Division of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, Finland.
Bioorg Med Chem. 2010 Feb 15;18(4):1573-82. doi: 10.1016/j.bmc.2010.01.003. Epub 2010 Jan 7.
Betulin, a naturally occurring abundant triterpene is converted in four steps to 3,28-di-O-acetyllupa-12,18-diene. When various 4-substituted urazoles were oxidized to the corresponding urazines with iodobenzene diacetate in the presence of 3,28-di-O-acetyllupa-12,18-diene, new heterocyclic betulin derivatives were produced. These betulin derivatives were examined in a microplate assay at 50 microM for their ability to inhibit the growth of Leishmania donovani axenic amastigotes, a species that causes the fatal visceral leishmaniasis. GI(50) (concentration for 50% growth inhibition) values of the most effective compounds were determined and their cytotoxicity on the human macrophage cell line THP-1 evaluated. The anti-leishmanial activity on L. donovani amastigotes growing in macrophages was also examined. The heterocycloadduct between 3,28-di-O-acetyllupa-12,18-diene and 4-methylurazine was the most effective derivative with an GI(50)=8.9 microM against L. donovani amastigotes.
白桦脂醇是一种天然存在的丰富三萜，可经四步反应转化为 3,28-二-O-乙酰卢卡-12,18-二烯。当各种 4-取代的尿嘧啶在 3,28-二-O-乙酰卢卡-12,18-二烯存在下用二乙酰碘苯氧化为相应的尿嘧啶嗪时，会产生新的杂环白桦脂醇衍生物。在 50μM 的微孔板测定法中，这些白桦脂醇衍生物被检测其抑制利什曼原虫无鞭毛体生长的能力，该物种可导致致命的内脏利什曼病。确定了最有效化合物的 GI（50）（50%生长抑制浓度）值，并评估了它们对人巨噬细胞系 THP-1 的细胞毒性。还检测了在巨噬细胞中生长的利什曼原虫无鞭毛体的抗利什曼活性。3,28-二-O-乙酰卢卡-12,18-二烯与 4-甲基尿嘧啶的杂环加合物是最有效的衍生物，对利什曼原虫无鞭毛体的 GI（50）为 8.9μM。
