Cytotoxicity and Nanoassembly Characteristics of Aromatic Amides of Oleanolic Acid and Ursolic Acid.

A series of more than 20 new amides of oleanolic acid and ursolic acid with selected aromatic amines were synthesized, and the structures of all compounds were analyzed and elucidated. Moreover, the compounds were subjected to the cytotoxicity assays in four cancer cell lines (CCRF-CEM, MCF7, HeLa, and G-361), using normal human fibroblasts (BJ) as reference cells for determining the toxicity of the investigated compounds. The 1,10-phenanthroline derivatives , , , and showed the highest cytotoxicity in all four cancer cell lines, but they were comparably toxic in human fibroblasts. The most promising results were achieved with and showing high cytotoxicity in the cancer cell lines and no toxicity in human fibroblasts. They were subjected to the investigation of the in vitro cell apoptosis, resulting in a confirmation of activation of apoptotic pathways in the CCRF-CEM cell line. The structure-activity relationships were documented by the cytotoxicity of vs. , and of vs , showing reverse effects in CCRF-CEM and MCF7 cancer cell lines. To investigate nanoassembly, initial screening of the target compounds by ultraviolet (UV) spectrometry was performed. Compounds , , , and , soluble both in methanol and in water, were selected for a more detailed investigation by transmission electron microscopy (TEM) microscopy and were found to form spherical nanoassemblies, frequently interconnected in small agglomerates and/or loose networks, while the other target compounds of this series showed no nanoassembling based on the TEM imaging. For each investigated compound, the nanoassemblies formed in methanol were substantially bigger than those formed in water.