Biological Activities of Natural and Semi-Synthetic Pseudo-Guaianolides: Inhibition of Transcription Factors
Author
Summary, in English
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.
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.
Department/s
Publishing year
2014
Language
English
Document type
Dissertation
Publisher
Lund University (Media-Tryck)
Topic
- Chemical Sciences
Keywords
- pseudo-guaianolides
- sesquiterpene lactones
- NF-κB
Status
Published
Supervisor
ISBN/ISSN/Other
- ISBN: 978-91-7422-358-3
Defence date
13 June 2014
Defence time
09:30
Defence place
Lecture hall C, Center of Chemistry and Chemical Engineering, Getingevägen 60, Lund University Faculty of Engineering, Lund
Opponent
- Marc Stadler (Prof. Dr.)