Alkylated peptide

J Urban, T Vaisar, R Shen, MS Lee. Lability of JV-alkylated peptides towards TFA cleavage. Int J Pept Prot Res 47, 182, 1996. 

Disulfide connectivities of a partially reduced and alkylated peptide can be identified by the pairwise recognition of the specifically derivatized PTH-Cys on sequencing/46 PTH-Cys(Cam) and PTH-Cys(CM) are reported to elute on the ABI sequencer with PTH-Glu and PTH-Ser, respectively/46 and PTH-Cys(NEM) after PTH-Pro. 49 Therefore, it is important to know the primary structure of the target molecule in advance and to focus on the determination of its disulfide arrangement during sequence analysis in order to avoid mis-assignment of the amino adds at the cycles of the modified cysteine residues. 

Taking advantage of the side-chain linkage of C-terminal trifunctional amino acids to solid supports, related iV-mono(alkyl)amides or Ai-bis(alkyl)amides serve for the production of C-terminally lipidated peptides. So far, this approach has been reported only for the synthesis of a C-terminally mono-alkylated peptide.1 1 ... 

As an alternative, a rather unusual strategy for the synthesis of cyclic tetrapeptides utilizes the deprotonation of the backbone amides of cyclic tetrapeptides with LDA and subsequent alkylation to produce N-alkylated peptides, which can be achieved regio- and... 

The commercial availability of protected /V-methyl amino acids [(Me)Xaa] of many proteinogenic amino acids (as well as other V-alkyl amino acids), the availability of procedures for the synthesis of protected V-alkyl analogues of all the protein amino acids, and the availability of synthetic procedures for site-selective alkylation during SPPS (see Section 10.1.2.1) allows the alkylation of nearly all peptide bonds in a given parent peptide. The synthesis of a series of V-alkyl peptide analogues based on the sequence of a given bioactive peptide (linear or cyclic) in which each peptide bond is successively alkylated and evaluation of the biological activity of this series will be called herein A-alkyl-scan (for example Me-scan, Et-scan, etc.)... 

Since TV-methyl amino acids are the most abundant TV-alkyl amino acid in naturally occurring N-alkylated peptides it is apparent that much attention has been devoted to the synthesis of these amino acids. 

Houghten and co-workers[145] introduced a method for combinatorial synthesis of a per-alkylated peptide library using nonspecific N-alkylation. The peptides were synthesized by SMPS methodology 146 in combination with repetitive amide N-alkylation on the solid support after each coupling step. Peptides were synthesized on MBHA-PSty resin using Fmoc chemistry. After Fmoc deprotection the a-amino group was protected by Trt to prevent N -alkylation and to allow only amide alkylation. The on-resin amide alkylation was achieved by amide proton abstraction using LiOtBu in THF followed by nonfunctionalized alkyl and aryl halides in DMSO. 

Scheme 36 SPPS of N-Alkylated Peptides by the Bis(trichloromethyl) Carbonate Method,3°l...

Table 11 Solid-Phase Synthesis of N-Alkylated Peptides 0,1 g m.w.aii.202]... 

Deprotection and Removal from the Resin of N-Alkylated Peptides that Contain Acid-Labile Side-Chain Protection General Procedure 28168 ... 

---