• Biological activities of natural and semi-synthetic pseudo-guaianolides: Inhibition of transcription factors.

      Villagomez, Rodrigo (Media-Tryck, Lund University, Sweden, 2014, 2014-06)
      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.