Association (micellization) and partitioning of aglycon triterpenoids

Micellization and solution properties of the aglycon triterpenoids asiatic acid (AA) and madecassic acid (MA) were examined experimentally and in computational simulations. AA and MA belong to the large class of bioactive aglycon triterpenoids, for which limited physicochemical data are available. In this study, solubility, partition coefficient, critical micelle concentrations (CMC), and surface tensions of AA and MA were measured. Reverse phase HPLC data, supported by dye probe experiments and drop shape analysis, showed the CMC in phosphate buffered saline (PBS) to be 15±2 μM15±2 μM, and 86±9 μM86±9 μM for AA and MA, respectively. The surface tensions of AA and MA in PBS were 64.1 and 64.4 mN/m, respectively. Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry indicated the aggregation numbers of AA and MA to be 5 to 7. Molecular dynamics simulations confirmed that molecular association could occur between 5 and 7 molecules in solution. The IC50 of AA and MA on human small cell carcinoma and human glioblastoma cell lines was 25±5 μM25±5 μM and 66±13 μM66±13 μM, respectively. The IC50 is within the range of calculated CMC of AA and MA in bioassay media, suggesting that the micellar aggregates may lead to their cytotoxicity.

GROMACS simulations indicate that asiatic acid and madecassic acid form small micelles with aggregate number 5–7. The IC50 coincided with CMC, suggesting that the micellar association may be responsible for cytotoxicity. (Figure: (left) molecular dynamics simulation of asiatic acid (AA) molecules self-assembly, forming a 5–7 molecule aggregate; (right) viability of DMS114 and HTB-14 cells treated with AA.)Figure optionsDownload as PowerPoint slide