Pharmacology & Pharmacy
 Vol.3 No.2(2012), Article ID:18701,5 pages DOI:10.4236/pp.2012.32018

Biological Activity of Betulinic Acid: A Review

Mansour Ghaffari Moghaddam1, Faujan Bin H. Ahmad2*, Alireza Samzadeh-Kermani1

1Department of Chemistry, Faculty of Science, University of Zabol, Zabol, Iran; 2Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, Selangor, Malaysia.

Email: *faujan@science.upm.edu.my

Received January 15th, 2012; revised February 18th, 2012; accepted March 6th, 2012

Keywords: Betulinic Acid; Betulin; Triterpene; Natural Product; Medicinal Properties

ABSTRACT

Betulinic acid is a known natural product which has gained a lot of attention in the recent years since it exhibits a variety of biological and medicinal properties. This review provides the most important biological properties of betulinic acid.

1. Introduction

Betulinic acid, (3β-hydroxy-lup-20(29)-en-28-oic acid) (Figure 1) is a naturally occurring pentacyclic lupanetype triterpenoid which exhibits a variety of biological and medicinal properties such as inhibition of human immunodeficiency virus (HIV) [1,2], anti-bacterial [2,3], anti-malarial [4], anti-inflammatory [5-8] anthelmintic [9], antinociceptive [10], anti-HSV-1 [11,12], and anticancer activities [13-16]. Betulinic acid is widely distributed throughout the plant kingdom [17]. The birch tree (Betula spp., Betulaceae) is one of the most widely reported sources of betulinic acid and betulin which can be obtained in considerable quantities [18-20]. Betulinic acid could be also isolated from various sources include Ziziphus spp. (Rhamnaceae) [16,21,22], Syzygium spp. (Myrtaceae) [1,23], Diospyros spp. (Ebenaceae) [24-26] and Paeonia spp. (Paeoniaceae) [27]. The reduced congener of betulinic acid, betulin (3β-lup-20(29)-ene-3, 28-diol) (Figure 1), was one of the first natural products isolated in 1788 from the bark of the white birch, Betula alba [28]. This review focuses on the pharmacological properties of betulinic acid.

2. Anticancer Activity

Kumar et al. [29] isolated betulinic acid from the methanolic extract of Dillenia indica L. fruits. The methanolic extract showed significant anti-leukemic activity in human leukemic cell lines U937, HL60 and K562. The isolated betulinic acid showed IC50 of values at 13.73, 12.84, 15.27 mg/ml in U937, HL60 and K562 cell lines, respectively.

Betulinic acid was isolated from the MeOH extract of the aerial part of Vietnamese Orthosiphon stamineus and tested for its cytotoxicity towards highly liver metastatic murine colon 26-L5 carcinoma cells [30]. It was found that betulinic acid shows the cytotoxicity with an ED50 value of 75.4 μg/ml.

Betulinic acid was obtained from the ethanol extract of Engelhardtia serrata Bl. by bioassay-guided isolation and was tested for its cytotoxic and apoptosis-inducing activities against the K562 cell line [31]. Betulinic acid showed an inhibitory activity on the growth of K562 tumor cell line with IC50 value of 6.25 μg/ml and also induced 35% apoptosis at 25 μg/ml.

Betulinic acid was isolated from the CHCl3 extract of the bark of Bischofia javanica and was evaluated for its inhibitory effects on DNA Topoisomerases (Topos) II activity [32]. Betulinic acid was found to be catalytic inhibitor of Topo II activity with IC50 value of 56.12 µM which was comparable to that of 52.38 µM for a classic Topo II inhibitor, etoposide. It was suggested that betulinic acid is potent DNA Topo II inhibitor. The ED50 values of betulinic acid and etoposide were found to be 7.19 and 2.59 µM against A549 cancer cell line.

Betulinic acid was isolated from the methanol extract of the dried leaves of Nerium oleanderand and was tested for its in vitro anticancer activity on the basis of the cell growth inhibitory activities toward three kinds of human cell lines, i.e. WI-38 fibroblast cells, VA-13 malignant tumor cells, and HepG2 human liver tumor cells [33]. Betulinic acid showed significant cell growth inhibitory to WI-38 cells, moderate cell growth inhibitory activity to VA-13 cells and moderate cell growth inhibitory activity to HepG2 with IC50 values of 1.3, 11.6 and 21 µM, respectively.

Figure 1. Structures of betulinic acid and betulin.

