Hederagenin amide derivatives as potential antiproliferative agents.

In this study, a series of C-28 amides derivatives of hederagenin with or without the presence of an acetyl group at positions 3 and 23 in ring A, were synthetized aiming to develop potent cytotoxic agents. Their structures were confirmed by MS, IR, ¹H NMR and ¹³C NMR spectroscopic analyses and their cytotoxic activities were screened in SRB assays using a panel of six human cancer cell lines. The majority of the amide derivatives were cytotoxic for a variety of human tumor cell lines. In general, the hydroxylated derivatives (1a-1d; EC₅₀ in the range 1.2-22.5 μM) were less active than the acetylated derivatives (2a-2n; EC₅₀ in the range 0.4-9.0 μM). Hydroxylated derivative bearing pyrrolidinyl substituent 1c, was the most active for HT29 human line cells (EC₅₀ = 1.2 μM), however their acetylated derivative 2c was the most potent and selective against A2780, FaDu, SW1736 cells, showing EC₅₀ values between 0.4 and 1.7 μM and SI between 5.6 and 24. Staining experiments combined with fluorescence microscopy indicate that the cell membrane became permeable, and finally a process of secondary necrosis was observed. In addition, the docking results showed that acetylated compounds display more affinity to HER2 than to USP7, indicating that HER2 is a most probable receptor, both proteins found in tumor cell line A2780.