A concise, total synthesis of the TMC-95A/B proteasome inhibitors

Albrecht, Brian K.; Williams, Robert M.

doi:10.1073/pnas.0308432101

Cited by 62 publications

(36 citation statements)

References 50 publications

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“…Garners aldehyde [39] and the corresponding bromide), but most of these reactions yielded an epimeric mixture of the compounds. We then used Kocienski-modified Julia olefination (Scheme 1), [40] utilizing an aldehyde 9 [41] and a sulfone 10, [42] both of which were derived from d-serine. The reaction proceeded without epimerization to give the key intermediate 11, which was converted to the protected meso-DAP 12 and 13.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Diaminopimelic Acid Containing Peptidoglycan Fragments and Tracheal Cytotoxin (TCT) and Investigation of Their Biological Functions

Kawasaki

Karasudani

Otsuka

et al. 2008

Chemistry A European J

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Bacterial cell wall peptidoglycan (PGN) is a potent immunostimulator and immune adjuvant. The PGN of Gram-negative bacteria and some Gram-positive bacteria contain meso-diaminopimelic acid (meso-DAP), and we have recently shown that the intracellular protein Nod1 is a PGN receptor and recognizes DAP-containing peptides. In this study, we achieved the synthesis of DAP-containing PGN fragments, including the first chemical synthesis of tracheal cytotoxin (TCT), GlcNAc-(beta1-4)-(anhydro)MurNAc-L-Ala-gamma-D-Glu-meso-DAP-D-Ala, and a repeating-unit of DAP-type PGN, GlcNAc-(beta1-4)-MurNAc-L-Ala-gamma-D-Glu-meso-DAP-D-Ala. For the synthesis of PGN fragments, we first established a new synthetic method for an orthogonally protected meso-DAP derivative, and then we constructed the glycopeptide structures. The ability of these fragments to stimulate human Nod1, as well as differences in Nod1 recognition of the variety of synthesized ligand structures were examined. The results showed that the substitution of the N terminus of iE-DAP is necessary for stronger Nod1 recognition, but the structure of the substituent seems not to be strictly recognized. The importance of the carboxyl group at the 2-position of DAP for human Nod1 stimulation was also shown.

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Section: Resultsmentioning

confidence: 99%

Synthesis of Diaminopimelic Acid Containing Peptidoglycan Fragments and Tracheal Cytotoxin (TCT) and Investigation of Their Biological Functions

Kawasaki

Karasudani

Otsuka

et al. 2008

Chemistry A European J

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“…In this approach, we chose to employ 5-phenyl-tetrazolyl (PT) sulfone 9 (prepared following a modified procedure reported by Albrecht et al 31 ), as it has been reported to be less prone to self-condensation than the benzothiazolyl sulfone. 32 The synthesis of 3b is described in Scheme 1.…”

Section: ' Results and Discussionmentioning

confidence: 99%

C-Linked Antifreeze Glycoprotein (C-AFGP) Analogues as Novel Cryoprotectants

Leclère¹,

Kwok²,

et al. 2011

Bioconjugate Chem.

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Significant cell damage occurs during cryopreservation resulting in a decreased number of viable and functional cells post-thawing. Recent studies have correlated the unsuccessful outcome of regenerative therapies with poor cell viability after cryopreservation. Cell damage from ice recrystallization during freeze-thawing is one cause of decreased viability after cryopreservation. We have assessed the ability of two C-AFGPs that are potent inhibitors of ice recrystallization to increase cell viability after cryopreservation. Our results indicate that a 1-1.5 mg/mL (0.5-0.8 mM) solution of C-AFGP 1 is an excellent alternative to a 2.5% DMSO solution for the cryopreservation of human embryonic liver cells.

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“…Synthetic organic chemists have shown considerable interest in TMC-95A because of its unusual chemical structure, its potency and its unique inhibition mechanism [189]. Several total syntheses have been achieved, but they have not provided sufficient material for broad biological evaluation [190][191][192]. Simpler and more accessible TMC-95 macrocyclic analogues 39-42 have been synthesized in order to explore their SAR (figure 20) [185,186,[193][194][195][196][197][198][199].…”

Section: Tmc-95 and Derivativesmentioning

confidence: 99%

Proteasome Inhibitors: Recent Advances and New Perspectives In Medicinal Chemistry

Genin¹,

Reboud‐Ravaux²,

Vidal

2010

CTMC

107

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The search for proteasome inhibitors began fifteen years ago. These inhibitors proved to be powerful tools for investigating many important cellular processes regulated by the ubiquitin-proteasome pathway. Targeting the proteasome pathway can also lead to new treatments for disorders like cancer, muscular dystrophies, inflammation and immune diseases. This is already true for cancer; the FDA approved bortezomib, a potent proteasome inhibitor, for treating multiple myeloma in 2003, and mantle cell lymphoma in 2006. The chemical structures identified in some of the early proteasome inhibitors have led to the development of new anti-cancer drugs (CEP-18770, Carfilzomib, NPI-0052). All these molecules are covalent bonding inhibitors that react with the catalytic Thr1-O(gamma) of the three types of active site. This review covers recent developments in medicinal chemistry of natural and synthetic proteasome inhibitors. Advances in non-covalent inhibitors that have no reactive group will be highlighted as they should minimize side-effects. New structures and new modes of action have been recently identified that open the door to new drug candidates for treating a range of diseases.

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A concise, total synthesis of the TMC-95A/B proteasome inhibitors

Cited by 62 publications

References 50 publications

Synthesis of Diaminopimelic Acid Containing Peptidoglycan Fragments and Tracheal Cytotoxin (TCT) and Investigation of Their Biological Functions

Synthesis of Diaminopimelic Acid Containing Peptidoglycan Fragments and Tracheal Cytotoxin (TCT) and Investigation of Their Biological Functions

C-Linked Antifreeze Glycoprotein (C-AFGP) Analogues as Novel Cryoprotectants

Proteasome Inhibitors: Recent Advances and New Perspectives In Medicinal Chemistry

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