Selective Alkylation and Acylation of α and ε Amino Groups with PEG in a Somatostatin Analogue: Tailored Chemistry for Optimized Bioconjugates

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Abstract
The effects of the type and location of polymer grafting on the biological activity of different mono-PEG derivatives of the somatostatin analogue RC160 were evaluated. A chemical strategy to obtain mono-PEG alkylation or acylation of the peptide's α-terminal or lysil-ε primary amines was devised. Selective BOC protection of the two available primary amines, followed by reaction with two different PEG reagents and removal of the protecting group, was carried out. Chemical characterization, structural studies, and the evaluation of the biological activity of the bioconjugates synthesized allowed the identification of the one having characteristics more suitable for therapeutic application. This corresponds to the mono-ε-lysil-pegylated form, obtained by reductive alkylation, where the amine's positive charge is preserved. The results obtained suggest the importance of preliminary studies in the development of new polymer−peptide conjugates with improved pharmacological properties.