Carboxamides peptides

Coupling of 4-(4-hydroxymethyl-3-methoxyphenoxy)-butyric acid (HMPB, for synthesis of peptide acids) or p-[(R S)-a-[l- (9H- fluorenyl- methoxyform-amido]- 2,4- dimethoxybenzyl] - phenoxyacetic acid (modified Rink linker, for synthesis of carboxamide peptides) linkers to MBHA resin For Fmoc chemistry several types of solid supports are available, which include hydroxymethyl-based, aminomethyl-based, and trityl chloride resins. We describe the use of the MBHA resin. In this case the respective linker (to achieve peptide acid or amide) is coupled to the resin and first amino acid is then coupled to the linker. Attachment of the linker to the resin is a reaction between the carboxyl-group of the linker and amino-group of the MBHA resin. Commercially available resins with linkers already attached could also be used. 

The thiation procedure described here is an example of a general synthetic method for the conversion of carbonyl to thiocarbonyl groups. Similar transformations have been carried out with ketones, carboxamides,esters,thioesters, 1 actones, " thiol actones, - imides, enaminones, and protected peptides. ... 

B. H. Geierstanger, D. E. Wemmer, and P. B. Dervan. Antiparallel side-by-side dimeric motif for sequence-specific recognition in the minor groove of DNA by the designed peptide 1-methylimidazole-2-carboxamide netropsin. Proc. Natl. 

While the N-acetyl group likely protects the N-terminus from the action of ami-nopeptidases and the carboxamide moiety protects the C-terminus from carboxy-peptidases, these features alone do not prevent degradation of the control peptide. 

Solid-phase synthesis of biomolecules, of which peptides are the prime example, is well established. The search for more effective therapeutic agents creates a need for different strategies to synthesize peptides with C-terminal end groups other than the usual carboxylic acid and carboxamide functionalities. Methods described herein are readily generalized to small nitrogen-containing organic molecules. 

FIGURE 5.16 Production of amides by cleavage of benzhydryl amides. Recognition that removal by acidolysis of benzhydryl protectors from carboxamides gave the amides (B) led to development of benzhydrylamine (BHA) resin (C).33 Treatment with HF of a peptide amide that has been assembled on a BHA resin using Boc/Bzl chemistry gives the peptide amide (D). Peptide amide is also obtainable by ammonolysis of the resin-bound benzyl ester (A), a reaction that is more efficient if gaseous NH3 is employed (see Section 8.3). 

Fuzeon (enfuvirtide) is an anti-HIV drug. It interferes with the entry of HIV into the CD4 cell. It is a synthetic peptide with 36 amino acids, the N terminus is acetylated while the C terminal forms a carboxamide. The peptide binds to the gp41 subunit of the HIV envelope glycoprotein and prevents the HIV from fusing with CD4. 

Peptides are oligomers or polymers of amino acids linked together by a carboxamide group. An example of a pentapeptide is... 

Carboxypeptidase A"" (CPA, EC 3.4.17.1) is a proteolytic enzyme that cleaves C-terminal amino acid residues with hydrophobic side chains selectively. Several X-ray structures are available" The active site of CPA consists of a hydrophobic pocket (primary substrate recognition site) that is primarily responsible for the substrate specificity, a guanidinium moiety of Argl45 that forms hydrogen bonds to the carboxylate of the substrate, and Glu270, whose carboxylate plays a critical role, functioning either as a nucleophile to attack the scissUe carboxamide carbonyl carbon of the substrate or as a base to activate the zinc-bound water molecule, which in turn attacks the scissile peptide bond ". However, semiempirical calculations had shown that the direct attack of... 

However, sulfonamides are much more difficult to hydrolyze back to the amine than are carboxamides. In peptide synthesis (Section 25-7C) the commonly used sulfonyl protecting groups are 4-methylbenzenesulfonyl or 4-bromo-benzenesulfonyl groups. These groups can be removed as necessary from the sulfonamide by reduction with sodium metal in liquid ammonia ... 

The power of the Passerini and Ugi reactions in constructing polyfunctional molecules has been well appreciated since the early studies. The classical Passerini and Ugi reactions afford a-acyloxy carboxamides and a-acylamino amides respectively, that can be easily manipulated by post-condensation reactions, generating molecular diversity for drug discovery and natural product synthesis [22], This strategy has been widely applied to the synthesis of natural peptides and open-chain peptide mimetics covered in this section. 

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