Abstract
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 language | English |
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Qualification | Doctor Degree |
Awarding Institution |
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Supervisors/Advisors |
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Award date | 6 Sep 2013 |
Place of Publication | Espoo |
Publisher | |
Print ISBNs | 978-951-38-8013-2 |
Electronic ISBNs | 978-951-38-8014-9 |
Publication status | Published - 2013 |
MoE publication type | G5 Doctoral dissertation (article) |
Keywords
- betulin
- betulinic acid
- terpene
- organic synthesis
- derivative
- bioactivity
- Semliki Forest virus
- Leishmania sp.
- Chlamydia pneumoniae