An alternative approach to the synthesis of peptides containing a cystathionine bridge

Harjani, Jitendra R.; Yap, Beow Keat; Norton, Raymond S.; Baell, Jonathan B.

doi:10.1016/j.tet.2016.04.051

Cited by 3 publications

(3 citation statements)

References 30 publications

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“…A novel cysteine derivative, N α ‐mono‐methoxytrityl‐cysteinyl‐α‐allyl ester (Mmt‐Cys‐OAll) was also produced efficiently with suitable orthogonal protecting groups (Scheme B). A similar conceptual approach has recently been reported by Baell and co‐workers in a simple cyclic peptide system . Our work improves on this with respect to the higher yields of the amino acid precursors and application to forming a lactam within a complex peptidic system.…”

Section: Figuresupporting

confidence: 54%

“…As imilar conceptual approach has recently been reported by Baell and co-workers in as imple cyclic peptide system. [30] Our work improves on this with respect to the higher yields of the amino acid precursors and application to forming al actam within ac omplex peptidic system. TheF moc SPPS of A[S-CH 2 ] human insulin, containing the homoalaninyl-type residue (or g-carba moiety) at CysA11, is described herein.…”

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confidence: 83%

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Total Chemical Synthesis of an Intra‐A‐Chain Cystathionine Human Insulin Analogue with Enhanced Thermal Stability

et al. 2016

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Despite recent advances in the treatment of diabetes mellitus, storage of insulin formulations at 4 °C is still necessary to minimize chemical degradation. This is problematic in tropical regions where reliable refrigeration is not ubiquitous. Some degradation byproducts are caused by disulfide shuffling of cystine that leads to covalently bonded oligomers. Consequently we examined the utility of the non-reducible cystine isostere, cystathionine, within the A-chain. Reported herein is an efficient method for forming this mimic using simple monomeric building blocks. The intra-A-chain cystathionine insulin analogue was obtained in good overall yield, chemically characterized and demonstrated to possess native binding affinity for the insulin receptor isoform B. It was also shown to possess significantly enhanced thermal stability indicating potential application to next-generation insulin analogues.

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Section: Figuresupporting

confidence: 54%

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confidence: 83%

Total Chemical Synthesis of an Intra‐A‐Chain Cystathionine Human Insulin Analogue with Enhanced Thermal Stability

et al. 2016

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“…Surprisingly, less complex chemical transformations like on‐resin nucleophilic substitutions are rare. Very few examples describe the introduction of halogenated amino acids such as bromo‐ or chlorohomoalanine [10] that were only used to integrate stable cystathione as disulfide mimetics [10b,11] . However, iodohomoalanine was not used in this regard, and the potential of halogenated homoalanine for LSF and consequently peptide diversification was also not demonstrated.…”

Section: Introductionmentioning

confidence: 99%

Late‐Stage Functionalisation of Peptides on the Solid Phase by an Iodination‐Substitution Approach

Werner

Pampel

Pham

et al. 2022

Chemistry A European J

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The functionalisation of peptides at a late synthesis stage holds great potential, for example, for the synthesis of peptide pharmaceuticals, fluorescent biosensors or peptidomimetics. Here we describe an on‐resin iodination‐substitution reaction sequence on homoserine that is also suitable for peptide modification in a combinatorial format. The reaction sequence is accessible to a wide range of sulfur nucleophiles with various functional groups including boronic acids, hydroxy groups or aromatic amines. In this way, methionine‐like thioethers or thioesters and thiosulfonates are accessible. Next to sulfur nucleophiles, selenols, pyridines and carboxylic acids were successfully used as nucleophiles, whereas phenols did not react. The late‐stage iodination‐substitution approach is not only applicable to short peptides but also to the more complex 34‐amino‐acid WW domains. We applied this strategy to introduce 7‐mercapto‐4‐methylcoumarin into a switchable ZnII responsive WW domain to design an iFRET‐based ZnII sensor.

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Total Chemical Synthesis of an Intra‐A‐Chain Cystathionine Human Insulin Analogue with Enhanced Thermal Stability

et al. 2016

View full text Add to dashboard Cite

Despite recent advances in the treatment of diabetes mellitus, storage of insulin formulations at 4 °C is still necessary to minimize chemical degradation. This is problematic in tropical regions where reliable refrigeration is not ubiquitous. Some degradation byproducts are caused by disulfide shuffling of cystine that leads to covalently bonded oligomers. Consequently we examined the utility of the non‐reducible cystine isostere, cystathionine, within the A‐chain. Reported herein is an efficient method for forming this mimic using simple monomeric building blocks. The intra‐A‐chain cystathionine insulin analogue was obtained in good overall yield, chemically characterized and demonstrated to possess native binding affinity for the insulin receptor isoform B. It was also shown to possess significantly enhanced thermal stability indicating potential application to next‐generation insulin analogues.

show abstract

An alternative approach to the synthesis of peptides containing a cystathionine bridge

Cited by 3 publications

References 30 publications

Total Chemical Synthesis of an Intra‐A‐Chain Cystathionine Human Insulin Analogue with Enhanced Thermal Stability

Total Chemical Synthesis of an Intra‐A‐Chain Cystathionine Human Insulin Analogue with Enhanced Thermal Stability

Late‐Stage Functionalisation of Peptides on the Solid Phase by an Iodination‐Substitution Approach

Total Chemical Synthesis of an Intra‐A‐Chain Cystathionine Human Insulin Analogue with Enhanced Thermal Stability

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