Pseudopeptides backbone groups

The dimethoxybenzyl group was used for backbone protection of the pseudopeptides of the form Xaai/r(CH2N)Gly (Xaa = amino acid). It is introduced by reductive alkylation with the aldehyde and NaCNBH3. Acidolysis with TFMSA in TFA/thioanisole is used to remove it from the amine, but the efficiency is dependent upon the peptide sequence. ... 

As stated above, we define pseudopeptides as compounds having a modified peptide backbone, namely with at least one peptide bond replaced by a bioisosteric surrogate (summarized in Table 6.7) [139][181][234], Such surrogate groups are nonhydrolyzable by nature, or hydrolyzable only under severe conditions in the case of the S02-NH bond. In the vast majority of published pseudopeptides, only one or a very few peptide bonds had been replaced and most monomeric units are amino acids, meaning that such pseudopeptides do qualify as peptides. 

The replacement of amide bonds by retro-in-verso amide replacements (71, 72) and other amide bond isosteres generates pseudopeptides (11). This process was first used to stabilize peptide hormones in vivo and later to prepare transition state analog (TSA) inhibitors. Systematic efforts to convert good in vitro inhibitors into good in vivo inhibitors became the driving force for further development of peptidomimetics. Figure 15.17 illustrates some of the peptide backbone modifications that have been made in an effort to increase bioavailability. Replacement of scissile amide (CONH) bonds with groups insensitive to hydrolysis (e.g., CHaNH) has been extensively practiced. Reviews of this work have appeared (11,73). Removal of the proton donors and... 

Figure 15.17. Isosteres that replace peptide backbone amide groups to generate pseudopeptides.

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