Synthesis and anti-leishmanial activity of heterocyclic betulin derivatives

Sami Alakurtti; Tuomo Heiska; Alexandros Kiriazis; Nina Sacerdoti-Sierra; Charles L. Jaffe; Jari Yli-Kauhaluoma

doi:10.1016/j.bmc.2010.01.003

Synthesis and anti-leishmanial activity of heterocyclic betulin derivatives

Sami Alakurtti, Tuomo Heiska, Alexandros Kiriazis, Nina Sacerdoti-Sierra, Charles L. Jaffe, Jari Yli-Kauhaluoma^*

^*Corresponding author for this work

Department of Microbiology and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

59 Scopus citations

Abstract

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 μM for their ability to inhibit the growth of Leishmania donovani axenic amastigotes, a species that causes the fatal visceral leishmaniasis. GI₅₀ (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 GI₅₀ = 8.9 μM against L. donovani amastigotes.

Original language	English
Pages (from-to)	1573-1582
Number of pages	10
Journal	Bioorganic and Medicinal Chemistry
Volume	18
Issue number	4
DOIs	https://doi.org/10.1016/j.bmc.2010.01.003
State	Published - 15 Feb 2010

Bibliographical note

Funding Information:
The financial support from the Finnish Funding Agency for Technology and Innovation (Tekes), Foundation for Research of Natural Resources in Finland, Marjatta ja Eino Kollin Säätiö, Academy of Finland (Grant 108376) and the projects by the European Commission (Contract No LSHB-CT-2004-503467 and EU-KBBE-227239) are gratefully acknowledged. C.L.J. holds the Michael and Penny Feiwel Chair in Dermatology and is grateful to the American Friends of Hebrew University for financial support of this project. We thank Adjunct Professor Salme Koskimies for valuable discussions.

Keywords

Antiprotozoal agents
Betulin
Cycloaddition
Leishmania sp.
Terpenoids

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10.1016/j.bmc.2010.01.003

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title = "Synthesis and anti-leishmanial activity of heterocyclic betulin derivatives",

abstract = "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 μM for their ability to inhibit the growth of Leishmania donovani axenic amastigotes, a species that causes the fatal visceral leishmaniasis. GI50 (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 GI50 = 8.9 μM against L. donovani amastigotes.",

keywords = "Antiprotozoal agents, Betulin, Cycloaddition, Leishmania sp., Terpenoids",

author = "Sami Alakurtti and Tuomo Heiska and Alexandros Kiriazis and Nina Sacerdoti-Sierra and Jaffe, {Charles L.} and Jari Yli-Kauhaluoma",

note = "Funding Information: The financial support from the Finnish Funding Agency for Technology and Innovation (Tekes), Foundation for Research of Natural Resources in Finland, Marjatta ja Eino Kollin S{\"a}{\"a}ti{\"o}, Academy of Finland (Grant 108376) and the projects by the European Commission (Contract No LSHB-CT-2004-503467 and EU-KBBE-227239) are gratefully acknowledged. C.L.J. holds the Michael and Penny Feiwel Chair in Dermatology and is grateful to the American Friends of Hebrew University for financial support of this project. We thank Adjunct Professor Salme Koskimies for valuable discussions. ",

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AU - Jaffe, Charles L.

AU - Yli-Kauhaluoma, Jari

N1 - Funding Information: The financial support from the Finnish Funding Agency for Technology and Innovation (Tekes), Foundation for Research of Natural Resources in Finland, Marjatta ja Eino Kollin Säätiö, Academy of Finland (Grant 108376) and the projects by the European Commission (Contract No LSHB-CT-2004-503467 and EU-KBBE-227239) are gratefully acknowledged. C.L.J. holds the Michael and Penny Feiwel Chair in Dermatology and is grateful to the American Friends of Hebrew University for financial support of this project. We thank Adjunct Professor Salme Koskimies for valuable discussions.

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Synthesis and anti-leishmanial activity of heterocyclic betulin derivatives

Abstract

Bibliographical note

Keywords

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