Biological Activities of Natural and Semi-Synthetic Pseudo-Guaianolides: Inhibition of Transcription Factors
Författare
Summary, in 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
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.
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.
Avdelning/ar
Publiceringsår
2014
Språk
Engelska
Dokumenttyp
Doktorsavhandling
Förlag
Lund University (Media-Tryck)
Ämne
- Chemical Sciences
Nyckelord
- pseudo-guaianolides
- sesquiterpene lactones
- NF-κB
Status
Published
Handledare
ISBN/ISSN/Övrigt
- ISBN: 978-91-7422-358-3
Försvarsdatum
13 juni 2014
Försvarstid
09:30
Försvarsplats
Lecture hall C, Center of Chemistry and Chemical Engineering, Getingevägen 60, Lund University Faculty of Engineering, Lund
Opponent
- Marc Stadler (Prof. Dr.)