Faculty of Pharmacy, Division of Pharmaceutical Chemistry, University of Helsinki, Helsinki, Finland.
J Antibiot (Tokyo). 2010 Mar;63(3):123-6. doi: 10.1038/ja.2010.2. Epub 2010 Feb 5.
Leishmanicidal activity of 24 derivatives of naturally occurring and abundant triterpenes belonging to the lupane series, betulin, betulinic acid and betulonic acid, is described in this study. The easily modified positions of the lupane skeleton, the hydroxy groups of C-3 and C-28, as well as the carbon-carbon double bond C-20-C-29 were used as a starting point to prepare a library of triterpenoid derivatives for bioactivity studies. The compounds were evaluated against Leishmania donovani axenic amastigotes on a microplate assay at 50 microM. GI(50) values of the most effective compounds were evaluated, as well as their cytotoxicity on the human macrophage cell line THP-1, and anti-leishmanial activity against L. donovani-infected THP-1 macrophages was determined. Betulonic acid was the most potent derivative, yielding a GI(50) value of 14.6 microM. Promising and distinct structure-activity relationships were observed, and these compounds can be regarded as significant lead molecules for further improvement and optimization.
本研究描述了 24 种天然存在且丰富的五环三萜类化合物（包括白桦脂醇、白桦脂酸和白桦脂酸）的衍生物对利什曼原虫的杀利什曼原虫活性。五环三萜骨架的可修饰位置，即 C-3 和 C-28 位的羟基以及 C-20-C-29 位的碳-碳双键被用作制备用于生物活性研究的三萜类衍生物文库的起点。在 50μM 的微孔板测定中，评估了化合物对无鞭毛体的活性。评估了最有效的化合物的 GI（50）值，以及它们对人巨噬细胞系 THP-1 的细胞毒性，并测定了它们对感染 L. donovani 的 THP-1 巨噬细胞的抗利什曼活性。白桦脂酸是最有效的衍生物，其 GI（50）值为 14.6μM。观察到了有前途的、明显的构效关系，这些化合物可被视为进一步改进和优化的重要先导分子。
