Monothioether cyclic peptide
Monothioether type cyclic peptide is a kind of synthetic pathway of ether cyclic peptide
1) The main structure of peptide chain was prepared and regenerated into ether bond to realize cyclization;
2) Firstly, the ether structure was prepared and regenerated into amide bond (or other bond) to realize cyclization.
The synthesis of monothioether type cyclopeptides has attracted more and more attention because of its slow metabolism in vivo and non immunogenicity. There are three kinds of solid state synthesis methods
① . substitution method.
This method is a common method for the preparation of monothioether cyclic peptide. It transforms the side chain Oh into a br, and then takes place intramolecular nucleophilic substitution with – SH group on the peptide chain to obtain monothioether cyclic peptide.
Base catalysis is the most important reaction condition for Bi, and tertiary amine (triethylamine, Methylmorpholine or DBU) is generally used to make the nucleophilic reaction proceed.
In the synthesis of linear peptide, the acid containing br bond was directly added to condense the amino part of the main chain peptide, and then nucleophilic substitution was carried out, which eliminated the structural transformation of the related residues and was more convenient
② Michael addition method.
After introducing sulfhydryl group into the resin, Michael addition takes place under the catalysis of free mercapto group, and then the side chain protection is removed. The mono thioether cyclic peptide can be obtained by cutting off the carrier.
Sharma et al. Used Wang resin as carrier, added TFA and tes / DCM reagent to introduce sulfhydryl group, and used Diem / NMP to catalyze cyclization to obtain the target cyclic peptide.
③ Pcor method.
Firstly, Cys was introduced into the peptide chain for deprotection, then free SH attacked linker to form target cyclic peptide, and linker cleaved to remove the carrier. The N-terminal a-amino group needs to be protected in the synthesis process, otherwise oxime linker will be aminated.
Unsaturated cyclic peptide
In the direct synthesis of peptide chain, the peptide containing unsaturated bond will also be selected in the assembly of peptide chain, so that some more active cyclic peptide analogues can be obtained.
Bang et al. Synthesized cyclopeptides containing olefins on the ring by introducing unsaturated groups into the straight chain peptide and then adding the cyclization reagent by solid-phase Hormer Emmons reaction.
The results show that among the cyclization reagents (such as DPPA, pybrop, Hatu), EDC / hoat can effectively inhibit the formation of dimer, and the cyclization effect is good.
If there are unsaturated hydrocarbons and iodobenzene on the straight chain peptide, the palladium reagent can also be used for Heck reaction to produce unsaturated cyclic peptide.
Akaji et al. Successfully synthesized pentacyclic peptide through this pathway. The ethylene reaction of palladium reagent can be successfully completed at room temperature without water or inert gas.
Turner et al. Also used click chemistry to synthesize a series of small molecular cyclic peptides at room temperature. The cyclization can be completed within 6 h, and the product is pure, and the side reaction of monomer is less.
Nitrogen bridged cyclic peptide
There are few solid-phase synthesis of this kind of cyclic peptide. Generally, the N-terminal of peptide chain is introduced into haloacetyl group, and then nucleophilic substitution occurs with Lys side chain to obtain cyclic peptide (as shown in the figure). In this method, attention should be paid to not more than two active side chain sites on the same peptide chain.
Mannich base cyclic peptide
If Tyr group exists on the peptide chain, the N-terminal amino group can be regarded as an amine component, and Mannich base cyclic peptide can be obtained by adding aldehyde group.
Note: the content is derived from “research progress in the synthesis of cyclic peptides based on solid phase method”
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