The Echinocandins: Total and Semi-Synthetic Approaches in Antifungal Drug Discovery

摘要

The echinocandins are a new class of antifungal lipopeptides for the treatment of serious nosocomial mycoses.nThe three currently approved drugs, caspofungin, micafungin, and anidulafungin, were each discovered through the syntheticnmodification of echinocandin natural products obtained from fermentation. This review is intended for the medicinalnchemist who is actively pursuing or has a general interest in the synthetic modification of natural products as a meansnto identify drug candidates. It provides a survey of the synthetic strategies that produced the approved echinocandin therapeuticsnand a discussion of more recent efforts to identify a new generation of echinocandin drug candidates. Both totalnsynthetic approaches starting from the constituent amino acids and semi-synthetic approaches relying on fermentationproducednlipopeptide are addressed. These various efforts by chemists from industry and academia have not only illuminatednthe interesting chemistry of these natural products, but have provided the means by which improvements in antifungalnpotency and spectrum, pharmacokinetic profile, solubility, stability, and safety can be realized. The ultimate success ofnthese efforts can be judged by considering the important role the echinocandins are already playing in the treatment of seriousnfungal infection.