The Development of Strategies and Methods for the Preparation of Physiologically Important Small Molecules

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY/ABSTRACT Over the past 3.5 decades, 28% of all newly approved FDA drugs have either been natural products or natural product analogs, while 27% have been entirely synthetic in origin. Although more difficult to quantify, bioactive natural products have served as the inspiration for the design of many compounds in the latter group. Thus, the isolation, study, and development of new synthetic methods and strategies to access natural products and other similar molecules is not only a worthy pursuit, but a critical component of biomedical research and drug development. These efforts also contribute novel elements of synthetic strategy and methods to the lexicon of synthetic chemistry. This application describes the pursuit of two different natural products that fall into distinct general classes (macrolide and alkaloid) as exemplars of the work that will be performed under the auspices of this grant. Additionally, the proposal describes briefly, recent progress from our laboratories in the total synthesis of a third bioactive natural product. The latter serves to illustrate the breadth of targets that we typically pursue. The more detailed examples include ongoing efforts to prepare aleutianamine analogs and nargenicin, two compounds respectively possessing distinct and interesting biological activities against pancreatic cancer and M. tuberculosis. In addition to advancing the science of synthetic chemistry through the development of new strategies and methods for small molecule synthesis, the proposed efforts provide a superb environment for students to develop the knowledge, laboratory skills, and chemical intuition that will enable them to continue, in either the private sector or academia, to provide society with complex small molecule drugs. At present, the research directions that are detailed herein are at a different stage of development and this development will continue to evolve over the course of the grant period. In addition to direct contributions to biomedical science afforded by the latter, as eluded to above, our synthetic efforts have (and will continue to) educate graduate students and postdoctoral researchers in the planning and execution of complex molecule synthesis.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE From 1981 to 2024, approximately 28% of all new drugs approved for use were derived directly or indirectly from natural products. This application proposes studies that will enable the laboratory synthesis of several natural products representing a broad array of the known classes. All the targeted compounds are of therapeutic interest and thus in pursuing these studies, the researchers involved in this project will not only advance our access to physiologically important molecules but also will learn the techniques needed to manipulate molecules and thereby prepare nearly any type of drug or drug-like molecule.