title: Reactivity, Selectivity, and Reaction Mechanisms of Aminoguanidine, Hydralazine, Pyridoxamine, and Carnosine as Sequestering Agents of Reactive Carbonyl Species: A Comparative Study.
abstract: Reactive carbonyl species (RCS) are endogenous or exogenous byproducts involved in the pathogenic mechanisms of different oxidative-based disorders. Detoxification of RCS by carbonyl quenchers is a promising therapeutic strategy. Among the most studied quenchers are aminoguanidine, hydralazine, pyridoxamine, and carnosine; their quenching activity towards four RCS (4-hydroxy-trans-2-nonenal, methylglyoxal, glyoxal, and malondialdehyde) was herein analyzed and compared. Their ability to prevent protein carbonylation was evaluated in vitro by using an innovative method based on high-resolution mass spectrometry (HRMS). The reactivity of the compounds was RCS dependent: carnosine efficiently quenched 4-hydroxy-trans-2-nonenal, pyridoxamine was particularly active towards malondialdehyde, aminoguanidine was active towards methylglyoxal and glyoxal, and hydralazine efficiently quenched all RCS. Reaction products were generated in vitro and were characterized by HRMS. Molecular modeling studies revealed that the reactivity was controlled by specific stereoelectronic parameters that could be used for the rational design of improved carbonyl quenchers.
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, via Mangiagalli, 25, 20133, Milano, Italy. mara.colzani@unimi.it.
authors.forename: Mara
authors.identifier: http://orcid.org/0000-0003-3395-2537
authors.initials: M
authors.lastname: Colzani
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, via Mangiagalli, 25, 20133, Milano, Italy.
authors.forename: Danilo
authors.initials: D
authors.lastname: De Maddis
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, via Mangiagalli, 25, 20133, Milano, Italy.
authors.forename: Gaia
authors.initials: G
authors.lastname: Casali
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, via Mangiagalli, 25, 20133, Milano, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Carini
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, via Mangiagalli, 25, 20133, Milano, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Vistoli
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, via Mangiagalli, 25, 20133, Milano, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Aldini
mesh_terms: D000447:Aldehydes / Q000037:antagonists & inhibitors*; D002336:Carnosine / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006037:Glyoxal / Q000037:antagonists & inhibitors*; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006830:Hydralazine / Q000737:chemistry / Q000494:pharmacology; D008315:Malondialdehyde / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D011733:Pyridoxamine / Q000737:chemistry / Q000494:pharmacology; D011765:Pyruvaldehyde / Q000037:antagonists & inhibitors*; D064449:Sequestering Agents / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000447:Aldehydes; D006146:Guanidines; D064449:Sequestering Agents; D006830:Hydralazine; D008315:Malondialdehyde; D006037:Glyoxal; D011733:Pyridoxamine; D011765:Pyruvaldehyde; D002336:Carnosine; C027576:4-hydroxy-2-nonenal; C004479:pimagedine
keywords: carbonyl quenching; liquid chromatography; mass spectrometry; molecular modeling; reactive carbonyl species