Paper Citing NAMD - Abstract
Vistoli, Giulio; Orioli, Marica; Pedretti, Alessandro; Regazzoni, Luca; Canevotti, Renato; Negrisoli, Gianpaolo; Carini, Marina; Aldini, Giancarlo
Design, Synthesis, and Evaluation of Carnosine Derivatives as Selective and Efficient Sequestering Agents of Cytotoxic Reactive Carbonyl Species
CHEMMEDCHEM, 4:967-975, JUN 2009
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, P-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 camosine 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, P-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.
