Synthetic Derivatives of Natural ent‐Kaurane Atractyligenin Disclose Anticancer Properties in Colon Cancer Cells, Triggering Apoptotic Cell Demise

The antitumor activity of different ent‐kaurane diterpenes has been extensively studied. Several investigations have demonstrated the excellent antitumor activity of synthetic derivatives of the diterpene atractyligenin. In this research, a series of new synthetic amides and their 15,19‐di‐oxo analogues obtained from atractyligenin by modifying the C‐2, C‐15, and C‐19 positions were designed in order to dispose of a set of derivatives with different substitutions at the amidic nitrogen. Using different concentrations of the obtained compounds (10–300 μM) a reduction in cell viability of HCT116 colon cancer cells was observed at 48 h of treatment. All the di‐oxidized compounds were more effective than their alcoholic precursors. The di‐oxidized compounds had already reduced the viability of two colon cancer cells (HCT116 and Caco‐2) at 24 h when used at low doses (2.5–15 μM), while they turned out to be poorly effective in differentiated Caco‐2 cells, a model of polarized enterocytes. The data reported here provide evidence that di‐oxidized compounds induced apoptotic cell death, as demonstrated by the appearance of condensed and fragmented DNA in treated cells, as well as the activation of caspase‐3 and fragmentation of its target PARP‐1.