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Biological Activities of Natural and Semi-Synthetic Pseudo-Guaianolides: Inhibition of Transcription Factors

  • Rodrigo Villagomez
Publishing year: 2014
Language: English
Document type: Dissertation
Publisher: Lund University (Media-Tryck)


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.
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.


Lecture hall C, Center of Chemistry and Chemical Engineering, Getingevägen 60, Lund University Faculty of Engineering, Lund
  • Marc Stadler (Prof. Dr.)


  • Chemical Sciences
  • pseudo-guaianolides
  • sesquiterpene lactones
  • NF-κB


  • Olov Sterner
  • ISBN: 978-91-7422-358-3