New Developments in NMR Methodologies with Special Roles in Natural Product Discovery

Recent advancements in NMR spectroscopy have been pivotal to the discovery of molecules that hold promise as human drugs. A sizeable portion of these newly discovered bioactive compounds are natural products, organic molecules produced by living things such as plants and microorganisms. Natural products provide an ideal vantage point for examining recent NMR advancements, because these molecules pose myriad structure elucidation challenges resulting from their diverse structures and low abundances within complex mixtures. This chapter discusses recent developments in NMR technologies and methods, as applied toward discovery of novel natural products that may hold potential as pharmaceuticals. Discussion of NMR advancements focuses on several areas that have recently emerged or matured, highlighting (1) higher magnetic fields and improved probes (e.g., microprobes and cryoprobes) that have dramatically enhanced the sensitivity of NMR during the past decade and opened doors for structure determination of minute quantities of highly bioactive natural products, (2) hyphenated NMR methods (e.g., LC-NMR, GC-NMR, CE-NMR) for structure elucidation of low abundance or unstable metabolites and dereplication of known natural products, and (3) approaches for the direct identification of molecules within mixtures, including metabolomics-based strategies for metabolite discovery. Each of these highlighted advancements in NMR-based drug discovery is presented in the context of one or more natural product exemplars.

Keywords: 2D NMR, Capillary NMR, CapNMR, CE-NMR, cITP-NMR, Correlation spectroscopy, Cryoprobe, De-replication, Drug discovery, GC-NMR, Heteronuclear multiple bond correlation, Heteronuclear single quantum correlation, HPLC-NMR, HPLC-SPE-NMR, Hyphenated NMR, LC-MS-NMR, Metabolomics, Microprobe, Natural product, Nuclear overhauser effect spectroscopy, Rotating frame overhauser effect spectroscopy, Secondary metabolite.