Pharmacological properties of the ubiquitous natural product betulin

Alakurtti, Sami; Mäkelä, Taru; Koskimies, Salme; Yli‐Kauhaluoma, Jari

doi:10.1016/j.ejps.2006.04.006

Cited by 565 publications

(364 citation statements)

References 74 publications

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“…All the compounds assayed were able to reduce the multiplication of intracellular amastigotes of Leishmania as compared with the uninfected control cultures (Table 4). In the subgroup of simple betulin derivatives (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15), only four compounds (1, 2, 6 and 12) were tested against intracellular L. infantum and L. donovani amastigotes. Betulin 1 showed best activity (49.3 and 42.8%, respectively), whereas rest of the compounds showed similar or decreased activity.…”

Section: Effect Of Betulin Derivatives On Leishmania Amastigotes In Mmentioning

confidence: 99%

“…This compound can be transformed into betulinic acid either by chemical transformation or biotransformation. 14,15 It has been suggested that betulinic acid has anticancer, anti-HIV and antimicrobial properties. 16,17 Some related compounds have shown antileishmanial activity against L. donovani (promastigotes and amastigotes) 18 and L. amazonensis.…”

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: Effect Of Betulin Derivatives On Leishmania Amastigotes In Mmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…Indeed, in addition to its potential anticancer activities (10,17), a number of BA compounds are active against HIV and other viruses, bacteria, malaria, and helminthes (13,15,17), and the new BA derivatives described here should also be tested for these applications. …”

Section: Molecular Cancer Therapeutics 2117mentioning

confidence: 99%

“…BA also suppresses growth and induces apoptosis of other human cancer cells, including brain cancer cells, neuroblastomas, ovarian carcinomas, and leukemias (reviewed in ref. 15), whereas normal cells such as dermal fibroblasts and peripheral blood lymphocytes are much less sensitive to growth inhibition by this agent (16). Despite a lack of toxicity in these studies, BA is a very weak antineoplastic agent; micromolar concentrations were needed to block cell proliferation in vitro, and doses as high as 250 mg/kg body weight were required to suppress the growth of melanomas in athymic mice (10).…”

Section: Introductionmentioning

confidence: 99%

Novel semisynthetic analogues of betulinic acid with diverse cytoprotective, antiproliferative, and proapoptotic activities

Liby¹,

Honda

Williams³

et al. 2007

Molecular Cancer Therapeutics

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Betulinic acid (BA), a pentacyclic triterpene isolated from birch bark and other plants, selectively inhibits the growth of human cancer cell lines. However, the poor potency of BA hinders its clinical development, despite a lack of toxicity in animal studies even at high concentrations. Here, we describe six BA derivatives that are markedly more potent than BA for inhibiting inducible nitric oxide synthase, activating phase 2 cytoprotective enzymes, and inducing apoptosis in cancer cells and in Bax/Bak À/À fibroblasts, which lack two key proteins involved in the intrinsic, mitochondrial-dependent apoptotic pathway. Notably, adding a cyano-enone functionality in the A ring of BA enhanced its cytoprotective properties, but replacing the cyano group with a methoxycarbonyl strikingly increased potency in the apoptosis assays. Higher plasma and tissue levels were obtained with the new BA analogues, especially CBA-Im [1-(2-cyano-3-oxolupa-1,20(29)-dien-28-oyl)imidazole], compared with BA itself and at concentrations that were active in vitro. These results suggest that BA is a useful platform for drug development, and the enhanced potency and varied biological activities of CBA-Im make it a promising candidate for further chemoprevention or chemotherapeutic studies.

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“…1) and its derivatives as penta-cyclic triterpenes have attracted attention due to their diverse pharmacological activities. among which anti-HIV and anti-tumor activities are of prime concern (Aiken and Chen 2005;Alakurtti et al 2006;Saxena et al 2006;Csuk 2014). The bioactive molecules' utilization from natural products offered exciting possibilities for the development of successful therapies.…”

Section: Introductionmentioning

confidence: 99%

An efficient process for the transformation of betulin to betulinic acid by a strain of Bacillus megaterium

Kumar

Dubey

2017

3 Biotech

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Betulinic acid as a derivative of betulin is widely reported for its anti-HIV and antitumor activities. Betulin has three most significant positions, i.e., primary hydroxyl group at position C-28, secondary hydroxyl group at position C-3, and alkene moiety at position C-20, where chemical modifications were performed to yield pharmacologically more active derivatives. Bioconversion optimization was performed for the enhancement in the percentage of conversion using statistical approach by opting temperature, pH and betulin concentration as independent variables. Three hundred fifty isolates were screened from natural sources under selective medium containing up to 3 g/l of betulin for their tolerance and bioconversion efficiency. Isolate KD235 was found to grow in 3 g/l betulin with 23.34 ± 0.57 g/l biomass and 0.67 ± 0.06 g/l betulinic acid production. New isolate KD235 was characterized by molecular analysis and named as Bacillus megaterium KD235. Molecular characterization of a potentially active isolate for the transformation of betulin to betulinic acid was suggested as isolate Bacillus megaterium KD235. Maximum bioconversion (22 ± 1.5%) was found at optimized conditions, i.e., pH 6.5, temperature 30°C and at 3 g/l betulin. Validations of experiments as *11% more bioconversion i.e., 1 ± 0.1 g/l betulinic acid were obtained using 5 l lab fermenter as compared to shake flask.

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Pharmacological properties of the ubiquitous natural product betulin

Cited by 565 publications

References 74 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

Novel semisynthetic analogues of betulinic acid with diverse cytoprotective, antiproliferative, and proapoptotic activities

An efficient process for the transformation of betulin to betulinic acid by a strain of Bacillus megaterium

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