In order to be successful in random screening, high chemical diversity needs to be applied. During the early to mid-1990s, the interest in natural products for screening decreased because combinatorial chemistry was believed to deliver large chemical libraries with the required diversity at much lower cost and at higher speed than the traditional synthesis or natural product screening. However, although the diversity that can be generated by synthetic chemistry is broad, many natural products cannot be synthesized in a cost-effective way, if at all. Therefore, natural compounds are used today (again) in many pharmaceutical or agrochemical companies to increase the diversity of their screening libraries or as scaffolds for the synthesis of natural compound-like libraries (1,5,7,8,14).
One obviously important factor for the discovery of novel secondary products is sourcing of the material (1,3,5-7,23). Several strategies have been developed, although it is not yet clear which of the strategies will lead to the most cost-effective means of discovery of new plant-derived drugs or drug leads. In addition, any "bioprospecting" must observe the rules of the United Nations Convention on Biological Diversity, which recognizes the right of countries over the biological resources within their boundaries. The source country should be involved in the discovery process and should benefit by technology transfer and commercial rights to novel products.
1. Use of information from traditional medicine, the most used or widely used strategy. Chinese medicine and Indian medicine have proved to be particularly valuable sources for plant species accumulating medicinally active compounds (1-9).
2. Sourcing from extreme and/or as yet untouched ecosystems (4,79).
3. Ecological observations. For example, individual plant species or lines not attacked by certain diseases may contain fungicidal compounds (6,7,23).
4. Chemotaxonomy, which is particularly useful for discovering species with a higher yield or modified lead structures (2,3,7,8).
5. Use of biologically activated plants, e.g., after infection, infestation by insects, or under extreme environmental conditions (7).
6. Use of cell cultures with different growth conditions and/or induction by microbial elicitors. This technology, which offers great commercial potential, is currently used by some specialized companies (30) (see, e.g., www.phytera.com).
In principle, two different approaches are applied today (Fig. 2):
1. The traditional approach of using crude extracts followed by purification of active principles after the discovery of activity in a particular screening system.
2. The alternative approach, which first separates the constituents of a plant extract and then applies such more or less pure products to the screening process.
Strategy 1 has been used since quinine and morphine were discovered more than hundred years ago (3,4,8). Large numbers of crude extracts can be prepared in a cost-effective manner, and such extracts are applied in cellular or noncellular screening protocols. The obvious advantage of this procedure is the low cost of extract preparation, which allows screening of many samples in a short time. Early discovery of known metabolites by thin-layer chromatography (TLC), liquid chromatography-mass spectrometry (LC-MS), or other technologies has eliminated the most important disadvantage of this technology: rediscovery of known metabolites. However, the major disadvantage is still the high investment in extraction and purifi-
Plants or plant cell cultures
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