Synthesis and anti-leishmanial activity of heterocyclic betulin derivatives

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

doi:10.1016/j.bmc.2010.01.003

Cited by 60 publications

(67 citation statements)

References 21 publications

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“…Better antileishmanial efficiency of betulin heterocycloadducts with less bulky N-and O-substituents is in accordance with our earlier results with L. donovani axenic amastigotes (strain MHOM/SD/1962/ 1S-Cl2d; IC 50 30 mM) and intracellular amastigotes in THP-1 macrophages, where this compound showed 53% inhibition at 25 mM. 20 The activity found with 16 against intracellular Leishmania, without substantial toxicity for host cells, points to the interest of carrying out further tests of this compound on animal models. The mechanism of action of betulin and betulin derivatives has been only partially explored (it prevents DNA cleavage and the formation of topoisomerase-DNA complex), 18,[27][28][29] and internalization by Leishmania is unknown.…”

Section: Discussionsupporting

confidence: 91%

“…In the subgroup of heterocyclic betulin derivatives (16)(17)(18)(19)(20), clearer structure-activity relationship trend could be observed. Compounds with sterically less bulky R3 and R4 groups showed better activity, when compared with more hindered derivatives.…”

Section: Effect Of Betulin Derivatives On Promastigote Stagementioning

confidence: 95%

“…The chemical synthesis and detailed characterization data of the betulin derivatives are reported in our previous publications. 15,20,22 Lyophilized compounds were resuspended in dimethyl sulfoxide for a 10-mM stock solution. The concentration of dimethyl sulfoxide in the working solution was no greater than 0.5% in any experiment.…”

Section: Compounds Testedmentioning

confidence: 99%

“…On the other hand, 28-O-cinnamoylbetulin 2 was less active against amastigotes. From the subgroup of heterocyclic betulin derivatives (16)(17)(18)(19)(20), compounds 16, …”

Section: Effect Of Betulin Derivatives On Leishmania Amastigotes In Mmentioning

confidence: 99%

“…19 More recently, studies have been carried out on the effect of a high number of betulinic derivatives on axenic amastigotes and amastigotes of L. donovani in the THP-1 cell line. 20 It was found that the compound with greater antileishmanial capacity (heterocycloadduct between 3.28-di-O-acetyllupa-12,18-diene and 4-methylurazine) showed a 50% growth inhibition (IC 50 ) of 8.9 mM against amastigotes, although the compound showed a 30% toxicity for the THP-1 macrophage line. This toxicity possibly rules out its potential therapeutic use.…”

Section: Introductionmentioning

confidence: 99%

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Toxicity of betulin derivatives and in vitro effect on promastigotes and amastigotes of Leishmania infantum and L. donovani

et al. 2011

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The toxicity and antileishmanial activity of 20 betulin derivatives were studied. The toxicity of betulin and synthesized compounds was determined using a bacterial test (Microtox) and two mammalian cell lines (CHO-K1 and J774). The antileishmanial activity of compounds (50 lM) was examined in both the promastigote and intracellular amastigote stages of Leishmania infantum and L. donovani. No correlation was found among the toxicity tests. All the compounds showed significant antipromastigote activity. The antiproliferative capacity of derivatives was dependent on the parasite stage studied, and no substantial differences were found between Leishmania species. Betulin, 3,28-di-O-acetylbetulin and L-aspartyl amide of betulonic acid showed moderate activity against amastigotes. The highest inhibition of intracellular amastigote multiplication was achieved with a low micromolar concentration (IC 50 ca 9 lM) of heterocyclic betulin derivative 3,28-di-O-acetyllup-13(18)-ene with N-ethyltriazolo moiety 16, without significant toxicity for mammalian cells. These results point to the interest of this lead compound for further in vitro and in vivo tests.

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Section: Discussionsupporting

confidence: 91%

Section: Effect Of Betulin Derivatives On Promastigote Stagementioning

confidence: 95%

Section: Compounds Testedmentioning

confidence: 99%

“…On the other hand, 28-O-cinnamoylbetulin 2 was less active against amastigotes. From the subgroup of heterocyclic betulin derivatives (16)(17)(18)(19)(20), compounds 16, …”

Section: Effect Of Betulin Derivatives On Leishmania Amastigotes In Mmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Toxicity of betulin derivatives and in vitro effect on promastigotes and amastigotes of Leishmania infantum and L. donovani

et al. 2011

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Improving Physical Properties via CH Oxidation: Chemical and Enzymatic Approaches

et al. 2014

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Physicochemical properties constitute a key factor for the success of a drug candidate. Whereas many strategies to improve the physicochemical properties of small heterocycletype leads exist, complex hydrocarbon skeletons are more challenging to derivatize because of the absence of functional groups. A variety of C À H oxidation methods have been explored on the betulin skeleton to improve the solubility of this very bioactive, yet poorly water-soluble, natural product. Capitalizing on the innate reactivity of the molecule, as well as the few molecular handles present on the core, allowed oxidations at different positions across the pentacyclic structure. Enzymatic oxidations afforded several orthogonal oxidations to chemical methods. Solubility measurements showed an enhancement for many of the synthesized compounds.

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Improving Physical Properties via CH Oxidation: Chemical and Enzymatic Approaches

et al. 2014

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Physicochemical properties constitute a key factor for the success of a drug candidate. Whereas many strategies to improve the physicochemical properties of small heterocycle-type leads exist, complex hydrocarbon skeletons are more challenging to derivatize due to the absence of functional groups. A variety of C–H oxidation methods have been explored on the betulin skeleton to improve the solubility of this very bioactive, yet poorly water soluble, natural product. Capitalizing on the innate reactivity of the molecule, as well as the few molecular handles present on the core, allowed for oxidations at different positions across the pentacyclic structure. Enzymatic oxidations afforded several orthogonal oxidations to chemical methods. Solubility measurements showed an enhancement for many of the synthesized compounds.

show abstract

Synthesis and anti-leishmanial activity of heterocyclic betulin derivatives

Cited by 60 publications

References 21 publications

Toxicity of betulin derivatives and in vitro effect on promastigotes and amastigotes of Leishmania infantum and L. donovani

Toxicity of betulin derivatives and in vitro effect on promastigotes and amastigotes of Leishmania infantum and L. donovani

Improving Physical Properties via CH Oxidation: Chemical and Enzymatic Approaches

Improving Physical Properties via CH Oxidation: Chemical and Enzymatic Approaches

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