Salinosporamide Natural Products: Potent 20 S Proteasome Inhibitors as Promising Cancer Chemotherapeutics

Proteasome inhibitors are rapidly evolving as potent treatment options in cancer therapy. One of the most promising drug candidates of this type is salinosporamide A from the bacterium Salinispora tropica. This marine natural product possesses a complex, densely functionalized γ-lactam-β- lactone pharmacophore, which is responsible for its irreversible binding to its target, the β subunit of the 20S proteasome. Salinosporamide A entered phase I clinical trials for the treatment of multiple myeloma only three years after its discovery. The strong biological activity and the challenging structure of this compound have fueled intense academic and industrial research in recent years, which has led to the development of more than ten syntheses, the elucidation of its biosynthetic pathway, and the generation of promising structure-activity relationships and oncological data. Salinosporamide A thus serves as an intriguing example of the successful interplay of modern drug discovery and biomedical research, medicinal chemistry and pharmacology, natural product synthesis and analysis, as well as biosynthesis and bioengineering. A young family: The salinosporamides (picture: salinosporamide A), γ-lactam-β-lactone marine natural products isolated from Salinispora tropica, are irreversible proteasome inhibitors and constitute a potent new class of small molecules for cancer drugs. This Review highlights the impressive achievements of recent multidisciplinary research on the discovery, biosynthesis, bioengineering, total synthesis, and biomedical evaluation of this young natural product family. Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.