Structure-Activity Relationships of Sesquiterpene Lactones

ABSTRACT: Sesquiterpene lactones (STLs) are one of the largest biogenetically homogenous groups of natural products known. Currently, the Dictionary of Natural Products holds a total of over 11000 entries on sesquiterpenes, of which almost 5000 contain at least one lactone group. One reason for the large number of individual compounds and the associated structural diversity of this class of natural products is most certainly related to their enormously broad spectrum of biological activities, rendering them a highly valuable defense tool for those organisms synthesizing them. It is thus no surprise that the plant family from which most STLs have been isolated, i.e. the Compositae, is among the largest and ecologically most diverse plant families on our planet. Many of the biological activities of the most common types of STLs are known to be mediated by a simple general chemical mechanism, i.e. alkylation of biological macromolecules in terms of Michael type additions. These effects have been surveyed in numerous comprehensive reviews. Moreover, some very specific receptor-mediated activities of less frequent types of STLs are known. Quite surprisingly, despite the plethora of reports on STL bioactivity, only very few systematic studies on structure-activity relationships have been carried out. Detailed studies of this kind, however, would be highly desirable with respect to several aspects of medicinal/pharmaceutical, agrochemical and ecological interest. Most importantly, many STL-containing plants have been used in traditional medicines of all cultures for many centuries and continue to be utilized also in modern phytotherapy. Therapeutic use of STLs as pure chemicals is - in spite of their broad utilization in form of plants or crude extracts-restricted to very few examples, which is mainly due to a lack of knowledge on the structural requirements for selectivity with respect to a desired biological activity. It may, however, be conceived, that STLs could play a valuable role as lead structures to new therapeutic agents, if more information, especially in the form of quantitative structure-activity relationships (QSAR), existed. The present chapter attempts to present an overview on the current knowledge on structure-activity relationships of STLs of different types and different activities. Selected examples of current research in the author’s laboratory on structure-reactivity- and structure-activity relationships of STLs are presented.