ReviewPharmacological properties of the ubiquitous natural product betulin
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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