Access to α,α-Disubstituted Disilylated Amino Acids and Their Use in Solid-Phase Peptide Synthesis

Abstract

A concise synthetic pathway yielding to hydrophobic α,α-disubstituted disilylated amino acids based on a hydrosilylation reaction is described. As a first example of utilization in solid-phase peptide synthesis, TESDpg was introduced in replacement of Aib in an alamethicin sequence, leading to analogues with modified physicochemical properties and conserved helical structures. This study highlights the potential of these new amino acids as tools for peptide modulation.

Solid‐Phase Synthesis of the Peptaibol Alamethicin U‐22324 by Using a Double‐Linker Strategy

“…The antimicrobial activities for synthetic peptaibol 1 were lower than those reported in the literature. [26] These methods can potentially be applied to future alamethicin studies. Interestingly, recent studies have documented that substitution of the native amino acids in alamethicin with -silicon-3-amino acids results in a 20-fold increase in membrane permeability, [25] and the incorporation of α,α-substituted disilylated amino acids modified the physicochemical properties of the alamethicin analogues.…”

Incorporation of β‐Silicon‐β3‐Amino Acids in the Antimicrobial Peptide Alamethicin Provides a 20‐Fold Increase in Membrane Permeabilization

“…In a recent study, the α,α‐disubstituted disilylated amino acid TESDpg was synthesized and incorporated into different positions in the antimicrobial peptide alamethicin . The study showed that the α‐helical structure of alamethicin was retained; however, the antimicrobial activity against B. subtilis was lost for all the peptide analogues, possibly due to steric hindrance from the bulky amino acid preventing self‐association of the peptide in the membrane.…”

Hydrophobic α,α-Disubstituted Disilylated TESDpg Induces Incipient 310-Helix in Short Tripeptide Sequence

“…The pioneering combination of both characteristics, silicon and α,α-disubstitution, has been explored by our research group, and recently, a constrained sila analogue of GABA (γ-amino butyric acid) was also reported by Ramesh et al The synthesis of the first disubstituted disilylated amino acids has been recently reported (Figure ). These compounds are particularly attractive because they combine α,α-disubstituted conformational constraint and very interesting lipophilic characteristic thanks to the silicon atom present in both side chains.…”

“…As an example of application in bioactive peptide, triethylsilyl α,α-di- n -propylglycine, namely TESDpg, when inserted in the sequence of the antimicrobial peptide alamethicin to replace Aib, did not alter its secondary structure, while the antimicrobial activity was lost . Incorporation of β-silicon-β3-amino acids in alamethicin was also investigated, leading to a 20-fold increase in calcein release compared to wild-type alamethicin …”

“…The TESDpg was hence coupled for the first time in solution, and both the free amino function and the carboxylic acid function were proved to be reactive under classical coupling reaction conditions. Until now, this disubstituted disilylated amino acid was only used under microwaves-assisted SPPS and was efficiently coupled with variable yields depending on the substitution position …”