Arylnitroalkenes as scavengers of macrophage-generated oxidants.
Oxygen and nitrogen derived molecules mediated oxidation and nitration have been involved in several pathological conditions. Conversely, nitric oxide and hydrogen peroxide are important signalization intermediates, whose concentrations are tightly regulated by specialized enzyme repertoires and should remain undisturbed by the addition of exogenous antioxidant molecules, as already demonstrated by intervention studies with antioxidant vitamins. Our goal was to develop specific antioxidants able to scavenge peroxynitrite anion, as well the radicals derived from the homolytic decomposition of its conjugated acid, nitrogen dioxide and hydroxyl radical. Fourteen substituted nitroalkenes, seven 4-substituted 1-(2-nitro-1Z-ethenyl)benzene, and seven 4-substituted (2-nitro-1Z-propenyl)benzene, with different stereochemical and electronic characteristics were synthesized and tested. Compounds with the electron donor group N,N-dimethylamino showed the highest reaction rates against peroxynitrite, and also reacted with its homolytic decomposition products, OH and NO₂. While 1,1-dimethylamino-4-(2-nitro-1Z-ethenyl)benzene came up as a lead for future developments without the risk of interfering with signalization pathways, since it was highly specific for peroxynitrite and peroxynitrite derived radicals, its methylated analogous 1,1-dimethylamino-4-(2-nitro-1Z-propenyl)benzene was less specific and also reacted with NO and O₂(-), the biological precursor of H₂O₂.
Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Iguá 4225, Montevideo 11400, Uruguay; Center for Free Radicals and Biomedical Research, Facultad de Medicina, Universidad de la República, Gral. Flores 2125, Montevideo 11800, Uruguay.
Laura
L
Celano
Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Iguá 4225, Montevideo 11400, Uruguay.
Claudio
C
Carabio
Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, Iguá 4225, Montevideo 11400, Uruguay.
Renata
R
Frache
Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Iguá 4225, Montevideo 11400, Uruguay; Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, Iguá 4225, Montevideo 11400, Uruguay.
Nicolás
N
Cataldo
Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, Iguá 4225, Montevideo 11400, Uruguay.
Hugo
H
Cerecetto
Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, Iguá 4225, Montevideo 11400, Uruguay. Electronic address: megonzal@fq.edu.uy.
Mercedes
M
González
Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Iguá 4225, Montevideo 11400, Uruguay; Center for Free Radicals and Biomedical Research, Facultad de Medicina, Universidad de la República, Gral. Flores 2125, Montevideo 11800, Uruguay. Electronic address: leonorthomson@gmail.com.
Leonor
L
Thomson
D000475:Alkenes / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism*
D000475:Alkenes; D016877:Oxidants
Antioxidants; Nitric oxide; Nitroalkenes; Nitrogen dioxide; Peroxynitrite; Scavengers