Synthesis of betulin derivatives against intracellular pathogens: Dissertation

Sami Alakurtti

    Research output: ThesisDissertationCollection of Articles


    Birch (Betula spp.) is utilized in huge quantities in the forest industry throughout the Northern Hemisphere, and low-value side-stream birch bark is burnt for energy. Outer birch bark is rich in (up to 30% dry weight) triterpene betulin, which is readily isolable by solvent extraction. Betulin can be used both in its raw form and as a starting material for more valuable products and fine chemicals. The increasing drug resistance of numerous microbes and viruses is an issue of global concern, and new inexpensive therapeutic agents are urgently needed. In this study two sets of betulin derivatives were synthesized and screened as antiviral, antileishmanial and antibacterial agents. The first set includes relatively easily synthesizable betulin derivatives, such as esters and various oxidation products. The second set includes novel heterocyclic betulin derivatives, where the triazole ring is fused by the Diels-Alder reaction to the lupane skeleton of betulin. Alphavirus Semliki Forest virus (SFV) is distributed by mosquitoes and infects avian and mammalian hosts. Some alphaviruses may cause fatal encephalitis in humans, although the number of cases is small. On the other hand, some alphaviruses have caused millions of cases of serious illnesses characterized by fever, rash and painful arthralgia. There is currently no efficient medical treatment against alphaviruses. In the antiviral assay, 18 betulin-derived compounds displayed good activity against SFV with low-micromolar 50% inhibitory concentration values combined with low cytotoxicity. In addition, three assayed potent and representative compounds displayed synergistic effect with modified nucleoside analogue against SFV, and similar good antiviral efficacy against another alphavirus, Sindbis virus. The neglected tropical disease leishmaniasis is caused by protozoan parasites belonging to the genus Leishmania, and is transmitted to mammalian hosts by sandflies. It is estimated that around 12 million people are currently infected, mostly in developing countries. The most severe form, visceral leishmaniasis, is fatal if not treated. There are currently several drugs marketed for the treatment of leishmaniasis. However, none of these are fully effective against Leishmania, and severe side effects, often requiring hospitalization, are common. In addition, parasite resistance to drugs is a serious growing problem. In the present study, the most potent betulin derivatives displayed low-micromolar 50% growth inhibition values against L. donovani amastigotes. Good inhibition activity was well retained against L. donovani amastigotes growing inside macrophages. However, in some cases betulin derivatives also showed cytotoxicity to host macrophage cell line. Chlamydia pneumoniae is a common Gram-negative human pathogen mainly causing mild respiratory infections, which can lead to pneumonia or bronchitis. There is also strong evidence that associates C. pneumoniae with other severe diseases, such as atherosclerotic cardiovascular diseases as well as some neurodegenerative diseases, such as Alzheimer's disease and multiple sclerosis. C. pneumoniae is susceptible to antibiotics that interfere with DNA and protein synthesis. However, its complex life cycle and its chlamydial persistence, which can last for years, as well as, importantly, the lack of specific diagnostic tests for detection of the organism in clinical samples, make the current treatment regimens unsatisfactory. Out of 32 betulin derivatives, five betulin derivatives showed high (>70% growth inhibition) antichlamydial activity against C. pneumoniae at 1 µM concentration. The most potent derivative displayed a remarkable 50% inhibition at nanomolar concentration.
    Original languageEnglish
    QualificationDoctor Degree
    Awarding Institution
    • University of Helsinki
    • Yli-Kauhaluoma, Jari, Supervisor, External person
    Award date6 Sept 2013
    Place of PublicationEspoo
    Print ISBNs978-951-38-8013-2
    Electronic ISBNs978-951-38-8014-9
    Publication statusPublished - 2013
    MoE publication typeG5 Doctoral dissertation (article)


    • betulin
    • betulinic acid
    • terpene
    • organic synthesis
    • derivative
    • bioactivity
    • Semliki Forest virus
    • Leishmania sp.
    • Chlamydia pneumoniae


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