Generating a Generation of Proteasome Inhibitors: From Microbial Fermentation to Total Synthesis of Salinosporamide A (Marizomib) and Other Salinosporamides

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.

Advances toward the Synthesis of Functionalized γ-Lactams

“…42 More importantly, it was identified as a potent 20S proteasome inhibitor and is undergoing clinical trials for the treatment of multiple myeloma. 4,10,48 The proteasome is an ATP-dependent multi-catalytic, multi-subunit protease complex responsible for ubiquitinylation-the process of tagging damaged/unneeded proteins for degradation. 6 Inhibition of the proteasome results in accumulation of intracellular proteins, disrupting cellular homeostasis and ultimately inducing apoptosis.…”

Targeting the Proteasome in Melanoma

“…It has been demonstrated that inhibition of the proteasome induces cell death in both normal and neoplastic cells, that cancer cells possess elevated levels of proteasome activity and are more sensitive to proteasome inhibitors than normal cells and, even more, that proteasome inhibition sensitizes neoplastic cells to other proapoptotic stimulus such as chemo o radiation therapy, probably by the NFkappaB pathway. These and other findings provided strong rationale for targeting the proteasome for the treatment of cancer (Voorhees 2006, Potts 2010, Chen 2010b. One of the principal actions of proteasome inhibitors are the regulation of cell cycle control molecules.…”

“…This process has been named the "ubiquitin-dependent degradation of protein" (Sorokin 2009). Substrates for this non-lysosomal protein degradation pathway include misfolded and defective proteins, as well as others that are selectively polyubiquitin-tagged and targeted for degradation by the ubiquitin-proteasome system (Potts 2010). Proteins differ greatly from each other in lifetime, and the lifetime of protein molecules in an organism depends on their role.…”

“…Thus, besides involving in normal cellular functions and homeostasis, the alteration of proteasomal activity contributes to the pathological states of several clinical disorders including inflammation, neurodegeneration and cancer. These critical roles, together with the ubiquitious nature of the proteolytic 20S core particle, suggest multiple potential applications for proteasome inhibition for several pathological conditions such as inflammation / autoimmune diseases and cancer therapy (Potts 2010, Chen Current Protein 2010. Many of the proteins degraded by the proteasome are molecules involved in cell proliferation and apoptosis, such as cyclins and cyclin dependent kinases, the proapoptotic protein p53, members of the Bcl2 family, the nuclear transcription factor NFkappaB, etc.…”

Total Synthesis of Biologically Active Natural Products Based on Highly Selective Synthetic Methodologies

“…The combination of the fascinating biological profile and structural complexity has attracted intense interest in the chemical and biological research communities. [91][92][93][94][95][96][97] Our strategy for the synthesis of salinosporamide A (73) relies on racemization-free indium-catalyzed cyclization of chiral amide 84 (Chart 19). We envisaged that the C3 quaternary center could be constructed stereoselectively from cyclized compound 85 by intramolecular delivery of an oxygen atom from the C2 substituent to the exo olefin, and another C4 quaternary center would be created by selective reduction of the ester located in the convex face of the rigid bicyclic structure.…”