PEG Thiazolidine-2-thione, a Novel Reagent for Facile Protein Modification:  Conjugation of Bovine Hemoglobin

Greenwald, Richard B.; Pendri, Annapurna; Martinez, Anthony; Gilbert, Carl W.; Bradley, Patricia

doi:10.1021/bc960059o

Cited by 43 publications

(34 citation statements)

References 6 publications

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“…The compounds with thiazolidine-2-thione unit exhibit extensive biological activities, such as hepatoprotective, 1 antibacterial, 2 antifungal, 3 analgesic, 4 insecticide, 5 protein modification, 6 antiinflammatory and immunosuppressive activities. 7 Meantime, they have also important applications to organic synthesis, material chemistry, etc.…”

Section: Introductionmentioning

confidence: 99%

Facile One-pot Synthesis of Ethyl 3-Alkyl-4-hydroxy-2-thioxothiazolidine-4-carboxylates

Zhang

Zheng

et al. 2006

Chin. J. Chem.

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Ethyl 3-alkyl-4-hydroxy-2-thioxothiazolidine-4-carboxylates were prepared in excellent yields from the reaction of corresponding primary amines with carbon disulfide and ethyl 3-bromo-2-oxopropanoate in the presence of anhydrous potassium phosphate in DMF at room temperature within 1 h. The structures of the highly functionalized products were corroborated spectroscopically (IR, 1 H NMR, 13 C NMR, EI-MS) and by elemental analyses. A plausible mechanism for such type of cyclization was proposed.Keywords ethyl 3-alkyl-4-hydroxy-2-thioxothiazolidine-4-carboxylate, primary amine, ethyl 3-bromo-2-oxopropanoate, one-pot synthesis, anhydrous potassium phosphate Scheme 2 Possible pathway for the formation of compounds 7Ethyl 3-alkyl-4-hydroxy-2-thioxothiazolidine-4-carboxylate Chin.

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Section: Introductionmentioning

confidence: 99%

Facile One-pot Synthesis of Ethyl 3-Alkyl-4-hydroxy-2-thioxothiazolidine-4-carboxylates

Zhang

Zheng

et al. 2006

Chin. J. Chem.

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“…Another reagent, polyethylene glycol (PEG), has been used to decorate the surface of Hb and conjugate the proteins into polymers. Early PEG‐based modification of bovine Hb, relied on active ester chemistry, which resulted in a loss of the net positive charge of the protein “nonconservative” due to the binding of approximately 10 PEG arms on the Hb surface 32. More recent approaches have utilized site‐specific chemical modification of Hb molecule.…”

Section: Discussionmentioning

confidence: 99%

O‐raffinose crosslinked hemoglobin lacks site‐specific chemistry in the central cavity: Structural and functional consequences of β93Cys modification

et al. 2005

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Reacting human deoxyHbA0 with oxidized raffinose (O-raffinose), a trisaccharide, results in a low oxygen affinity "blood substitute," stabilized in a noncooperative T-conformation and possesses readily oxidizable rhombic heme. In this study, we fractionated the O-raffinose-modified HbA0 heterogeneous polymer (O-R-PolyHbA0) into six distinct fractions with a molecular weight distribution ranging from 64 to approximately 600 kDa using size-exclusion chromatography (SEC). Oxygen equilibrium and kinetics binding parameters of all fractions were nearly identical, reflecting a lack of heterogeneity in ligand binding properties among O-R-PolyHbA0 species (Hill coefficient n equal to 1.0). Several mass spectrometry techniques were used to evaluate undigested and digested HbA0, O-R-PolyHbA0, and O-R-PolyHbA0 fractions. Proposed sites of intramolecular crosslinking (i.e., beta1Lys82, beta2Lys82, and beta1Val1) were not found to be the predominant site of crosslinking within the central cavity. Intermolecular crosslinking with O-raffinose results in no discernible site of amino acids modifications with the exception of beta93Cys and alpha104Cys. Based on accessible surface area (ASA) calculations in intact deoxyHbA0, slight conformational changes are required to allow for the S on alpha104Cys to be modified during the reaction with O-raffinose or its partially oxidized product(s). The stabilization of HbA0 in the T-conformation may not be a direct correlate of O-raffinose induced changes, but an indirect consequence of changing hydration in the water-filled central cavity and/or the distal heme pocket leading in the latter case to accelerated iron oxidation. Structural data presented here when taken together with the oxidative instability of O-R-PolyHbA0 may provide some basis for the reported toxicity of this oxygen carrier.

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“…This activating group, which has been successfully used by Tao et al for the synthesis of poly(N-(2-hydroxypropyl)methacrylamide)-protein conjugates, 70 has a hydrolysis half-life of several hours as compared to minutes for NHS esters. 71,72 The thiazolidine-2-thione group, however, has been reported to undergo side reactions with thiol groups. Squaric acid mediated coupling reactions overcome these problems as they are selective towards amines (without side reactions to other nucleophilic groups) and have a very high hydrolysis half-life (see above).…”

Section: Peptide-protein Conjugatesmentioning

confidence: 99%

Be squared: expanding the horizon of squaric acid-mediated conjugations

2013

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Squaric acid diesters can be applied as reagents to couple two amino-functional compounds. Consecutive coupling of two amines allows the synthesis of asymmetric squaric acid bisamides with either low molecular weight compounds but also biomolecules or polymers. The key feature of the squaric acid diester mediated coupling is the reduced reactivity of the resulting ester-amide after the first amidation step of the diester. This allows the sequential amidation and generation of asymmetric squaramides with high selectivity and in high yields. This article gives an overview of the well-established squaric acid diester mediated coupling reactions for glycoconjugates and presents recent advances that aim to expand this very versatile reaction protocol to the modification of peptides and proteins.

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PEG Thiazolidine-2-thione, a Novel Reagent for Facile Protein Modification: Conjugation of Bovine Hemoglobin

Cited by 43 publications

References 6 publications

Facile One-pot Synthesis of Ethyl 3-Alkyl-4-hydroxy-2-thioxothiazolidine-4-carboxylates

Facile One-pot Synthesis of Ethyl 3-Alkyl-4-hydroxy-2-thioxothiazolidine-4-carboxylates

O‐raffinose crosslinked hemoglobin lacks site‐specific chemistry in the central cavity: Structural and functional consequences of β93Cys modification

Be squared: expanding the horizon of squaric acid-mediated conjugations

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