Preparation and Application of an Inexpensive α-Formylglycine Building Block Compatible with Fmoc Solid-Phase Peptide Synthesis

Abstract

α-Formylglycine (fGly) is a rare residue located in the active site of sulfatases, and serves as a precursor to pharmaceu-tically-relevant motifs. The installation of fGly motifs into peptides is currently challenging due to degradation under the acidic and nucleophile-rich conditions accompanying resin cleavage during solid-phase peptide synthesis. We report the synthesis of acid and nucleophile tolerant α-formylglycine building blocks from vitamin C, and use them to prepare Callyaerin A, a macrocyclic peptide containing an fGly-derived motif.

Preparation and Application of an Inexpensive α-Formylglycine Building Block Compatible with Fmoc Solid-Phase Peptide Synthesis

“…Although under harsh conditions amino acids such as Met, Trp, Tyr, and Ser/Thr can be susceptible periodate oxidation, by performing reactions at neutral pH and low temperature with controlled reaction stoichiometry, akin to the conditions used here, these residues have been shown to tolerate NaIO 4 . , Furthermore, addition of excess Met to the reaction has been shown to further reduce overoxidation of peptides with no loss of biological activity, notably in the case of the polypeptide chemokine RANTES which contains Met and also multiple disulfide forming Cys residues, which are highly susceptible to periodate oxidation . We therefore propose our building block may have broad applications in the fields of bioconjugation and pharmacology, particularly as bioconjugations using formylglycine are currently underexplored, the biological mechanisms of formylglycine installation has not yet been unequivocally elucidated and formylglycine-derived motifs are present in many pharmaceutically-relevant compounds, including the tuberactinomycin , and callyaerin ,,,, families of antibiotics.…”