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

Abstract: 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.