Synthesis and anti-leishmanial activity of heterocyclic betulin derivatives

被引:58
作者
Alakurtti, Sami [1 ,2 ]
Heiska, Tuomo [1 ]
Kiriazis, Alexandros [1 ]
Sacerdoti-Sierra, Nina [3 ]
Jaffe, Charles L. [3 ]
Yli-Kauhaluoma, Jari [1 ]
机构
[1] Univ Helsinki, Fac Pharm, Div Pharmaceut Chem, FI-00014 Helsinki, Finland
[2] VTT Tech Res Ctr Finland, FI-02044 Espoo, Finland
[3] Hebrew Univ Jerusalem, Hadassah Med Sch, IMRIC, Dept Microbiol & Mol Genet, IL-91220 Jerusalem, Israel
基金
芬兰科学院;
关键词
Antiprotozoal agents; Betulin; Cycloaddition; Leishmania sp; Terpenoids; INDIAN VISCERAL LEISHMANIASIS; NATURAL-PRODUCTS; IN-VITRO; ACID; APOPTOSIS; AMASTIGOTES; TRITERPENES; DISCOVERY; INDUCTION; DONOVANI;
D O I
10.1016/j.bmc.2010.01.003
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 mu M 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 mu M against L. donovani amastigotes. (C) 2010 Elsevier Ltd. All rights reserved.
引用
收藏
页码:1573 / 1582
页数:10
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