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.

CHROMATOGRAPHY: LIQUID | Nuclear Magnetic Resonance Detectors

Formation of heterocyclic products in michael reactions of ascorbic acid with α,β-unsaturated compounds. 3rd communication . Structural analysis of michael adducts of ascorbic acid by 13C-nmr spectroscopy in the solid state †‡

Metabolism and excretion of 1-hydroxymethylpyrene, the proximate metabolite of the carcinogen 1-methylpyrene, in rats.

On-line coupling of capillary hplc with 1h nmr spectroscopy

The invention relates to a method for producing nonporous silica gel particles which have an adjustable uniform size of less than 15 µm and on or onto the surface of which biologically and/or chemically active substances are immobilized or applied. Also disclosed is the use thereof, preferably for separating molecules, enriching samples, or performing chromatography, catalysis, analysis, bonding reactions, or other chemical reactions.

Klaus Albert

Papers

CHROMATOGRAPHY: LIQUID | Nuclear Magnetic Resonance Detectors

Formation of heterocyclic products in michael reactions of ascorbic acid with α,β-unsaturated compounds. 3rd communication . Structural analysis of michael adducts of ascorbic acid by 13C-nmr spectroscopy in the solid state †‡

Metabolism and excretion of 1-hydroxymethylpyrene, the proximate metabolite of the carcinogen 1-methylpyrene, in rats.

On-line coupling of capillary hplc with 1h nmr spectroscopy

Method for applying substances onto nonporous silica gel particles