3. Anti-HIV Activity

Betulinic acid was isolated from the MeOH extract of the leaves of Syzrgium claviflorum by Fujioka et al. [2] and was tested on HIV-1 replication in H9 lymphocyte cells. It was found that betulinic acid shows an inhibitory activity against HIV-1 replication with an EC50 value of 1.4 µM and inhibited uninfected H9 cell growth with an IC50 value of 13 µM. This finding prompted them to prepare derivatives of betulinic acid and to evaluate their antiHIV activity.

Theo et al. [34] isolated betulinic acid from the stem bark of Peltophorum africanum, a traditional South African medicinal plant. They evaluated it for the inhibitory activities against HIV-1NL4-3 (X4-HIV-1) and HIV-1JRCSF (R5-HIV-1). Betulinic acid inhibited against HIV-1NL4-3 and HIV-1JRCSF with IC50 values of 0.04 and 0.002 µg/ml, respectively. They suggested that betulinic acid could be used as potential therapeutics for HIV-1.

Betulinic acid was isolated from the leaves and twigs of Cratoxylum arborescens and was tested in the HIV-1 RT assay and syncytium assay [35]. Betulinic acid showed anti-HIV-1 activity in the syncytium assay with IC50 value of 9.8 µg/ml and in the RT assay with IC50 of 10.8 µg/ml. The results showed that betulinic acid is the most active of isolated compounds in the syncytium assay.

4. Anti-Bacterial Activity

Woldemichael et al. [36] isolated betulinic acid from the CH2Cl2-MeOH extract of the Argentinean legume Caesalpinia paraguariensis Burk and tested it against Bacillus subtilis, methicillin-sensitive and -resistant Staphylococcus aureus, Escherichia coli, and Candida albicans. Betulinic acid was found to be inactive against the tested organisms with MICs (minimum inhibitory concentrations) greater than 128 μg/ml.

Betulinic acid was isolated from the crude chloroform bark extract of Syncarpia glomulifera (Myrtaceae) by Setzer et al. [37]. It was found that the crude extract of S. glomulifera shows anti-bacterial and cytotoxic activity. They reported that the relatively large abundance (10% of the crude extract) and high degree of activity of betulinic acid are responsible for the bioactivity of the crude bark extract.

The stem bark of the Brazilian medicinal plant Zizyphus joazeiro was phytochemically investigated by Schü- hly et al. [4]. Betulinic acid was isolated from the dichloromethane extract which showed a considerable activity against Gram-positive bacteria.

The anti-bacterial activity of isolated betulinic acid from leaves of Vitex negundo L. was tested against Bacillus subtilis and Escherichia coli, by the paper disc method [3]. Betulinic acid did not show any inhibition zone (total area-disc area) against Escherichia coli at concentrations of 1000 µg/disc, 500 µg/disc, 250 µg/disc and 125 µg/disc. However, betulinic acid showed 18.8 mm2 of inhibition zone against Bacillus subtilis at concentration of 1000 µg/disc while at a concentration of 500 µg/disc and below, the betulinic acid did not show any inhibition zone. Kanamycin was used as a standard compound which showed an inhibition zone of 207.2 mm2 at a concentration of 0.05 µg/ml.

The extract of Forsythia suspensa VAHL was studied by Shin et al. [38]. It showed a strong inhibition of the urease activity of Helicobacter pylori. The active compounds were isolated from the extract of Forsythia suspense VAHL. Two active compounds, betulinic acid and oleanolic acid, were found in the extract. At the same concentration level, betulinic acid inhibited urease activity of H. pylori stronger than oleanolic acid.

5. Antimalarial Activity

The in vitro and in vivo antimalarial activity of betulinic acid was investigated [39]. Betulinic acid was isolated from an ethanol extract of the root bark of the Tanzanian tree Uapaca nitida Müll-Arg. (Euphorbiaceæ). The in vitro antiplasmodial IC50 values of betulinic acid against chloroquine resistant (K1) and sensitive (T9-96) Plasmodium falciparum were found to be 19.6 µg/ml and 25.9 µg/ml, respectively. Betulinic acid was also tested for in vivo activity in a murine malaria model (P. berghei). It was found that the top dosage employed of 250 mg/kg/day is ineffective at reducing parasitaemia.

Bringmann et al. [5] was isolated betulinic acid from the Triphyophyllum peltatum and Ancistrocladus heyneanus. In vitro antimalarial activity of betulinic acid was tested against asexual erythrocytic stages of the human malaria parasite Plasmodium falciparum. Betulinic acid showed the antimalarial activity between of moderate to good.

6. Other Biological Activities

Zhang et al. [40] isolated betulinic acid from the ethanol extract of Tovomita krukovii. They found that betulinic acid shows inhibitory effects against Candida albicans secreted aspartic proteases (SAP) with IC50 values of 6.5 μg/ml.

