Solid phase reductive alkylation techniques in analogue peptide bond and sidechain modification

Abstract

The presence of a reduced peptide bond in a biologically active peptide usually has profound effects on conformation and potency. The CH 2NH group may be a useful tool for delineating important hydrogen-bonding points and may also offer a general strategy for the production of enzyme resistance and potent competitive antagonists containing minimal structural alteration. The introduction of the group by solid phase reductive alkylation with a protected amino acid aldehyde offers a rapid route to peptides containing one or even many bond replacements. Potential racemization problems have been investigated and appear to be mostly related to the LiAlH 4 reduction of ammo acid dimethylhydroxamates to the aldehydes. Conditions are presented which prevent this, however, prolonged storage of amino acid aldehydes does appear to result in substantial racemization. The stability of commonly used side chain protecting groups to synthetic conditions was also investigated. The reactivity of the CH 2NH group to subsequent coupling reactions is surprisingly low. Its utility as an additional derivatization point in analogue design is examined. Some biological effects of peptide bond replacement and also solid-phase N-alkylation of several types of peptide hormones are discussed.