DESCRIPTION (provided by applicant): Most pharmaceutical compounds are flat, two-dimensional structures that have a high potency but often suffer from a lack of selectivity. Poor selectivity can result in unwanted side-interactions that may manifest themselves as dangerous side effects. In contrast, three-dimensionally complex leads are often very selective, making highly desirable targets of stereochemically rich or structurally intricate natural products. The core structure of psiguadial A, euglobal V, and related macrocarpals embodies these attractive traits. The proposed research aims to synthesize these desirable natural products in accordance with their hypothesized biosyntheses. This route will utilize an intermolecular o-quinone methide initiated cyclization cascade. Polycyclization reactions have been extensively studied in synthesis. However, both the nature of initiation and structural architecture achieved are unprecedented as cascade polycyclization reactions. The successful development of this reaction will open new possibilities for initiating cationic polycyclizations and challenge chemist to reach new levels of complexity with them. After synthesis, collaborations have been arranged to thoroughly investigate the scope and origin of their biological activity. In collaboration with he National Cancer Institute, these natural products will be assayed in the NCI-60 cell screen and analyzed with the COMPARE algorithm to give insights into the activity and possible mechanism of action. These studies will be augmented through a collaborative effort with the Skaggs Institute of Chemical Biology. Advanced proteomics techniques will be used to identify the cellular target of these natural products. Detailing the biological role of these natural products will lead to new discoveries in protein annotation and contribute to our understanding of small-molecule-protein interactions. Thelong-term goals of this research are 1) to expand the utility of o-quinone methides by investigating their reactivity towards activated olefins and developing a novel polycycization cascade reaction, and 2) to investigate the cellular targets responsible for macrocarpal biological activity, including psiguadial A and euglobal V anticancer activity. These studies will investigate the potential of macrocarpals as lysine-reactive molecular probes that would be powerful tools for determining the functional state of enzymes. In line with these goals, the Specific Aims of the proposed research are: 1) To develop a synthesis of psiguadial A, euglobal V, and related macrocarpal compounds drawing inspiration from their biosyntheses. 2) Investigate the biological activity of psiguadial A, euglobal V, and related macrocarpal natural products by establishing cancer cell selectivity profiles, investigating its mechanism of action, and uncovering cellular targets via activity-based protein profiling (ABPP).

Between 1981-2006, an estimated 60% of new anticancer pharmaceuticals were either natural products, modified natural products, or compounds with a natural product derived pharmacophore. Thus, the exploration of synthetic routes to natural products has had, and will continue to have, an irreplaceable impact on human health. The proposed research will synthesize a suite of macrocarpal natural products and explore the origin of their biological activity, and evaluate their potential as molecular probes to investigate the functional states of enzymes.