Department of Natural Sciences, Savannah State University, Savannah, GA 31404, USA.
Bioorg Med Chem Lett. 2012 Feb 15;22(4):1734-8. doi: 10.1016/j.bmcl.2011.12.102. Epub 2011 Dec 28.
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.
白桦脂酸是一种具有高体外细胞毒性的天然化合物，对许多癌细胞都有很高的杀伤力。然而，由于该化合物的水溶性差，严重限制了其在体内癌症研究中的应用。我们制备了白桦脂酸的新型离子衍生物，具有更高的水溶性，同时又保持了该化合物的结构完整性和功能性。结果表明，这些新型离子衍生物对不同的癌细胞系如黑色素瘤 A375、神经母细胞瘤 SH-SY5Y 和乳腺癌 MCF7 具有更高的抑制作用。对于 A375 细胞系，衍生物 5 的 IC50 值低至 36 μM（而白桦脂酸的 IC50 值为 154 μM）；对于 MCF7 细胞系，衍生物 5 的 IC50 值也低至 25 μM（而白桦脂酸的 IC50 值为 112 μM）。这些新型衍生物的高细胞毒性与其大大提高的水溶性有关。我们的测定方法使用了少量 DMSO 来辅助这些衍生物的溶解，以证明提高水溶性的优势，并模拟体内研究条件。基于 MTT 和 LDH 测定方法的细胞活力研究证实了我们的白桦脂酸离子衍生物（特别是 4 和 5）对不同癌细胞的高抑制作用。
