The potential of N-alkoxymethyl groups as peptide backbone protectants

Fernández-Llamazares, Ana I.; Spengler, Jan; Alberício, Fernando

doi:10.1016/j.tetlet.2013.10.149

Cited by 6 publications

(2 citation statements)

References 15 publications

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“…More recently, the N-alkoxymethyl-based amide backbone protecting group, the ethyloxymethyl (Etom) 206 (Table 7), was proposed by Spengler and Albericio and its efficiency on enhancing solubility was proved for the Fmoc/tBu strategy by SPPS. This group is incorporated into the sequence under standard conditions as the dipeptide Alloc-N-(Etom)AA 2 -N(Etom)-AA 1 -OH, previously synthesized in the solution-phase.…”

Section: Ortho-mercaptobenzyl Structure-basedmentioning

confidence: 99%

The road to the synthesis of “difficult peptides”

2016

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The last decade has witnessed a renaissance of peptides as drugs. This progress, together with advances in the structural behavior of peptides, has attracted the interest of the pharmaceutical industry in these molecules as potential APIs. In the past, major peptide-based drugs were inspired by sequences extracted from natural structures of low molecular weight. In contrast, nowadays, the peptides being studied by academic and industrial groups comprise more sophisticated sequences. For instance, they consist of long amino acid chains and show a high tendency to form aggregates. Some researchers have claimed that preparing medium-sized proteins is now feasible with chemical ligation techniques, in contrast to medium-sized peptide syntheses. The complexity associated with the synthesis of certain peptides is exemplified by the so-called "difficult peptides", a concept introduced in the 80's. This refers to sequences that show inter- or intra-molecular β-sheet interactions significant enough to form aggregates during peptide synthesis. These structural associations are stabilized and mediated by non-covalent hydrogen bonds that arise on the backbone of the peptide and-depending on the sequence-are favored. The tendency of peptide chains to aggregate is translated into a list of common behavioral features attributed to "difficult peptides" which hinder their synthesis. In this regard, this manuscript summarizes the strategies used to overcome the inherent difficulties associated with the synthesis of known "difficult peptides". Here we evaluate several external factors, as well as methods to incorporate chemical modifications into sequences, in order to describe the strategies that are effective for the synthesis of "difficult peptides". These approaches have been classified and ordered to provide an extensive guide for achieving the synthesis of peptides with the aforementioned features.

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Section: Ortho-mercaptobenzyl Structure-basedmentioning

confidence: 99%

The road to the synthesis of “difficult peptides”

2016

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“… 15 , 16 Many novel backbone protection strategies have been developed but the increased steric hindrance that accompanies the introduction of a secondary amine into a sequence prohibits quantitative coupling using standard conditions (except with glycine) and has limited the wider adoption of these new backbone protection strategies. 17 A solution to overcome this obstacle harnessed an intramolecular acyl transfer. This was achieved by the use of 2-hydroxy-4-methoxybenzyl (Hmb) 3 which can be considered as a simple modification of Dmb 2 ( Scheme 1 ).…”

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confidence: 99%