Polycyclic terpenoid natural products are endowed with a broad range of medicinally relevant biological activities. Taxol and artemisinin are two premier examples of life-saving terpenoids; the former is used clinically to treat several cancers, while the latter is a critical antimalarial agent used worldwide. Chemical synthesis approaches to natural products provide opportunities to make compounds that might be scarcely available from nature, to generate analogues that are only available by total synthesis, and to make probe molecules for increased understanding of the underlying biology. A balance of innovative strategy and new chemical methodology promises efficient syntheses of small molecules that can provide answers to important biological questions that are not easily solved by other means. As part of our laboratory's long-term goal to enhance efficiency in the synthesis of complex natural products to facilitate important studies in biology, the objective of the proposed research is to develop concise and creative synthesis designs and empowering methodological advances to permit access to many bioactive diterpenoid natural products. The rationale for this work is that synthetic chemistry is critical to the development of natural product ?hit molecules? into legitimate preclinical lead compounds by analogue production, by identification of structure-activity relationships, by the synthesis of chemical probe molecules for mechanism of action studies, and more. An efficient total synthesis of targeted natural products provides a platform from which to address each of these key areas of research.
Our specific aims i nclude (1) the synthesis of the lissoclimide family of cytotoxic translation inhibitors, to aid in refining our understanding of the molecular basis of protein synthesis inhibition using biological and biochemical assays, as well as the tools of structural biology; (2) the application of methodology developed for the lissoclimides to develop efficient syntheses of a range of other complex, polycyclic diterpenoids; and (3) the development of new radical bicyclization strategies for the synthesis of two architecturally complex anti-infective natural products. The proposed research is significant because chemical synthesis will provide access to a broad range of biologically important secondary metabolites and analogues with which to interrogate key processes; at the same time, the underlying synthesis designs and methodologies will lead to vertical advancement of the field of organic chemistry. These contributions are innovative by virtue of the chemistry-driven, multi-faceted investigations into the mechanism of ribosome inhibition by the lissoclimides, the development of new stereocontrolled polyene cyclization strategies to access particularly challenging diterpenoid natural products, and the elaboration of new radical bicyclization strategies to make complex polycyclic architectures relevant to bioactive natural products.
The proposed research focuses on the chemical synthesis of structurally complex and biologically active diterpenoid natural products. The targeted compounds include the lissoclimide anti-cancer agents that exert their activity through inhibition of the cell's protein synthesis by binding the ribosome; our synthesis design for the lissoclimides will also be applied more broadly to other biologically active polycyclic diterpenoids, and other antiinfective diterpenoids will be made using new applications of radical bicyclization reactions. The study is highly relevant to human health because the goal compounds have promising anti-cancer, anti-infective, and other activities, and their biological properties will be studied in detail with exceptional collaborators.