Enwerem et al. [10] examined the anthelmintic activity of the methanol, hexane and ethyl acetate extracts of the stem bark of Berlina grandiflora. The ethyl acetate extract was found to be the most active. The isolated betulinic acid from the ethyl acetate fraction at 100 and 500 ppm showed stronger anthelmintic activities than piperazine.

Krogh et al. [41] was isolated betulinic acid from a medicinal plant Ipomoea pes-caprae (L.) R. Br. The results demonstrated that betulinic acid shows pronounced antinociceptive properties in the writhing test and formalin test in mic.

Betulinic acid was isolated from Diospyros leucomelas and was tested for anti-inflammatory activity in the carrageenan and serotonin paw edema and TPA and EPP ear edema [26]. The results showed that betulinic acid is the most affected.

The antifeedant activity of isolated betulinic acid from the leaves of Vitex negundo L. was studied against the third instar larvae of castor semilooper (Achoea janata) [42]. The percentage feeding reduction, at a dosage of 10 μg/cm2, for betulinic acid was 71.18%, 84.75% and 73.34% after 24, 48 and 72 hr time period, respectively.

Betulinic acid was isolated from the methyl ethyl ketone extract of Tetracera boiviniana and was monitored for DNA polymerase β inhibition [43]. Betulinic acid showed an inhibition of DNA polymerase β with IC50 value of 14 µM in the presence of bovine serum albumin (BSA) and 6.5 µM in the absence of BSA.

Domínguez-Carmona et al. [44] isolated betulinic acid from the crude extract of the leaves of Pentalinon andrieuxii (Apocynaceae). They tested betulinic acid for its antiprotozoal activity against Leishmania amazonensis (LA), Leishmania braziliensis (M2903), Trypanosoma cruzi tulahuen (TULA) and Plasmodium falciparum (F32). Betulinic acid showed a moderate trypanocidal activity against T. cruzi with IC50 value of 50.0 µM and a good antiplasmodial activity with IC50 value of 22.5 µM against P. falciparum. No any leishmanicidal activity was detected for betulinic acid against L. amazonensis and L. braziliensis.

Betulinic acid was isolated from the MeOH extract of the roots of Saussurea lappa C. B. Clarke (Compositae) and was evaluated in vitro for protein tyrosine phosphatase 1B (PTP1B) inhibitory activity [45]. Betulinic acid inhibited PTP1B activity with IC50 value of 0.7 µg/ml, which was comparable to those of ursolic acid and RK-682 used as positive controls.

Substantial amounts of betulinic acid was obtained from the stem barks of five Uapaca species (Euphorbiaceae) include Uapaca acuminata, Uapaca guineensis, Uapaca heudolotti, Uapaca paludosa and Uapaca vandhoutei [46]. Isolated betulinic acid was screened in vitro for inhibitory activity against Trypanosoma brucei glycolytic enzyme GAPDH. Betulinic acid inhibited T. brucei GAPDH with an IC50 value of 240 μM and was a competitive reversible inhibitor of this enzyme with respect to its cofactor NAD+.

Betulinic acid was obtained from the dried and powdered roots of Clusia nemorosa L. (Clusiaceae) and was tested for its antiobese activity in the adult male Swiss mice on a high-fat diet (HFD) [47]. It was found that mice treated with betulinic acid (50 mg/L, in drinking water) and fed a HFD showed significantly decreased body weights, abdominal fat accumulation, blood glucose, plasma triglycerides, and total cholesterol relative to their respective controls fed no betulinic acid during 15 weeks. It was suggested that betulinic acid has an antiobese potential through modulation of fat and carbohydrate metabolism.

Betulinic acid was isolated and identified from the methanolic extract of the stem bark of Clusia ellipticifolia and was studied for its antinociceptive activity [48]. The pharmacological study using the abdominal contortions model induced by acetic acid showed significant antinociceptive activities to the isolated compounds and the highest effect was attributed to the betulinic acid.

Betulinic acid was isolated from the powdered rose hip with and without fruits (Rosae pseudofructus cum/sine fructibus, Rosa canina L., Rosaceae) and was tested in vitro for inhibition of cyclooxygenase (COX-1, COX-2) and 5-LOX-mediated leukotriene B4 (LTB4) formation [49]. Betulinic acid was found to act as moderate inhibitors of COX-1, COX-2 and LT formation in vitro with IC50 values of >125, >125 and 102.2 µM, respectively.

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NOTES

*Corresponding author.

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