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

Author

  • Rodrigo Villagomez

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.

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.)