Natural products and their derivatives have historically been invaluable as a source of therapeutic agents. However, in the past decade, research into natural products in the pharmaceutical industry has declined, owing to issues such as the lack of compatibility of traditional natural-product extract libraries with high-throughput screening. However, as discussed in this review, recent technological advances that help to address these issues, coupled with unrealized expectations from current lead-generation strategies, have led to a renewed interest in natural products in drug discovery.

The evolving role of natural products in drug discovery

Natural products have been a rich source of compounds for drug discovery. However, their use has diminished in the past two decades, in part because of technical barriers to screening natural products in high-throughput assays against molecular targets. Here, we review strategies for natural product screening that harness the recent technical advances that have reduced these barriers. We also assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products, and highlight recent examples of natural products in antimicrobial drug discovery and as inhibitors of protein-protein interactions. The growing appreciation of functional assays and phenotypic screens may further contribute to a revival of interest in natural products for drug discovery.

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The re-emergence of natural products for drug discovery in the genomics era

One of the initial steps in the development of therapeutic agents is the identification of lead compounds that bind to the receptor or enzyme target of interest. Many analogs of these lead compounds are then synthesized to define the key recognition elements for maximal activity. In general, many compounds must be evaluated in both the lead identification and optimization steps. Increasing burdens have been placed on these efforts due to the large number of new therapeutic targets that continue to be identified thorough modern molecular biology methods.1 To address this demand, very powerful chemical and biological methods have been developed for the generation of large combinatorial libraries of peptides2 and oligonucleotides3 that are then screened against a receptor or enzyme to identify high-affinity ligands or potent inhibitors, respectively. While these studies have clearly demonstrated the power of library synthesis and screening strategies, peptides and oligonucleotides generally have poor oral activities and rapid in vivo clearance;4 therefore their utility as bioavailable therapeutic agents is often limited. Due to the favorable pharmacokinetic properties of many small organic molecules (<600-700 molecular weight),5 the design, synthesis, and evaluation of libraries of these compounds6 has rapidly become a major frontier in organic chemistry. Lorin A. Thompson was born in Lexington, KY, in 1970. He received the Bachelor of Science degree from the University of North Carolina, Chapel Hill, in 1992 where he worked under the guidance of Joseph Desimone. He is currently pursuing his doctorate in the laboratory of Jonathan Ellman at UC Berkeley where he is the 1994 Glaxo-Wellcome fellow. His research interests include the development of synthetic methodology for organic library construction.

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Synthesis and Applications of Small Molecule Libraries.

The impetus for developing analytical methods for phenolic compounds in natural products has proved to be multifaceted. Hundreds of publications on the analysis of this category of compounds have appeared over the past two decades. Traditional and more advanced techniques have come to prominence for sample preparation, separation, detection, and identification. This review provides an updated and extensive overview of methods and their applications in natural product matrices and samples of biological origin. In addition, it critically appraises recent developments and trends, and provides selected representative bibliographic examples.

Extraction, separation, and detection methods for phenolic acids and flavonoids

Chemical modification of silica surface by immobilization of functional groups for extractive concentration of metal ions.

Structure and Biosynthesis of Staphyloxanthin from Staphylococcus aureus

Characterization of bonded phases by solid-state NMR spectroscopy

Contributors. Preface. 1. LC NMR: Theory and Experiment (Klaus Albert). 1.1 Introduction. 1.2 NMR in a Flowing Liquid. 1.3 Design of Continuous Flow NMR Probes. 1.4 Experimental Arrangement for HPLC 1H NMR Coupling. 1.5 Practical Considerations, Solvent Suppression Techniques, Gradient Elution and Purity of HPLC Solvents. References. 2. LC NMR: Automation (Ulrich Braumann and Manfred Spraul). 2.1 Practical Use of LC NMR and LC NMR/MS. 2.2 Different Working Modes in LC NMR. 2.3 Use of Mass Spectrometry in the Set Up. 2.4 Measurement Procedures. 2.5 Conclusions. References. 3. Biomedical and Pharmaceutical Applications of HPLC NMR and HPLC NMR MS (John C. Lindon, Jeremy K. Nicholson and Ian D. Wilson). 3.1 Introduction. 3.2 Technical and Operational Overview. 3.3 Applications in Combinatorial Chemistry. 3.4 Application to Chemical Impurities. 3.5 Application to Chiral Separations of Pharmaceutical Mixtures. 3.6 Application to Natural Products. 3.7 Application to Chemical Reactivity of Drug Glucuronides. 3.8 Application to Futile Deacetylation Reactions. 3.9 Application to Trapping of Reactive Intermediates. 3.10 Application to Uptake and Transformation of Xenobiotics by Plants. 3.11 Separation of Lipoproteins and their Characterisation using HPLC NMR. 3.12 Superheated Water HPLC NMR and HPLC NMR MS Studies on Pharmaceuticals. 3.13 Application of Hypernation to a Mixture of Non Steroidal Anti Inflammatory Drugs. 3.14 Concluding Remarks. References. 4. Application of On Line LC NMR and Related Techniques to Drug Metabolism Studies (John P. Shockcor). 4.1 Introduction. 4.2 LC NMR Techniques. 4.3 Application of LC NMR MS to Drug Metabolism: The Structure Elucidation of Rat Urinary Metabolites of Efavirenz by LC NMR MS. Conclusions. References. 5. LC NMR for Natural Products Analysis. 5.1 Application of LC NMR and LC NMR MS Hyphenation to Natural Products Analysis (Martin Sandvoss). References. 5.2 Hyphenation of Modern Extraction Techniques to LC NMR for the Analysis of Geometrical Carotenoid Isomers in Functional Food and Biological Tissues (Tobias Glaser and Klaus Albert). References. 6. LC NMR in Environmental Analysis (Alfred Preiss and Markus Godejohann). 6.1 Introduction. 6.2 Target and Non Target Analysis. 6.3 LC NMR Coupling in Non Target Analysis. 6.4 Application of LC NMR and LC NMR in Combination with LC MS to Environmental Samples. 6.5 Simulation of Environmental Processes. 6.6 Conclusions. References. 7. Related Techniques Introduction. 7.1 GPC NMR Coupling (Heidrun Handel and Klaus Albert). References. 7.2 SFC NMR and SFE NMR (Holger Fischer and Klaus Albert). 7.3 Nanoliter NMR. 8. Future Developments Introduction. 8.1 HPLC 13C NMR (Klaus Albert). 8.2 Parallel NMR Detection (Andrew G. Webb, Jonathan V. Sweedler and Daniel Raftery). Concluding Remarks (Klaus Albert). Index.

On-line LC-NMR and related techniques

The application of silica-supported TEMPO as a recyclable catalyst in the Anelli oxidation of alcohols is reported. The catalyst is easily obtained in a one-step reductive amination procedure starting from a commercially available aminopropyl-functionalized silica. Details of the synthesis of the supported catalyst and its analysis by MAS NMR are presented. Various alcohol oxidations according to the Anelli protocol have been carried out and the stability of the applied silica-supported TEMPO has been studied.

Klaus Albert

Papers

Structure and Biosynthesis of Staphyloxanthin from Staphylococcus aureus

Characterization of bonded phases by solid-state NMR spectroscopy

On-line LC-NMR and related techniques

Silica-Supported TEMPO Catalysts: Synthesis and Application in the Anelli Oxidation of Alcohols

Characterization of chemically modified silica gels by 29Si and 13C cross-polarization and magic angle spinning nuclear magnetic resonance