Reactive carbonyl species (RCS) are typical products of degradative oxidative pathway of endogenous compounds such as sugars, polyunsaturated fatty acids and proteins. Indeed, RCS are important cytotoxic mediators as they are supposed to play a pathogenic role in several diseases including renal, hepatic, neurodegenerative diseases, diabetes and atherosclerosis. In the last few years, L-carnosine (b-Alanine-L-Histidine), an endogenous dipeptide present in millimolar concentrations in some tissues, was found to be a selective detoxifying agent of RCS. It is actively absorbed by hPepT1, but is rapidly hydrolyzed in human serum by carnsosinase, a specific dipeptidase, thus preventing an effective therapeutic application. Hence, the rational design of new carnosine analogues should increase the quenching activity of carnosine, maintain its selectivity, confer plasma stability against human serum carnosinase, and conserve an optimal recognition by hPepT1. As a result, a consistent variety of carnosine analogues have been hitherto synthesized such as derivatives bearing hydrazide or 1,2-diol moieties , and carbonamide derivatives bearing on the amide nitrogen alkyl or aryl groups . On the contrary, carnosine derivatives modified at the ring portion have been never reported in literature, despite the remarkable role of the nucleophilicity of the heterocyclic residue in the quenching activity. Consequently, we have designed and synthesized a set of analogues of carnosine with tiophene, furane, or pyrrole in place of imidazole. The choice of the three heteroaryl moieties has been driven by an in silico prediction of nucleophilicity based on quantummechanical simulations. RCS quenching ability was evaluated by monitoring the consumption of 4-hydroxy-trans-2-nonenal (HNE) and the reaction products identified and characterized by direct infusion high resolution MS (Orbitrap as MS analyzer).
Heteroaryl carnosine analogues: design, synthesis and carbonyl quenching activity / L. Fumagalli, C. Bolchi, M. Pallavicini, V. Straniero, L.G. Regazzoni, M. Carini, G. Aldini, G. Vistoli, E. Valoti. ((Intervento presentato al convegno Frontiers in medicinal chemistry meeting tenutosi a Stockholm nel 2011.
|Titolo:||Heteroaryl carnosine analogues: design, synthesis and carbonyl quenching activity|
|Data di pubblicazione:||19-giu-2011|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
|Enti collegati al convegno:||European Federation of Medicinal chemistry|
American Chemical society division of medicinal chemistry
Swedish Academy of Pharmaceutical Sciences
|Citazione:||Heteroaryl carnosine analogues: design, synthesis and carbonyl quenching activity / L. Fumagalli, C. Bolchi, M. Pallavicini, V. Straniero, L.G. Regazzoni, M. Carini, G. Aldini, G. Vistoli, E. Valoti. ((Intervento presentato al convegno Frontiers in medicinal chemistry meeting tenutosi a Stockholm nel 2011.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|