The demand for new chemical entities (NCEs) in lead discovery is greater now than at any time in the history of the pharmaceutical industry. Natural products have traditionally provided an excellent source of NCEs, often contributing structures that fall outside the diversity space encompassed by synthetic approaches [1]. Natural products represent a diverse range of chemistry classes, including secondary metabolites, peptides, proteins, polysaccharides, and oligonucleotides. Many commercial drugs are either natural products, or have their roots in natural product chemistry [2], and at present over 60% of small-molecule anticancer leads are natural product-derived [3]. A recent review [3] summarizing the contribution that natural products have made to drug discovery concluded that "natural products play a dominant role in the discovery of leads for the development of drugs." The reemphasis of natural products in drug discovery was the subject of a recent series of articles in Chemical and Engineering News [4-6], which stated that "the alarming decline in the number of new chemical entities in the past decade, from an average of 30 or so to as few as 17, has correlated with decreased interest in natural product discovery."

Integrated Strategies for Drug Discovery Using Mass Spectrometry, Edited by Mike S. Lee © 2005 John Wiley & Sons, Ltd.

One key factor in the success of any natural product discovery effort is minimizing the time required to identify active compounds from complex natural sources. The use of high throughput and parallel chromatographic techniques has considerably reduced this cycle time. Concomitantly, the broad use of liquid chromatography/mass spectrometry (LC-MS) has significantly improved the efficiency of natural product screening and structure elucidation, which will be the focus of this chapter. Indeed, mass spectrometry is now a tool that can impact many, if not all, of the stages of lead generation from natural products.

The discovery of novel biologically active compounds derived from nature has evolved from a relatively simple, linear "bioassay guided" process to one that encompasses several different approaches, as shown in Figure 6.1. The traditional approach to natural product screening involves selection of source material, extraction and assay of that material, and separation of components using bioassay-guided fractionation, culminating in the isolation and identification of a purified active. Conversely, in the natural product library approach, extracts are semipurified and concentrated prior to screening for activity— almost the reverse of the traditional process. Both of these avenues rely on a variety of mass spectrometry techniques, which can have a significant impact on their success.

This chapter explores in more detail the role of mass spectrometry in several phases of the natural product discovery process, including (1) selection of source material, (2) screening, (3) dereplication of known compounds, and (4) identification of unknowns. It is clear that over the last 10 years mass spectrometry has evolved into an indispensable tool in the generation of lead candidates from nature.

Traditional approach

In vivo/in vitro screen of mixture


Chromatographic separation into pure components

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