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

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

Mladena Glavaš  1   2 , Agata Gitlin-Domagalska  1 , Natalia Ptaszyńska  1 , Dominika Starego  1 , Sylwia Freza  3 , Dawid Dębowski  1 , Aleksandra Helbik-Maciejewska  1 , Anna Łęgowska  1 , Chaim Gilon  4 , Krzysztof Rolka  1
Affiliations

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

Mladena Glavaš et al. Molecules. .

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(a) The most prevalent guanidinylating reagents; (b) general structure of N-triflyl guanidines (E) and its derivatives N,N′-di-Boc-N″-triflylguanidine (F) and N,N′-di-Cbz-N″triflylguanidine (G).
Figure 2
Figure 2
Arginine derivatives with masked side chain (Ts = tosyl group; Hoc = hexyloxycarbonyl).
Scheme 1
Scheme 1
Synthetic pathway for the preparation of arginine building blocks with increased lipophilicity via guanidinylation of Fmoc-Orn.
Figure 3
Figure 3
Structure of AVP and its analogues. Pr = propyloxycarbonyl; Bu = butyloxycarbonyl; Hoc = hexyloxycarbonyl.
See this image and copyright information in PMC

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