Total Synthesis and Biological Activity of Lactacystin, Omuralide and Analogs.

Corey, E. J.; Li, Wei‐Dong Z.

doi:10.1248/cpb.47.1

Cited by 193 publications

(102 citation statements)

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“…[6a,b] Clasto-lactacystin-b-lactone, also called omuralide, [7] is remarkable since it was the first molecule discovered to be a truly specific inhibitor of the proteasome, a multicatalytic proteinase complex responsible for most nonlysosomal protein degradation in the cell. Omuralide is unique in that it specifically inhibits the proteolytic activity of the 20S subunit of the proteasome without inhibiting any other protease activities of the cell.…”

Section: Methodsmentioning

confidence: 99%

Salinosporamide A: A Highly Cytotoxic Proteasome Inhibitor from a Novel Microbial Source, a Marine Bacterium of the New Genus Salinospora

Feling¹,

Buchanan²,

Mincer³

et al. 2003

Angew Chem Int Ed

962

316

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We recently reported the cultivation and phylogenetic characterization of a new group of obligate marine actinomycete bacteria that is widely distributed in ocean sediments.[1] Analogous soil-derived actinomycetes have been the single most significant source of naturally occurring microbial antibiotics, [2] thus the discovery of a major new group of these bacteria in marine sediments suggests that the ocean represents an overlooked habitat from which to isolate these important microorganisms. Given that the rate of discovery of new biologically active compounds from common soil actinomycetes has been falling, [3] obligate marine actinomycetes represent a new resource for structurally diverse secondary metabolites.To date, we have isolated in excess of 2500 strains belonging to this new taxon for which we have proposed the genus name ™Salinospora∫ (a formal taxonomic description is in progress). ™Salinospora∫ strains, with previously undescribed 16S rRNA gene sequences, have been recovered from five distinct tropical/subtropical ocean systems [1] and from depths as great as À1100 m, which indicates that they represent a widely distributed and taxonomically diverse group of sediment bacteria. All isolates display an obligate requirement of ionic sodium for growth, thus indicating a high level of marine adaptation.In preliminary screening, a high percentage of the organic extracts of cultured ™Salinospora∫ strains possessed antibiotic and anticancer activities, which suggests that these bacteria are an excellent resource for drug discovery. Herein we report the results of our first chemical investigation of a member of the ™Salinospora∫ group and show that strain CNB-392 produces the chemically unique and highly bioactive metabolite salinosporamide A (1, Scheme 1). Salinosporamide A exhibits potent cancer cell cytotoxicity and appears to exert its cytotoxic effects through inhibition of the 20S proteasome.™Salinospora∫ strain CNB-392 was isolated from a heattreated marine sediment sample that was plated on a seawater-based agar nutrient medium. Liquid shake flask cultivation of this strain, followed by solid-phase extraction with Amberlite resin (XAD-16) and elution with acetone, resulted in a crude extract that was highly cytotoxic in vitro toward HCT-116 human colon carcinoma (IC 50 ca. 80 ng mL À1 ). Cytotoxicity-guided fractionation of the crude extract led to the isolation of salinosporamide A (1) as a colorless crystalline solid (yield: 7 mg L À1 ). The complete structural assignment of 1 was accomplished by spectral analysis and by a single-crystal X-ray diffraction study.Analysis of the low-resolution mass spectrum of salinosporamide A showed a characteristic [Mþ2] þ peak indicative of the presence of a chlorine atom. High-resolution massspectral analysis provided the molecular formula Comprehensive analysis of 2D NMR data, including the results of COSY, HMQC, and HMBC experiments, enabled the complete planar structure of salinosporamide A to be assigned, as in 1, to a 2-aza-6-oxabicyclo[3.2.0]heptane-3,7...

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Section: Methodsmentioning

confidence: 99%

Salinosporamide A: A Highly Cytotoxic Proteasome Inhibitor from a Novel Microbial Source, a Marine Bacterium of the New Genus Salinospora

Feling¹,

Buchanan²,

Mincer³

et al. 2003

Angew Chem Int Ed

962

316

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“…NPI-0052 is a nonpeptide proteasome inhibitor with structural similarity to Omuralide (Corey and Li, 1999), a beta-lactone derived from naturally occurring lactacystin. However, in contrast to Omuralide, NPI-0052 has a uniquely methylated C3 ring juncture, chlorinated alkyl group at C2, and cyclohexene ring at C5 (Figure 1).…”

mentioning

confidence: 99%

“…NPI-0052 inhibits proteasome activity by covalently modifying the active site threonine residues of the 20S proteasome (Corey and Li, 1999). Comparative study of the effect of NPI-0052 and Bortezomib on proteasomal activities using purified human erythrocyte 20S proteasomes and flurogenic substrates shows that (1) NPI-0052 inhibits CT-L and T-L activities at much lower concentrations than Bortezomib, and (2) higher concentrations of NPI-0052 than Bortezomib are required to inhibit C-L activity (Chauhan et al, 2005a).…”

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confidence: 99%

A novel proteasome inhibitor NPI-0052 as an anticancer therapy

2006

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Proteasome inhibitor Bortezomib/Velcade has emerged as an effective anticancer therapy for the treatment of relapsed and/or refractory multiple myeloma (MM), but prolonged treatment can be associated with toxicity and development of drug resistance. In this review, we discuss the recent discovery of a novel proteasome inhibitor, NPI-0052, that is distinct from Bortezomib in its chemical structure, mechanisms of action, and effects on proteasomal activities; most importantly, it overcomes resistance to conventional and Bortezomib therapies. In vivo studies using human MM xenografts shows that NPI-0052 is well tolerated, prolongs survival, and reduces tumour recurrence. These preclinical studies provided the basis for Phase-I clinical trial of NPI-0052 in relapsed/ refractory MM patients. The systemic regulation of protein synthesis and protein degradation is essential for normal cellular functioning. The ubiquitinproteasome pathway mediates intracellular protein degradation: first, protein is marked with a chain of small polypeptides called ubiquitin; E1 ubiquitin enzyme then activates ubiquitin and links it to the ubiquitin-conjugating enzyme E2 in an ATP-dependent manner; E3 ubiquitin ligase then links the ubiquitin molecule to the protein; a long polypeptide chain of ubiquitin moieties is formed; and finally, a multi-enzyme proteolytic complex 26S proteasome degrades protein into small fragments in an ATPdependent manner.

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“…11,12 Further experiments showed that in aqueous solutions at pH 8, lactacystin spontaneously converts into clasto-lactacystin b-lactone, later termed omuralide (2), which penetrates the cell and acylates, via b-lactone opening, an active site N-terminal threonine residue leading to inhibition of the proteasome. 13 The remarkable biological activity and intriguing structure of 2 has stimulated a great deal of interest from the synthetic community, and as a result a number of syntheses have been published to date.…”

mentioning

confidence: 99%

“…11,15,21 The synthetic strategies typically hinge on the efficient construction of the densely functionalized b-lactam core, and specifically, on the construction of the chiral tetrasubstituted carbon center (C5 of lactacystin). The two main synthetic themes are to either begin with peripheral, relatively readily accessible moieties (such at the C9 secondary alcohol), followed by construction of the core tetrasubstituted carbon center with assistance of the stereochemistry of the peripheral carbon atoms (e.g., Panek synthesis) or direct introduction of the tetrasubstituted carbon center through catalyst control (e.g., Shibasaki and Jacobsen syntheses).…”

mentioning

confidence: 99%