Synthesis of Novel Arginine Building Blocks with Increased Lipophilicity Compatible with Solid-Phase Peptide Synthesis

Mladena Glavaš; Agata Gitlin-Domagalska; Natalia Ptaszyńska; Dominika Starego; Sylwia Freza; Dawid Dębowski; Aleksandra Helbik-Maciejewska; Anna Łęgowska; Chaim Gilon; Krzysztof Rolka

doi:10.3390/molecules28237780

Synthesis of Novel Arginine Building Blocks with Increased Lipophilicity Compatible with Solid-Phase Peptide Synthesis

Molecules. 2023 Nov 25;28(23):7780. doi: 10.3390/molecules28237780.

Affiliations

¹ Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland.
² Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, 10 000 Zagreb, Croatia.
³ Department of Theoretical Chemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland.
⁴ Department of Organic Chemistry, Institute of Chemistry, The Hebrew University, Jerusalem 91904, Israel.

Abstract

Arginine, due to the guanidine moiety, increases peptides' hydrophilicity and enables interactions with charged molecules, but at the same time, its presence in a peptide chain might reduce its permeability through biological membranes. This might be resolved by temporary coverage of the peptide charge by lipophilic, enzyme-sensitive alkoxycarbonyl groups. Unfortunately, such a modification of a guanidine moiety has not been reported to date and turned out to be challenging. Here, we present a new, optimized strategy to obtain arginine building blocks with increased lipophilicity that were successfully utilized in the solid-phase peptide synthesis of novel arginine vasopressin prodrugs.

Keywords: SPPS; arginine building blocks; increased lipophilicity; prodrugs; vasopressin.

MeSH terms

Arginine* / chemistry
Guanidines
Peptides / chemistry
Solid-Phase Synthesis Techniques*

Substances

Arginine
Peptides
Guanidines

Grants and funding

2019/35/D/NZ7/00174/National Science Center