Design, synthesis, and evaluation of carnosine derivatives as selective and efficient sequestering agents of cytotoxic reactive carbonyl species.
Carnosine aryl derivatives as sequestering agents of RCS: Reactive carbonyl species (RCS) are cytotoxic mediators representing a novel drug target, as they are presumed to play a pathogenic role in several diseases. Carnosine is a selective RCS-sequestering agent, but is rapidly hydrolyzed by serum carnosinase. Herein we describe the in silico design, synthesis, and evaluation of a set of carnosine aryl derivatives.Reactive carbonyl species (RCS) are important cytotoxic mediators generated by lipid oxidation of polyunsaturated fatty acids (PUFAs) and represent a novel drug target, as they are presumed to play a pathogenic role in several diseases. L-Carnosine (L-CAR, beta-alanyl-L-histidine) is a specific detoxifying agent of RCS, but is rapidly hydrolyzed in human serum by carnosinase, a specific dipeptidase. Herein we describe the in silico design, synthesis, and biological evaluation of carnosine derivatives that are resistant to carnosinase and that have increased quenching efficacy. Stability against carnosinase-mediated turnover was achieved by isomerization of the histidine residue, leading to D-carnosine (D-CAR, beta-alanyl-D-histidine), which maintains the same quenching activity of L-carnosine. A molecular modeling approach was then used to design derivatives characterized by an increased quenching efficacy. The most promising candidates were synthesized, and their stability and quenching activity were evaluated. This study describes a set of aryl derivatives that are characterized by high stability in human plasma and a quenching activity toward 4-hydroxy-trans-2-nonenal (HNE), chosen as a model of RCS, up to threefold greater than D-carnosine.
Vistoli
Giulio
G
Dipartimento di Scienze Farmaceutiche "Pietro Pratesi", Facoltà di Farmacia, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy.
Orioli
Marica
M
Pedretti
Alessandro
A
Regazzoni
Luca
L
Canevotti
Renato
R
Negrisoli
Gianpaolo
G
Carini
Marina
M
Aldini
Giancarlo
G
D000171:Acrolein / Q000737:chemistry / Q000633:toxicity; D000447:Aldehydes / Q000737:chemistry / Q000633:toxicity*; D002336:Carnosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D055598:Chemical Phenomena; D004150:Dipeptidases / Q000378:metabolism; D015195:Drug Design; D004355:Drug Stability; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation
D000447:Aldehydes; D002614:Chelating Agents; D005231:Fatty Acids, Unsaturated; C462359:tert-4-hydroxy-2-nonenal; D000171:Acrolein; D002336:Carnosine; D004150:Dipeptidases; C019673:aminoacyl-histidine dipeptidase