Chemically engineered extracts as an alternative source of bioactive natural product-like compounds

Abstract

The access to libraries of molecules with interesting biomolecular properties is a limiting step in the drug discovery process. By virtue of a long molecular evolution process, natural products are recognized as biologically validated starting points in structural space for library development. We introduce here a strategy to generate natural product-like libraries. A semisynthetic mixture of compounds was produced by diversification of a natural product extract through the chemical transformation of common chemical functionalities in natural products into chemical functionalities rarely found in nature. The resulting mixture showed antifungal activity against Candida albicans, whereas the starting extract did not show such activity. Bioguided fractionation led to the isolation of a previously undescribed active semisynthetic pyrazole. The result illustrates how biological activity can be generated by designed chemical diversification of a natural product mixture, and represents the proof of principle of an alternative strategy for producing natural product-like libraries from natural products libraries.diversity ͉ natural products N atural products have been invaluable as platforms for developing front-line drugs (1-3). This value is in part due to the fact that their chemical diversity is complementary to the diversity found in synthetic libraries (4). Natural products are sterically more complex and have broader diversity of ring systems compared with synthetic and combinatorial counterparts (4, 5). Those structural features are the result of a long evolutionary selection process (6). Less than one-fifth of the ring systems found in natural products are represented in current trade drugs (7). On the other hand, drug and combinatorial molecules tend to include a higher number of nitrogen-, sulfur-, and halogen-containing groups (4,5,8).Because the identification of new chemotypes for drug development remains an urgent need in many therapeutic areas, innovative strategies for natural products to contribute their full range of chemical diversity are being developed. Such strategies range from the exploration of unconventional sources of natural compounds (9, 10) to the development of synthetic methodologies for the preparation of natural product-like libraries (11-15) through the diversification of natural product mixtures by combinatorial biosynthesis and related techniques (16 -21).We report here a strategy to generate bioactive compounds through chemical diversification of inactive natural product mixtures (i.e., natural extracts). Natural product extracts are natural libraries of complex composition, mostly uncharacterized, that usually contain a high number of molecules with different scaffolds and functionalities.Provided that a significant proportion of the different molecules present in a given extract is chemically altered, a considerable number of compounds will be generated; hence, changes in the biological properties of the mixture could be expected (22, 23).Our approach to modify as many compounds a...

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