Total synthesis of the-potent proteasome inhibitor epoxomicin: a useful tool for understanding proteasome biology

Sin, Nancy L.; Kim, Kyung Bo; Elofsson, Mikael; Meng, Lihao; Auth, Hak; Kwok, Benjamin H.; Crews, Craig M.

doi:10.1016/s0960-894x(99)00376-5

Cited by 188 publications

(138 citation statements)

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“…For lactacystin, attachment of a tritium atom in place of hydrogen yielded an affinity label that could identify its cellular target. 35 Similarly, epoxomicin was chemically converted into an affinity label by attachment of a biotin moiety. 34 Both of these labeled compounds Proteasome inhibitors; newer therapeutic agents SL Harer et al were crucial for the identification of the proteasome as their primary protein target.…”

Section: Synthetic Covalent Inhibitors (Suicide Substrates)mentioning

confidence: 99%

“…34 Both of these labeled compounds Proteasome inhibitors; newer therapeutic agents SL Harer et al were crucial for the identification of the proteasome as their primary protein target. 31,35 In addition to the obvious utility of these reagents for target identification, both classes of affinity probes can also be used to rapidly monitor proteasome activity under different physiological conditions. However, tritium-labeled lactacystin is difficult and expensive to synthesize, so its full potential as a probe will probably never be realized.…”

Section: Synthetic Covalent Inhibitors (Suicide Substrates)mentioning

confidence: 99%

“…The use of the isocoumarin compound 3,4-DCI as a proteasome inhibitor led to the identification of additional proteasomal proteolytic activities distinct from the chymotrypsin-like, trypsin-like and post-glutamyl peptide hydrolyzing activities. 4,23,35 The hydrolysis of certain protein substrates was accelerated in the presence of this isocoumarin inhibitor, 35 and products generated by DCI-treated proteasomes resulted in a majority of cleavages after branched aliphatic amino acids. The name branched amino-acid preferring (BrAAP) activity 23 was given for this distinct DCI-resistant activity.…”

Section: Synthetic Covalent Inhibitors (Suicide Substrates)mentioning

confidence: 99%

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Proteasome inhibitors mechanism; source for design of newer therapeutic agents

Harer

Bhatia

2012

J Antibiot

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The proteasome was first identified as a high MW protease complex that gets resolved into a series of low MW protein species upon denaturation. As the dominant protease dedicated to protein turnover, the proteasome shapes the cellular protein repertoire. Our knowledge of proteasome regulation and activity has improved considerably over the past decade. Novel inhibitors, in particular, have helped to advance our understanding of proteasome biology. They range from small peptide-based structures that can be modified to vary target specificity to large macromolecular inhibitors that include proteins. Although these reagents have an important role in establishing our current knowledge of the proteasome's catalytic mechanism, many questions remain. The future lies in designing compounds that can function as drugs to target processes involved in disease progression. Our focus in this chapter is to highlight the use of various classes of inhibitors to probe the mechanism of the proteasome and to identify its physiological significance in the cell, so that the mechanism of inhibition of proteasome will work as a definite source for design of protocols for newer therapeutic agents for the treatment of inflammation and in cancer therapy.

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Section: Synthetic Covalent Inhibitors (Suicide Substrates)mentioning

confidence: 99%

Section: Synthetic Covalent Inhibitors (Suicide Substrates)mentioning

confidence: 99%

Section: Synthetic Covalent Inhibitors (Suicide Substrates)mentioning

confidence: 99%

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Proteasome inhibitors mechanism; source for design of newer therapeutic agents

Harer

Bhatia

2012

J Antibiot

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“…MBHA resin equipped with a HMPB linker 9 was loaded with FmocThr(OtBu)OH 10. Solid phase peptide synthesis followed by mild acidic cleavage from the resin afforded glycopeptides 11 and 12 which were directly used in a condensation with known warhead 13 3 . To this end, the tert-butoxycarbonyl protective group of 13 was removed with trifluoroacetic acid.…”

Section: Synthesis Of Proteasome Probes 1-4mentioning

confidence: 99%

“…4,5 Building blocks 6 and 13 were synthesized using a modified literature procedure. 1,3 Diethyl ether (Et 2 O), ethyl acetate (EtOAc), light petroleum ether (PE) and toluene (Tol) were purchased from Riedel-de Haën. Acetonitrile (MeCN), dichloroethane, 5.80 (d, J = 8.7 Hz, 1H), 5.29 (t, J = 9.9, 9.9 Hz, 1H), 5.14 (t, J = 9.6, 9.6 Hz, 1H), 4.32-4.20 (m, 2H), 4.14 (dd, J = 12.5, 2.1 Hz, 1H), 3.91 (s, 2H), 3.87 (ddd, J = 9.8, 4.5, 2.1 Hz, 1H), 2.12 (s, 3H), 2.10 (s, 3H), 2.05 (s, 6H).…”

