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

by LÃ³pez SN, Ramallo IA, Sierra MG, Zacchino SA, Furlan RL
Proceedings of the National Academy of Sciences of the United States of America.

Article 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.

structurally diverse compound collections are necessary as sources for bioactive molecules

By: Anonymous - Tue 2/27/2007 AM

Everybody agrees that structurally diverse compound collections are necessary as sources for bioactive molecules. To find new drugs, industrial research seems to particularly enjoy mining synthetic collections using elaborate cheminformatic tools to go and buy the best candidates for testing, a management optimized strategy to shoot for the average while missing the innovative. On the other hand many synthetic chemists favor the view that natural products are the best innovative source of bioactives. Is there anything else in sight, for a change? The report by Lopez et al. on "chemical engineering" of natural product extracts refreshes bioactive discovery in a particularly simple and elegant manner. These authors report an experiment in which a crude natural product extract is reacted with hydrazine to effect chemoselective derivatization of carbonyl groups, which are abundant in natural products, to hydrazones and nitrogen containing heterocycles. In this manner, they create a new brew of compounds which, in contrast to natural products, contains nitrogen rich functional groups that are particularly favorable for bioactivity, thus providing for what Nature had obviously forgotten. This new witch's brew is then tested directly for biactivity to guide isolation of active compounds. In their example, the authors found an antifungal aromatic compound containing a pyrazole group apparently derived from the reaction of hydrazine with a simple flavone. Although the paper is only sketchy about the details, it is a great experiment, which, to my knowledge, is new. With such a simple setup, there is little doubt that many will follow in this path to discover new chemical wonders

Source: http://blogs.nature.com/thescepticalchymist/2...

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