Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120, Halle (Saale) Germany.
Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120, Halle (Saale) Germany.
Eur J Med Chem. 2016 Oct 21;122:452-464. doi: 10.1016/j.ejmech.2016.06.053. Epub 2016 Jul 1.
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.
2,3-二-O-乙酰基三萜酸衍生的酰胺具有 A 环中的（2β，3β）构型和两个乙酰基，先前已显示对人肿瘤细胞系具有高细胞毒性，但对非恶性小鼠成纤维细胞表现出低细胞毒性。在这项研究中，选择了八角酸（1）和 2-表-考来替酸（2）作为合成类似物的起点。虽然八角酸衍生的 3-喹啉基酰胺 9 在 SRB 测定中给出了低 EC50 值，但对所有细胞系均具有细胞毒性，而异构的 4-异喹啉基酰胺 21 对肿瘤细胞系具有非常高的细胞毒性，但对小鼠成纤维细胞 NIH 3T3 的细胞毒性明显降低。此外，当它为三乙酰化的 4-异喹啉基衍生物时，它对阿霉素耐药的卵巢癌细胞 A2780 的 EC50 为 80 nM。如通过附加实验（吖啶橙/碘化丙啶染色、荧光光谱和细胞周期研究）所示，这些化合物主要通过细胞凋亡起作用。
