N-(1-(benzylamino)-2-methyl-1-oxopropan-2-yl)grindelicamide, proved to be the most active product in all cell lines tested, with values of 0.95 (±0.38) μM against HBL-100 cells.

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