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Italic 5 2009, Varenna, September 1-4
S. Alakurtti,1 N. Sacerdoti-Sierra,2 L. Pohjala,3,4 C. L. Jaffe,2 P. Tammela,4 and J. Yli-Kauhaluoma1,5
1Technical Research Centre of Finland, VTT, Espoo, Finland 2Department of Microbiology and Molecular Genetics, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel 3Division of Pharmaceutical Biology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland 4Centre for Drug Research, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland 5Division of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland INTRODUCTION
Antiviral activities
•The most effective antiviral betulin derivatives are presented in Figure 3
Betulin 1 (Fig. 1) is an abundant naturally occurring triterpene
•Betulin 1 was moderately active against SFV (IC
•Principal extractive (up to 35% of dry weight) of the bark of birch trees •Potency was enhanced by oxidation of C-28 to betulinic acid 8 and by certain cyclic
•No economical use for this easily isolable compound at present ether or ester substituents, e.g. 28-O-tetrahydropyranylbetulin 9 and heterocycle 10
•Pulp mill plant can produce up to 1000 t/a of 95% pure betulin •Betulin derivatives generally show no or only low cytotoxicity •Possible source for polymers and a precursor of biologically active compounds•Betulin and its derivatives have many interesting pharmacological properties:1 •Cytotoxic activity against many tumour cell lines •Anti-HIV activity with new mechanisms of action •Leishmaniasis is a disease caused by protozoan parasites
•Affects millions of people in developing countries•Transmitted by sand flies 8 (13.1 µM)
9 (17.1 µM)
10 (19.7 µM)
Alphaviruses cause polyarthritis in avian and mammalian hosts
Figure 3. Chemical structures and IC
values of the most potent betulin derivatives •Consists of enveloped viruses having a single-stranded RNA genome against SFV. Positive control: 3’-amino-3’-deoxyadenosine (20 µM) yielding surviving fractions 12% - 25% in the assay.
•Distributed by Aedes sp. mosquitoes•Currently, available treatment is limited to relatively inefficient ribavirin Antibacterial activities
•The most potent antibacterial betulin derivatives are presented in Figure 4
Bacterial species cause illnesses from minor skin infections to life-threatening
•Inhibition of betulin derivatives at 50 µM was dependent on the bacterial strain: diseases such as pneumonia and endocarditis •Betulonic acid 3 (inhibition between 50% and 100%)
•Antibacterial resistance to current drugs have become increasing problem •Betulinic acid 8 (from 10% to 40%)
•Occurrence of multidrug-resistant Staphylococcus aureus (MRSA) is increasing •28-O-(N-acetylanthraniloyl)betulin 11 (from 60% to 100%)
•In this study betulin derivatives were screened against: •Most of the betulin derivatives inactive •Leishmania donovani axenic amastigotes2 •MIC value (minimum inhibitory concentration) for 11 against S. aureus was 0.4 µM (For
•(+)-Stranded RNA virus Semliki Forest virus (SFV)3 comparison: MIC for known antibiotic erythromycin was 0.7 µM) •Bacterial species (Staphylococcus aureus, Staphylococcus epidermidis, Bacillussubtilis and Micrococcus luteus)4 EXPERIMENTAL
•Simple betulin derivatives were synthesized by modifying OH groups at C-3 and C-28, Figure 4. Chemical structures of the most active betulin derivatives against S. aureus,
•More complex heterocyclic derivatives 2 of betulin were also synthesized
S. epidermidis, B. subtilis and M. luteus. CONCLUSIONS AND FUTURE PERSPECTIVES
•Betulin scaffold has potential for new antimicrobial agents •Betulonic acid seems to be effective against several microorganisms Fig. 1. Structure of betulin 1 and heterocyclic betulin derivatives 2.
•Comprehensive evaluation of the antimicrobial potential of betulin derivatives by: Antileishmanial assay
•Screened using a fluorescent viability microplate assay at 50 µM of betulin •Screening with larger collection of derivatives •In-depth analyses of the active compounds through selectivity profiling and (concentration for 50% growth inhibition) of the most promising compounds Antiviral assay
•Screened using luminescence reporter-gene assay at 50 µM of betulin derivative7
(50% inhibition concentration) values of the most potent betulin derivatives •Finnish Funding Agency for Technology and Innovation (Tekes) •Cytotoxicity was screened using intracellular ATP counter-screen with hepatocellular •Foundation for Research of Natural Resources in Finland Antibacterial assay
•Screened using microdilution assay at 50 µM of betulin derivative9 •Finnish Forest Cluster•European Commission (Grant 227239) RESULTS AND DISCUSSION
Antileishmanial activities
•The most effective antileishmanial betulin derivatives are presented in Figure 2
1. Alakurtti, S.; Mäkelä, T.; Koskimies, S.; Yli-Kauhaluoma, J. Eur. J. Pharm. Sci., 2006,
•The hetero cycloadduct 2b and betulonic acid 3 were the most potent derivatives
•In heterocyclic betulin derivatives less bulky R1 and R2 groups were more potent 2. Yli-Kauhaluoma, J.; Koskimies, S.; Alakurtti, S.; Minkkinen, J.; Heiska, T.; Sarcerdoti- •In simple betulin derivatives oxidation of betulin had beneficial impact on activity Sierra, N.; Jaffe, C.L. PCT/FI2007/050331.
3. Yli-Kauhaluoma, J.; Alakurtti, S.; Pohjala, L.; Ahola, T.; Vuorela, P.; Tammela, P.
2a, R1=Et, R2=Ac (30.0 µM)
4. Yli-Kauhaluoma, J.; Koskimies, S.; Alakurtti, S.; Mäkelä, T.; Tammela, P.
2b, R1=Me, R2=Ac (8.9 µM)
2c, R1=H, R2=Ac (25.5 µM)
2d, R1=Me, R2=COEt (25.2 µM)
5. Debrabant, A.; Joshi, M.; Pimenta, P.; Dwyer, D. Int. J. Parasitol. 2004, 34, 205.
3 (14.6 µM)
4 (56.0 µM)
6. Shimony, O.; Jaffe, C. J. Microbiol. Methods 2008, 75, 196.
7. Pohjala, L.; Barai, V.; Azhayev, A.; Lapinjoki, S.; Ahola, T. Antirvir Res. 2008, 78,
8. Pohjala, L.; Tammela, P.; Samanta, S.; Yli-Kauhaluoma, J.; Vuorela, P. Anal. Biochem. 2007, 362, 221.
9. Kreander, K.; Vuorela, P.; Tammela, P. Fol. Microbiol. 2006, 50, 487.
5 (21.2 µM)
6 (34.9 µM)
7 (22.8 µM)
Figure 2. Chemical structures and GI
values of the most potential betulin derivatives against L. donovani axenic amastigotes. Positive control Amphotericin B 95% inhibition at 1 µM.


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