Biological Activities of Natural and Semi-Synthetic Pseudo-Guaianolides: Inhibition of Transcription Factors
(2014)- Abstract
- Damsin (1) is a natural sesquiterpene lactone (SL) isolated from
Ambrosia arborescens Mill., a plant used in the Andes as antiinflammatory
medicine. This natural product is an inhibitor of NF-
κB, a protein complex that controls the transcription of many genes in
mammalian cells, and has a potential for standing model for the
development of new anti-cancer lead structures. In order to improve
the anti-cancer activity, the chemistry of 1 was explored and in the
process, dozens of derivatives were prepared. Damsin (1) inhibited
cell proliferation, DNA biosynthesis and formation of cytoplasmic
DNA histone complex in Caco-2 cells and further studies using... (More) - Damsin (1) is a natural sesquiterpene lactone (SL) isolated from
Ambrosia arborescens Mill., a plant used in the Andes as antiinflammatory
medicine. This natural product is an inhibitor of NF-
κB, a protein complex that controls the transcription of many genes in
mammalian cells, and has a potential for standing model for the
development of new anti-cancer lead structures. In order to improve
the anti-cancer activity, the chemistry of 1 was explored and in the
process, dozens of derivatives were prepared. Damsin (1) inhibited
cell proliferation, DNA biosynthesis and formation of cytoplasmic
DNA histone complex in Caco-2 cells and further studies using the
luciferase reporter system showed that it also inhibited expressions of
NF-κB and STAT3. Therefore, the NF-κB inhibitory capacity of
some derivatives was evaluated and two analogues, 31 and 32, were
found to be more potent. In order to have a preliminary evaluation
method of the derivatives, we developed fast and cheap biochemical
assay to study the effect of SLs in the binding capacity of NF-κB
(heterodimer RelA/p50) to the DNA recognition target. In this assay
the compounds 21, 22, 24, 25 and 26 had a high dissociation capacity
of the complex NF-κB/DNA. Finally, four compounds were selected
for MS characterization studies with recombinant NF-κB, the most
selective compound was 26 (compared with 1) by selective alkylation
of Cys-38 and Cys-120 in RelA. The Cystein-38 is crucial for the
transcriptional activity of NF-κB. (Less) - Abstract (Swedish)
- Popular Abstract in English
The sesquiterpene lactones is an important group of natural products,
and they are present in many medicinal plants. Their most important
biological activities are anti-inflammatory and anti-cancer activity,
although for many decades their potential use as drugs was dismissed.
The main reason for this was their alkylating capacity, reacting with
thiol functions in proteins and peptides and they were therefore
expected to be highly toxic. Nonetheless, the interest on this these
natural products, has grown significantly in later years, especially as
anti-cancer candidates and as NF-κB inhibitors. NF-κB is a
... (More) - Popular Abstract in English
The sesquiterpene lactones is an important group of natural products,
and they are present in many medicinal plants. Their most important
biological activities are anti-inflammatory and anti-cancer activity,
although for many decades their potential use as drugs was dismissed.
The main reason for this was their alkylating capacity, reacting with
thiol functions in proteins and peptides and they were therefore
expected to be highly toxic. Nonetheless, the interest on this these
natural products, has grown significantly in later years, especially as
anti-cancer candidates and as NF-κB inhibitors. NF-κB is a
transcription factor that has a crucial role for cancer development and
chronic inflammatory diseases.
This thesis focusses on the sesquiterpene lactone damsin, which is
isolated in high yields from an Andean plant (Ambrosia arborescens
Mill) used traditionally to treat inflammation. Our findings
demonstrated that this natural product inhibits cell proliferation, DNA
biosynthesis and the formation of cytoplasmic DNA (caco-2 cells), as
well as inhibits NF-κB and STAT3 transcription capacities.
Therefore, we considered damsin as a good starting material for the
preparation of novel NF-κB inhibitors. Some of our derivatives
demonstrated to be equally or more active than damsin (transcription
capacity in whole cells) and they also have a very interesting ability
to dissociate the complex NF-κB–DNA (biochemical assays). Finally,
the characterization of the ligand–NF-κB adducts (recombinant
protein) by mass spectrometry, demonstrated that one derivative has a
high selectivity for two of NF-κB:s cysteines, which both are critical
for the interaction with DNA when it acts as a transcription factor.
This will eventually open the door to the development of more
selective NF-κB inhibitors. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4438537
- author
- Villagomez, Rodrigo LU
- supervisor
-
- Olov Sterner LU
- opponent
-
- Prof. Dr. Stadler, Marc, Helmholtz Centre for Infection Research
- organization
- publishing date
- 2014
- type
- Thesis
- publication status
- published
- subject
- keywords
- pseudo-guaianolides, sesquiterpene lactones, NF-κB
- pages
- 191 pages
- publisher
- Lund University (Media-Tryck)
- defense location
- Lecture hall C, Center of Chemistry and Chemical Engineering, Getingevägen 60, Lund University Faculty of Engineering, Lund
- defense date
- 2014-06-13 09:30:00
- ISBN
- 978-91-7422-358-3
- language
- English
- LU publication?
- yes
- id
- c6bf8230-031c-4247-b06b-62292c27d098 (old id 4438537)
- date added to LUP
- 2016-04-04 11:25:33
- date last changed
- 2018-11-21 21:04:46
@phdthesis{c6bf8230-031c-4247-b06b-62292c27d098, abstract = {{Damsin (1) is a natural sesquiterpene lactone (SL) isolated from<br/><br> Ambrosia arborescens Mill., a plant used in the Andes as antiinflammatory<br/><br> medicine. This natural product is an inhibitor of NF-<br/><br> κB, a protein complex that controls the transcription of many genes in<br/><br> mammalian cells, and has a potential for standing model for the<br/><br> development of new anti-cancer lead structures. In order to improve<br/><br> the anti-cancer activity, the chemistry of 1 was explored and in the<br/><br> process, dozens of derivatives were prepared. Damsin (1) inhibited<br/><br> cell proliferation, DNA biosynthesis and formation of cytoplasmic<br/><br> DNA histone complex in Caco-2 cells and further studies using the<br/><br> luciferase reporter system showed that it also inhibited expressions of<br/><br> NF-κB and STAT3. Therefore, the NF-κB inhibitory capacity of<br/><br> some derivatives was evaluated and two analogues, 31 and 32, were<br/><br> found to be more potent. In order to have a preliminary evaluation<br/><br> method of the derivatives, we developed fast and cheap biochemical<br/><br> assay to study the effect of SLs in the binding capacity of NF-κB<br/><br> (heterodimer RelA/p50) to the DNA recognition target. In this assay<br/><br> the compounds 21, 22, 24, 25 and 26 had a high dissociation capacity<br/><br> of the complex NF-κB/DNA. Finally, four compounds were selected<br/><br> for MS characterization studies with recombinant NF-κB, the most<br/><br> selective compound was 26 (compared with 1) by selective alkylation<br/><br> of Cys-38 and Cys-120 in RelA. The Cystein-38 is crucial for the<br/><br> transcriptional activity of NF-κB.}}, author = {{Villagomez, Rodrigo}}, isbn = {{978-91-7422-358-3}}, keywords = {{pseudo-guaianolides; sesquiterpene lactones; NF-κB}}, language = {{eng}}, publisher = {{Lund University (Media-Tryck)}}, school = {{Lund University}}, title = {{Biological Activities of Natural and Semi-Synthetic Pseudo-Guaianolides: Inhibition of Transcription Factors}}, year = {{2014}}, }