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Exploring Secondary Amine Carnosine Derivatives: Design, Synthesis, and Properties

Authors :
Angelica Artasensi
Sarah Mazzotta
Ines Sanz
Licheng Lin
Giulio Vistoli
Laura Fumagalli
Luca Regazzoni
Source :
Molecules, Vol 29, Iss 21, p 5083 (2024)
Publication Year :
2024
Publisher :
MDPI AG, 2024.

Abstract

Carnosine is a naturally occurring dipeptide that has been advocated by some authors as an interesting scaffold for the development of potential therapeutic agents in view of the positive outcomes of its supplementation in animal models of human diseases. Its mode of action seems to depend on the quenching of toxic electrophiles, such as 4–hydroxynonenal (HNE). However, carnosine’s bioavailability in humans is lower than that in other mammals. The main reason for such an unfavorable pharmacokinetic profile is the activity of the enzyme human serum carnosinase (E.C. 3.4.13.20), which rapidly hydrolyzes carnosine upon absorption. Therefore, some studies have focused on the design of carnosinase-resistant derivatives that retain binding activity toward toxic electrophiles. Nevertheless, the structural modification of the N-terminus amino group of carnosine has rarely been considered, possibly because of its key role in the electrophile scavenging mechanism. This was proven, since some carnosine N-terminus modification generated inactive compounds, despite some derivatives retaining oral bioavailability and gaining resistance to carnosinase hydrolysis. Herein, we therefore report a study aimed at exploring whether the amino group of carnosine can be conveniently modified to develop carnosinase-resistant derivatives retaining the dipeptide activity toward toxic electrophiles.

Details

Language :
English
ISSN :
14203049
Volume :
29
Issue :
21
Database :
Directory of Open Access Journals
Journal :
Molecules
Publication Type :
Academic Journal
Accession number :
edsdoj.59c456df0a1b4c9d8f2ac0beb4da3cfc
Document Type :
article
Full Text :
https://doi.org/10.3390/molecules29215083