Over the past four decades, we have been studying the chemistry of defense and communication among terrestrial insects and other arthropods, a group of organisms that includes over half of all described species on earth. While many of the compounds we have characterized have simple structures (such as straight chain alkenes, carboxylic acids, aldehydes, phenols, benzoquinones ...), there are also many examples of biologically active alkaloids, isoprenoids (including steroids), and polyketides with novel structures which we have discovered in the course of this research. We plan to select some of the most interesting compounds as lead strutures for the preparation of pilot-scale libraries providing sufficient material to explore their biological properties in high-throuput screening. The proposed libraries consist of either a group of related congeneric natural products (such as the Myrmicaria alkaloids or the cardiotonic lucibufagins) or of a group of synthetic compounds derived from the structure of a synthetically accessible natural product (such as the spirocyclic Polyzonium alkaloids). This project is the culmination, from the viewpoint of drug discovery, of our many years of research in the field of terrestrial natural products chemistry. There are several reasons why this research should be of direct relevance to public health. First of all, there is the fact that each of the proposed libraries will be based on a naturally-occurring molecule of proven ability to interact with biological targets. In addition, the lead compounds and proposed derivatives generally represent molecular structures that have not yet been examined via high throughput screening. The likelihood of discovering activities within these libraries of relevance to areas such as neuropharmacology, infectious and parasitic diseases, or cancer is much greater than would be expected from a study of other areas of chemical space which are not based on small molecules of biological origin.
