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, H-1 NMR and C-13 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 mu M) were less active than the acetylated derivatives (2a-2n; EC50 in the range 0.4-9.0 mu M). Hydroxylated derivative bearing pyrrolidinyl substituent 1c, was the most active for HT29 human line cells (EC50 = 1.2 mu M), 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 mu M 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. (C) 2019 Elsevier Masson SAS. All rights reserved.