- A Facile N-Mercaptoethoxyglycinamide (MEGA) Linker Approach to Peptide Thioesterification and Cyclization
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The C-terminal electrophilic activation of peptides by α-thioesterification requires strongly acidic conditions or complex chemical manipulations, which ultimately limit functional group compatibility and broad utility. Herein, we report a readily accessible N-mercaptoethoxyglycinamide (MEGA) solid-phase linker for the facile synthesis of latent peptide α-thioesters. Incubating peptide-MEGA sequences with 2-mercaptoethanesulfonic acid at mildly acidic pH yielded α-thioesters that were directly used in NCL without purification. The MEGA linker yielded robust access to thioesters ranging in length from 4 to 35 amino acids, and greatly simplified the synthesis of cyclic peptides. Finally, the high utility of MEGA was demonstrated by the one-pot synthesis of a functional analog of the Sunflower Trypsin Inhibitor 1.
- Shelton, Patrick M. M.,Weller, Caroline E.,Chatterjee, Champak
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- K-Oxyma: A strong acylation-promoting, 2-ctc resin-friendly coupling additive
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Here we present a new formulation of the recently introduced OxymaPure additive for peptide bond formation, in which the N-hydroxylamine group is replaced by a potassium salt. The complete suppression of its acidity converts K-Oxyma into the most suitable coupling choice when peptides are assembled on highly acid-labile solid-supports. The coupling efficiency and diminished prospects for epimerization are conserved relative to OxymaPure. In addition, K-Oxyma displays excellent solubility in a variety of organic solvents and undergoes safer decomposition than classical 1-hydroxybenzotriazole additives. A new oxime-based coupling additive is introduced for peptide bond formation. The potassium salt of OxymaPure, K-Oxyma, is readily obtained from commercially available precursors. Unlike common N-hydroxylamines, K-Oxyma is compatible with extremely acid-labile solid-supports, displays excellent solubility, minimizes epimerization, and enhances coupling efficiency relative to OxymaPure. Copyright
- Cherkupally, Prabhakar,Acosta, Gerardo A.,Nieto-Rodriguez, Lidia,Spengler, Jan,Rodriguez, Hortensia,Khattab, Sherine N.,El-Faham, Ayman,Shamis, Marina,Luxembourg, Yoav,Prohens, Rafel,Subiros-Funosas, Ramon,Albericio, Fernando
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p. 6372 - 6378
(2013/10/21)
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- Multimerization of cRGD peptides by click chemistry: Synthetic strategies, chemical limitations, and influence on biological properties
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Integrin αvβ3 is overexpressed on endothelial cells of growing vessels as well as on several tumor types, and so integrin-binding radiolabeled cyclic RGD pentapeptides have attracted increasing interest for in vivo imaging of αvβ3 integrin expression by positron emission tomography (PET). Of the cRGD derivatives available for imaging applications, systems comprising multiple cRGD moieties have recently been shown to exhibit highly favorable properties in relation to monomers. To assess the synthetic limits of the cRGD-multimerization approach and thus the maximum multimer size achievable by using different efficient conjugation reactions, we prepared a variety of multimers that were further investigated in vitro with regard to their avidities to integrin αvβ3. The synthesized peptide multimers containing increasing numbers of cRGD moieties on PAMAM dendrimer scaffolds were prepared by different click chemistry coupling strategies. A cRGD hexadecimer was the largest construct that could be synthesized under optimized reaction conditions, thus identifying the current synthetic limitations for cRGD multimerization. The obtained multimeric systems were conjugated to a new DOTA-based chelator developed for the derivatization of sterically demanding structures and successfully labeled with 68Ga for a potential in vivo application. The evaluated multimers showed very high avidities-increasing with the number of cRGD moieties-in in vitro studies on immobilized αvβ3 integrin and U87MG cells, of up to 131-and 124-fold, respectively, relative to the underivatized monomer.
- Waengler, Carmen,Maschauer, Simone,Prante, Olaf,Schaefer, Martin,Schirrmacher, Ralf,Bartenstein, Peter,Eisenhut, Michael,Waengler, Bjoern
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experimental part
p. 2168 - 2181
(2011/12/15)
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