Section: General Proceduresmentioning

confidence: 99%

O-GlcNAc Peptide Epoxyketones Are Recognized by Mammalian Proteasomes

et al. 2009

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Proteasomes are multicatalytic proteinase complexes responsible for the degradation of cytosolic and nuclear proteins. In eukaryotes, proteasome substrates are normally marked for degradation through the attachment of ubiquitin chains at specific sites, and subsequent proteasome-mediated degradation takes place in a controlled and ATP-dependent fashion. 1 In mammals, some oligopeptides generated by proteasomes are presented to the immune surveillance system by major histocompatibility complex class I (MHC I) molecules. 2 Next to self-peptides, peptides derived from virally encoded proteins are also exposed at the cell surface in this fashion, and thus, mammalian proteasomes partake in combating viral infections. Mammals express several proteasome particles that appear to play specific roles in MHC I-mediated immune response. These are the constitutively expressed 26S proteasome, the immunoproteasome, and the recently discovered thymoproteasome. Of these, the latter two are expressed by the specific tissues where they exist next to the 26S proteasome. 3 In all mammalian proteasomes, the actual proteolytic activities reside in the core 20S particles, which are C 2 -symmetric barrels composed of two rings of seven distinct β-subunits (β1-β7) sandwiched between two rings composed of seven distinct R-subunits (R1-R7). 4 In 26S proteasomes, β1, β2, and β5 are catalytically active and cleave preferentially after acidic, basic, and hydrophobic residues, respectively. 5 These subunits are replaced by β1i, β2i, and β5i in immunoproteasomes and by β1i, β2i, and β5t in the thymoproteasome. The exact role and substrate preference of the combined seven catalytic subunits is the subject of extensive studies, and the same holds true for elucidating the nature of the peptides produced by proteasomes and recruited by the immune system. In this context, the immunogenicity of MHC I-associated phosphopeptides is wellestablished, and this implies the involvement of proteasomes in the turnover of phosphorylated proteins. 6 In the past decades, another major post-translational modification that occurs in the cytoplasm and the nucleus, namely, protein Ser/ Thr O-GlcNAcylation, has drawn considerable attention. 7 O-GlcNAcylation is a reversible process, in that O-GlcNAc transferase (OGT) glycosylates a serine or threonine residue and a hexosaminidase (O-GlcNAcase) is responsible for the removal of O-GlcNAc residues. Protein O-GlcNAcylation and proteasomal degradation occur in the same cellular compartments, and it is therefore not surprising that the two processes interface. O-GlcNAcylation of the proteasome down-regulates its activity, whereas O-GlcNAcylation of certain proteins appears to give some protection against proteasomal degradation. 8 At the same time, O-GlcNAcylated MHC I-derived peptides were evidenced in several studies, indicating that O-GlcNAcylated proteins can act as viable proteasome substrates. 9 In regard to whether the proteasome is capable of degrading O-GlcNAcylated proteins, we felt that activity-based profiling...

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Proteasome Inhibitors

Wehenkel

Kim

2010

Burger's Medicinal Chemistry and Drug Discovery

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The proteasome has emerged as a major player in regulating essential cellular activities such as cell proliferation and inflammation. The FDA approval of bortezomib, the first‐in‐class proteasome inhibitor drug, for treatment of recurring multiple myeloma, has validated the proteasome as a target for treatment of cancer. This has catalyzed intense medicinal chemistry and library screening efforts to develop novel or improved proteasome inhibitors. Currently, a number of proteasome inhibitors are being investigated in clinical trials for cancer therapy. In this section, particular attention is focused on these inhibitors under clinical trials as well as traditional medicine recently identified as proteasome inhibitors. In addition, we discuss some of the medicinal chemistry efforts in the course of development of proteasome inhibitors with better efficacy. Finally, we describe novel proteasome inhibitors that target specific subunits of proteasomes.

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Total synthesis of the-potent proteasome inhibitor epoxomicin: a useful tool for understanding proteasome biology

Cited by 188 publications

References 18 publications

Proteasome inhibitors mechanism; source for design of newer therapeutic agents

Proteasome inhibitors mechanism; source for design of newer therapeutic agents

O-GlcNAc Peptide Epoxyketones Are Recognized by Mammalian Proteasomes

Proteasome Inhibitors

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