Review
Pharmacological properties of the ubiquitous natural product betulin

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Abstract

Betulin (lup-20(29)-ene-3β,28-diol) is an abundant naturally occurring triterpene and it is found predominantly in bushes and trees forming the principal extractive (up to 30% of dry weight) of the bark of birch trees. Presently, there is no significant use for this easily isolable compound, which makes it a potentially important raw material for polymers and a precursor of biologically active compounds. Betulin can be easily converted to betulinic acid, which possesses a wide spectrum of biological and pharmacological activities. Betulinic acid has antimalarial and anti-inflammatory activities. Betulinic acid and its derivatives have especially shown anti-HIV activity and cytotoxicity against a variety of tumor cell lines comparable to some clinically used drugs. A new mechanism of action has been confirmed for some of the most promising anti-HIV derivatives, which makes them potentially useful additives to the current anti-HIV therapy. Betulinic acid is specifically cytotoxic to several tumor cell lines by inducing apoptosis in cells. Moreover, it is non-toxic up to 500 mg/kg body weight in mice. The literature concerning derivatization of betulin for structure–activity relationship (SAR) studies and its pharmacological properties is reviewed.

Introduction

Betulin 1, lup-20(29)-ene-3β,28-diol, also known as betulinol, betuline and betulinic alcohol (Fig. 1), is a pentacyclic triterpene alcohol with a lupane skeleton. Common structural features of the lupane skeleton are its five-membered ring E and isopropylidene group (Fig. 1). Although betulin 1 can also be isolated from other sources in small amounts, the extractive isolation of betulin 1 on an industrial scale from birch bark waste could be a large and feasible source of raw material. White birches are widespread in the northern latitudes of the world, and currently there is no economically significant use for this easily isolable compound. Betulin 1 can be isolated (up to 30% dry weight) from the birch bark by extraction with high boiling hydrocarbon solvents or with water azeotropes of alcohols (Eckerman and Ekman, 1985). The healing properties of birch bark and birch bark extracts have been known for a long time in folk medicine. Birch bark oil (Betulae pix) has been used for skin diseases, such as eczema and psoriasis (Hänsel et al., 1992). Betulin 1 can be used as such or after chemical modification as a starting compound for other useful materials and compounds, which possess various interesting pharmacological properties. Some reviews concerning betulin 1 and particularly its biologically more active derivatives, such as betulinic acid 2 have been published (Cichewicz and Kouzi, 2003, Baglin et al., 2003a, Eiznhamer and Xu, 2004, Aiken and Chen, 2005). Herein, the literature concerning derivatization of betulin for structure–activity relationship (SAR) studies and its pharmacological properties is reviewed.

Section snippets

Pharmacological properties of betulin derivatives

Betulin 1 has three positions in its structure, namely secondary hydroxy group at position C-3, primary hydroxy group at position C-28 and alkene moiety at position C-20, where chemical modifications can be easily performed to yield derivatives for structure–activity relationship (SAR) studies. Betulin 1 can be converted in two steps in 75% overall yield to pharmacologically more active betulinic acid 2 (Fig. 2; Kim et al., 1997).

It is clear from the chemical structure of betulin 1 that most of

Conclusions and future perspectives

The high availability of betulin 1 from the bark of birch trees makes it a potentially important raw material for polymers and it is an interesting precursor of biologically more active compounds. Betulin 1 can be easily converted to relatively non-toxic betulinic acid 2, which has shown to possess wide spectrum of biological activities. Betulinic acid 2 and its derivatives have been shown to possess antimalarial, anti-inflammatory and antifungal activity. Betulinic acid's 2 anti-HIV and

Acknowledgements

We thank National Technology Agency (Tekes) for financial support. This study was also supported by the Academy of Finland (Grant 108376) and the EU grant to Pro-KinaseResearch LSHB-2004-503467.

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