Abstract
The salinosporamides are potent proteasome inhibitors among which the parent marine-derived natural product salinosporamide A (marizomib; NPI-0052; 1) is currently in clinical trials for the treatment of various cancers. Methods to generate this class of compounds include fermentation and natural products chemistry, precursor-directed biosynthesis, mutasynthesis, semi-synthesis, and total synthesis. The end products range from biochemical tools for probing mechanism of action to clinical trials materials; in turn, the considerable efforts to produce the target molecules have expanded the technologies used to generate them. Here, the full complement of methods is reviewed, reflecting remarkable contributions from scientists of various disciplines over a period of 7 years since the first publication of the structure of 1.
Highlights
The ubiquitin and proteasome dependent proteolytic system (UPS) is the major pathway for regulated protein degradation in eukaryotic cells [1,2]
The two structurally distinct proteasome inhibitors, marizomib (1) and bortezomib, triggered differential apoptotic signaling pathways, suggesting a rationale for evaluating them in combination; combinations of low doses of the two agents triggered synergistic anti-MM activity [12,13,18]. These findings established the basis for a clinical development program, and an Investigational New Drug (IND) application was filed with the Food and Drug Administration (FDA) in 2005 [16,17]
The above account demonstrates that precursor-directed biosynthesis together with the use of proper media represents a powerful technique for increasing the production of minor salinosporamides and generating novel salinosporamides
Summary
The ubiquitin and proteasome dependent proteolytic system (UPS) is the major pathway for regulated protein degradation in eukaryotic cells [1,2]. Structurally unique proteasome inhibitors with the potential to treat patients that had failed or were not candidates for treatment with bortezomib have entered clinical trials [5] One such agent is the marine-derived natural product salinosporamide A (marizomib; NPI-0052; 1) (Figure 1) [15]. The two structurally distinct proteasome inhibitors, marizomib (1) and bortezomib, triggered differential apoptotic signaling pathways, suggesting a rationale for evaluating them in combination; combinations of low doses of the two agents triggered synergistic anti-MM activity [12,13,18] These findings established the basis for a clinical development program, and an Investigational New Drug (IND) application was filed with the FDA in 2005 [16,17].
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