Hydrazine peptides

A second type of glutamyl transfer reaction does not utilize amino acids as glutamo acceptors, but only NHj, hydroxylamine, or hydrazine. Peptides containing aspartyl residue can also serve as aspartyl donors which is an analogous reaction to the glutamyl transfer (120-122). The physiological meaning of these reactions remains to be clarified. 

Benzylthio or 2-benzyloxy derivatives of A-2-thiazoline-5-one (224) are readily opened by amines to give the amide derivatives (225) (Scheme 115) (459. 471). Compound 225 can be cyclized thermally to the corresponding thiohydantoins (459). Similarly, treatment of 4-substituted-2-phenylthiazol-5(4H)-ones (226) with amino acids, peptides, or hydrazine affords the corresponding Nfcti-thiobenzamidoacetylated derivatives (227) (Scheme 116) (455). 

This reaction forms the basis of one method of terminal residue analysis A peptide is treated with excess hydrazine in order to cleave all the peptide linkages One of the terminal amino acids is cleaved as the free amino acid and identified all the other ammo acid residues are converted to acyl hydrazides Which amino acid is identified by hydrazmolysis the N terminus or the C terminus ... 

The Dmab group was developed for glutamic acid protection during Fmoc/r-Bu based peptide synthesis. The group shows excellent acid stability and stability toward 20% piperidine in DMF. It is formed from the alcohol using the DCC protocol for ester formation and is cleaved with 2% hydrazine in DMF at rt. ... 

When the Ac group is removed (20% piperidine/DMF or 5% hydrazine/DMF), it becomes the Hmb group that is used to improve solubility and prevent aspar-tamide formation and is readily cleaved with TFA. The related 2-Fmoc-4-methoxybenzyl group has also been prepared and used in peptide synthesis. ... 

The polymeric resin used for Merrifield solid-phase peptide synthesis (Section 26.8) is prepared by treating polystyrene with iV-(hydroxymethyl) phthalimide and trifluoromethanesulfonic acid, followed by reaction with hydrazine. Propose a mechanism for both steps. 

The ring in oxadiazolinones 54 (R1 = 3-benzyloxyphenyl, CbzNH-L-leucine, R2 = H, Y = 0) in a reaction with hydrazine hydrate cleaved to afford product 55, which was then used in the syntheses of peptide mimetics <1998JME3923, 1999BMC599>. The reaction of oxadiazolinone 54 (R Fmoc, R2 = H, Y = 0) with primary... 

S-S Wang, ID Kulesha, DP Winter, R Makofske, R Kutny, J Meienhofer. Preparation of protected peptide hydrazides from the acids and hydrazine by dicyclohexylcarbo-diimide-hydroxybenzotriazole coupling. Int J Pept Prot Res 11, 297, 1978. 

Identification of carboxy-terminal amino acids was also attempted. Studies by Bergmann and his associates in the 1930s (see below) had characterized various peptidases with differing specificities. One of these was carboxypeptidase which required a free carboxy terminus adjacent to the peptide bond to be hydrolyzed. The specificity of the enzyme was limited but Lens in 1949 reported alanine to be at one end of insulin. Fromageot and his colleagues (1950) and Chibnall and Rees (1951) reduced the carboxy termini to B-aminoalcohols and showed glycine as well as alanine to be carboxy-terminal. Hydrazinolysis was also attempted the dry protein was treated with hydrazine at 100 °C for 6 h so that the carboxy-terminal amino acid was released as the free... 

Die Methode von Akabori. Werden Peptide odor Protcinc mit was-serfreiem Hydrazin crliitzt, so werden die Peptidbindungen gesprengt und es bilden sich Aminosaure-Hydrazide. Nur die C-terminate Amino-saure -wird als solche abgespalten. 

Alternatively to using prelipidated building blocks palmitoylation on resin is possible with the hydrazine linker. In Scheme 27 the synthesis route for the palmitoylated and farnesylated N-Ras peptide 78 is shown. Here the initial loading of trityl-protected cysteine to the hydrazine linker was mediated by A,A-diisopropylcarbodiimide (DIG) and HOBt. After Fmoc removal the proline was coupled using HBTU and HOBt. The trityl-protected dipeptide 75 was subsequently S-deprotected using TFA with triethylsilane (TES) as a scavenger. Farnesylation of the free thiol was achieved with an excess of farnesyl bromide. 

In summary, the hydrazine linker is currently the most suitable linker system for the synthesis of C-terminally methylated lipidated peptides. Allowing the incorporation of different types of lipid chain in combination with the MIC group at the N-terminus the hydrazine linker gives access to a variety of lipidated peptides of the Ras superfamily. 

Scheme 25 Assembly and cleavage of a NBD-functionalized, palmitoylated, and farnesylated peptide on the hydrazine linker.

Scheme 26 Selection of N-Ras-derived lipidated peptide sequences that were synthesized using the hydrazine linker.

Scheme 27 Synthesis of a palmitoylated and farnesylated N-Ras peptide with the hydrazine linker using the resin llpidatlon approach.

The polymer-bound p-nitrobenzophenone oxime (71d) has been found to be a suitable support for stepwise peptide synthesis. Protected peptides can be assembled on 70d by coupling and deprotection steps similar to those employed in the usual Merrifield solid-phase procedures (Scheme 39). Cleavage of peptides from 71d can be accomplished with hydrazine and amino acid esters under mild conditions, which do not affect benzyl ester side-chain protecting groups. 

A-Hydroxyphthalimide 178 was used as a source of the hydroxylamine reacting with trityl chloride resin 182 in the presence of triethylamine to obtain the A-hydroxyphth-alimide derivative 183. This intermediate is transformed to the desired hydroxylamine resin 184 by treatment with hydrazine. The peptidic and peptidomimetic hydroxamic acids 185 and 186 were synthesized using the described solid-supported reagent (Scheme 82). 

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