Chemical postevolution: Difference between revisions
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Revision as of 13:10, 25 January 2009
Chemical postevolution is the structural optimization of (already evolutionary optimized) natural products by synthetic chemical means. It is additional and often structurally orthogonal to natural evolution.[1] Whereas the term "Chemical Evolution" refers to an iterative optimization of any possible chemical structure, the term Chemical Postevolution especially refers to the biological improvement of antibiotic natural products by synthetic organic chemistry, primarily in antiinfective and anticancer research.
Application in drug discovery
Natural products have provided the majority of lead structures for marketed antibiotics.[2] But, only a few “pure” natural products fulfill the complex profile required for a pharmaceutical drug. A drug has to match additional physicochemical, pharmacological, toxicological and technical requirements that have not been selectors in the evolution of antibacterial secondary metabolites. On the other hand, natural products offer excellent starting points for medicinal chemistry. To create a drug, nature’s blueprints often have to be improved by semisynthesis or de novo synthesis to repair typical deficiencies such as limited stability, low solubility, narrow antibacterial spectrum, poor in vivo efficacy, etc. Chemical structure defines biological activity. Complementary to nature, a chemist can explore white spots in structural space and biological activity that have never been explored by any organism over the entire period of evolution.
Examples
Various natural antibiotics have already been optimized. Classical examples are the beta-lactam antibiotics (e.g. penicillin G to meticillin), the glycopeptides (chloroeremomycin to oritavancin) or the macrolides (erythromycin A to telithromycin). Since 2006 platensimycin.[3] has been the target for various synthetic studies aiming at a chemical postevolution of this potent FabF inhibitor. Various other classes of natural antibiotics are now in the focus of chemical postevolution.[4]
References
- ↑ F. von Nussbaum, M. Brands, B. Hinzen, S. Weigand, D. Häbich, Angew. Chem. 2006, 118, 5194–5254; Angew. Chem. Int. Ed. 2006, 45, 5072–5129. Antibacterial Natural Products in Medicinal Chemistry—Exodus or Revival? PMID 16881035
- ↑ C. Walsh, Antibiotics, actions, origins, resistance, 1. Aufl., ASM, Washington, DC, 2003
- ↑ Jun Wang et al, Platensimycin is a selective FabF inhibitor with potent antibiotic properties, Nature 441, 358-361 (18 May 2006) PMID 16710421
- ↑ K. C. Nicolaou, Jason S. Chen, David J. Edmonds, Anthony A. Estrada, Angew. Chem. 2009, 121, 670–732; Angew. Chem. Int. Ed. 2009, 48, 660-719. Recent Advances in the Chemistry and Biology of Naturally Occurring Antibiotics PMID 19130444