Synthetic procedure for N-Fmoc amino acyl-N-sulfanylethylaniline linker as crypto-peptide thioester precursor with application to native chemical ligation.

doi:10.1021/jo3011107

Paper

Synthetic procedure for N-Fmoc amino acyl-N-sulfanylethylaniline linker as crypto-peptide thioester precursor with application to native chemical ligation.

Published Aug 2, 2012 · Ken Sakamoto, Kohei Sato, Akira Shigenaga

The Journal of organic chemistry

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21

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Abstract

N-sulfanylethylanilide (SEAlide) peptides 1, obtainable using Fmoc-based solid-phase peptide synthesis (Fmoc SPPS), function as crypto-thioesters in native chemical ligation (NCL), yielding a wide variety of peptides/proteins. Their acylating potential with N-terminal cysteinyl peptides 2 can be tuned by the presence or absence of phosphate salts, leading to one-pot/multifragment ligation, operating under kinetically controlled conditions. SEAlide peptides have already been shown to be promising for use in protein synthesis; however, a widely applicable method for the synthesis of N-Fmoc amino acyl-N-sulfanylethylaniline linkers 4, required for the preparation of SEAlide peptides, is unavailable. The present study addresses the development of efficient condensation protocols of 20 naturally occurring amino acid derivatives to the N-sulfanylethylaniline linker 5. N-Fmoc amino acyl aniline linkers 4 of practical use in NCL chemistry, except in the case of the proline- or aspartic acid-containing linker, were successfully synthesized by coupling of POCl(3)- or SOCl(2)-activated Fmoc amino acid derivatives with sodium anilide species 6, without accompanying racemization and loss of side-chain protection. Furthermore, SEAlide peptides 7 possessing various C-terminal amino acids (Gly, His, Phe, Ala, Asn, Ser, Glu, and Val) were shown to be of practical use in NCL chemistry.

Study Snapshot

This study developed efficient condensation protocols for synthesizing N-Fmoc amino acyl-N-sulfanylethylaniline linkers, which are essential for SEAlide peptide preparation in native chemical ligation chemistry.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Synthetic procedure for N-Fmoc amino acyl-N-sulfanylethylaniline linker as crypto-peptide thioester precursor with application to native chemical ligation.

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References

N-to-C sequential ligation using peptidyl N,N-bis(2-mercaptoethyl)amide building blocks.

This novel N-to-C sequential chemical ligation approach offers a stable, efficient method for protein synthesis, with potential applications in medium-sized peptide and ubiquitin synthesis.

A one-pot three-segment ligation strategy for protein chemical synthesis.

This study presents a one-pot strategy for synthesizing small proteins with high yield and potential for protein-based therapeutics, using native peptide ligation.

Preformed selenoesters enable rapid native chemical ligation at intractable sites.

Preformed selenoesters enable rapid native chemical ligation at intractable sites, such as Pro-Cys, with two orders of magnitude faster rate enhancement compared to peptide -thioesters.

4-Methoxybenzyloxymethyl group as an Nπ-protecting group for histidine to eliminate side-chain-induced racemization in the Fmoc strategy

The 4-methoxybenzyloxymethyl group effectively prevents racemization during peptide synthesis using the Fmoc strategy, with formaldehyde side reactions effectively prevented using TFA treatment and MeONH 2 HCl.

Synthesis of Cyclic Peptides through an Intramolecular Amide Bond Rearrangement

This study demonstrates a straightforward method for synthesis of cyclic peptides, potentially increasing their therapeutic potential and oral bioavailability.

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