The aim of this project is an investigation of the mechanism by which guaianolide
lactones exert NF-kappaB and/or AP-1 inhibition in a strong, concentration
dependent manner, and to explain their activity as potential anti-inflammatory and
cytotoxic agents.
Sesquiterpene lactones are plant metabolites of a complex structure, with a limited
distribution and numerous pharmacological activities, so they are gaining scientific
interest and clinical applications. Species of the genus Laserpitium (Apiaceae) are
shown to be rich in these compounds, particularly guaianolides. In our previous
investigation, fourteen lactones were isolated, five of them being novel highly
esterified guaianolides. Some of the compounds exerted a strong and reproducible
inhibition of the activity of NF-kappaB in a series of first screening tests, and
cytotoxic activity in human breast adenocarcinoma cell lines.
Our goal is also to further investigate minor components of complex extracts of four
selected Laserpitium species in order to identify novel natural NF-kappaB
inhibitors.
Furthermore, using chemical modification and semisynthetic transformations of
functional groups and side chains in isolated molecules of interest, „chemical
space“ will be investigated, determining the structural features that contribute to the
above mentioned activities. By establishing the structure activity relationship of
isolated and modified molecules, our goal is to obtain candidates for clinical
application.