Synthesis of cyclic peptide disulfide–PHPMA conjugates via sequential active ester aminolysis and CuAAC coupling

Abstract

Cyclic peptide disulfides (CXC) are an important class of biomolecules. The conjugation of cyclic peptide disulfides to synthetic polymers, however, is often difficult due to the presence of the disulfide bond combined with other potentially reactive side chain amino acids, such as lysine. This report describes a general, protective group-free method for the conjugation of CXCs to synthetic polymers using a sequential active ester aminolysis and copper catalyzed azide–alkyne cycloaddition (CuAAC) strategy, which starts from a poly(pentafluorophenyl methacrylate) (PPFMA) precursor. This route not only allows the incorporation of CXCs, but can be further explored to attach additional amine containing molecules to generate multifunctional copolymers. Various CuAAC protocols have been evaluated to couple a small library of cyclic peptide disulfides to an alkyne bearing poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA) copolymer. The use of Cu(II)SO₄, THPTA, sodium ascorbate and aminoguanidine for the CuAAC coupling was found to be suitable to yield well-defined cyclic peptide disulfide–PHPMA conjugates as evidenced by ¹H-NMR and SEC analyses.