Selective killing of cancer cells with triterpenoic acid amides - The substantial role of an aromatic moiety alignment

•Amide derivatives of augustic, 2-epi-corosolic and asiatic acid were synthesized.•They were tested for their antitumor activity using human cancer cell lines.•An augustic acid derived 4-isoquinolinyl amide showed increased cytotoxicity.•A 4-isoquinolinyl derivative of asiatic acid (28) gave EC50 = 80 nM (A2780 cells).•The compounds act by apoptosis.

2,3-Di-O-acetyl-triterpenoic acid derived amides possessing a (2β, 3β) configuration in ring A and two acetyl groups were previously shown to possess high cytotoxicity for human tumor cell lines but to exhibit low cytotoxicity for non-malignant mouse fibroblasts. In this study, augustic acid (1) and 2-epi-corosolic acid (2) were chosen as starting points for the synthesis of analogs. While augustic acid derived 3-quinolinyl amide 9 gave low EC50 values in SRB assays but was cytotoxic for all lines, the isomeric 4-isoquinolinyl amide 21 was very cytotoxic for the tumor cell lines but significantly less cytotoxic for the mouse fibroblasts NIH 3T3. In addition, a triacetylated 4-isoquinolinyl derivative of asiatic acid (28) gave EC50 = 80 nM (for A2780 ovarian cancer cells). As shown by additional experiments (acridine orange/propidium iodide staining, fluorescence spectroscopy and cell cycle investigations) these compounds act mainly by apoptosis.

Graphical abstractA small structural difference (3-quinolinyl/4-isoquinolinyl) has a strong impact on cytotoxicity and malignant/non-malignant cell selectivity.Figure optionsDownload full-size imageDownload as PowerPoint slide