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

Abstract

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 IC₅₀ values for both MCF-7 (0.5 μm) and PC3 (0.3 μm) 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 (IC₅₀ =0.8 μm), 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 IC₅₀ values in the low micromolar range and high selectivity against MCF-7, Caco-2, and PC3 cancer cell lines.

Keywords: Buchwald-Hartwig reaction; cancer; cytotoxicity; goniothalamin; nitrogenated derivatives.