New ionic derivatives of betulinic acid as highly potent anti-cancer agents.

Betulinic acid is a natural compound with high in vitro cytotoxicity toward many cancer cells. However, the poor water solubility of this compound hampers an effective in vivo cancer study. We prepared new ionic derivatives of betulinic acid with higher water solubilities, without losing the structural integrity and functionality of this compound. As a result, these new ionic derivatives have shown much higher inhibitory effects against different cancer cell lines such as melanoma A375, neuroblastoma SH-SY5Y and breast adenocarcinoma MCF7. For A375 cell lines, the derivative 5 exhibited a low IC(50) value of 36 μM (vs 154 μM for betulinic acid); for MCF7 cell lines, the derivative 5 also exhibited a low IC(50) value of 25 μM (vs 112 μM for betulinic acid). The high cytotoxicity of these new derivatives can be linked to their greatly improved water solubility. Our assay method used little DMSO in aiding the dissolution of these derivatives to demonstrate the advantage of improved water solubility and to mimic the in vivo study conditions. The cell viability studies based on both MTT and LDH assay methods have confirmed the high inhibitory effect of our ionic derivatives of betulinic acid (particularly 4 and 5) against different cancer cells.