Synthesis of Nitrogen‐Containing Goniothalamin Analogues with Higher Cytotoxic Activity and Selectivity against Cancer Cells

Two series of racemic goniothalamin analogues displaying nitrogen‐containing groups were designed and synthesized. A total of 19 novel analogues were evaluated against a panel of four different cancer cell lines, along with the normal prostate cell line PNT2 to determine their selectivity. Among them, goniothalamin chloroacrylamide 13 e displayed the lowest IC 50 values for both MCF‐7 (0.5 μ m ) and PC3 (0.3 μ m ) cells, about 26‐fold more potent than goniothalamin ( 1 ). Besides its higher potency, compound 13 e also displayed much higher selectivity than goniothalamin. In contrast, goniothalamin isobutyramide 13 c was the most potent analogue against Caco‐2 cells (IC 50 =0.8 μ m ), about 10‐fold more potent and 17‐fold more selective than 1 . These results reveal the potential of compounds 13 c and 13 e for further in vivo studies, representing the first goniothalamin analogues with IC 50 values in the low micromolar range and high selectivity against MCF‐7, Caco‐2, and PC3 cancer cell lines.