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

Abstract

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.

Antileukemic Activity and Mechanism of Drug Resistance to the Marine Salinispora tropica Proteasome Inhibitor Salinosporamide A (Marizomib)

“…However, relevant clinical disadvantages of bortezomib relate to its unsuitability for oral administration, its toxicity profile comprising peripheral neuropathy, and the emergence of drug resistance phenomena (Kale and Moore, 2012). Salinosporamide A (NPI-0052, marizomib) is a naturally occurring proteasome inhibitor derived from the marine sediment actinomycetes Salinispora tropica and Salinispora arenicola (Feling et al, 2003;Gulder and Moore, 2010). This inhibitor, which belongs to the class of b-lactones, is a novel cancer treatment option since it is orally bioactive (Chauhan et al, 2005) and irreversibly inhibits all three proteolytic activities of the proteasome.…”

Mining the Cinnabaramide Biosynthetic Pathway to Generate Novel Proteasome Inhibitors

“…[13] Both cinnabaramides and salinosporamides exhibit potent cancer cell cytotoxicities and exert their effects through binding to the 20S proteasome core particle, thereby inducing cell cycle arrest and programmed cell death (apoptosis). [9,[14][15][16] The key to the superior activity of salinosporamide A versus the cinnabaramides is assumed to be the presence of the chlorine atom attached to the side chain, which is required for the drug's irreversible binding to its biological target and is thus a major reason for the compound's effectiveness against cancer. [17] We anticipated that the factor behind the varying side chains in the two compound classes should be a biosynthetic enzyme responsible for forming a hypothetical and unusual hexylmalonyl-CoA extender unit.…”

The Catalytic Diversity of Multimodular Polyketide Synthases: Natural Product Biosynthesis Beyond Textbook Assembly Rules

“…These include biosynthetic enzymes for the myxobacterial metabolites soraphen (24) [99][100][101], myxothiazol (25) [102], melithiazol (26) [103], chondramide (27) [104], thuggacin (28) [105], aurafurone (29) [106], stigmatellin (30) [107], and salinosporamide A (31) [108,109] (Fig. 8).…”