Inhibition of 6-hydroxydopamine-induced oxidative damage by 4,5-dihydro-3H-2-benzazepine N-oxides

A number of new analogs of 3,3-dimethyl-4,5-dihydro-3H-2-benzazepine 2-oxide, structurally related to the nitrone spin trap α-phenyl-N-tert-butylnitrone (PBN), were synthesized and evaluated for their activity in vitro as protectants against oxidative stress induced in rat brain mitochondria by 6-hydroxydopamine (6-OHDA), a neurotoxin producing experimental model of Parkinson's disease (PD). As assessed by a fluorimetric assay, all 2-benzazepine-based nitrones were shown to decrease hydroxyl radicals ({radical dot}OH) generated during 6-OHDA autoxidation. The inhibition effects on the {radical dot}OH formation shown by the 5-gem-dimethyl derivatives, 2-4 times higher than those of the corresponding 5-methyl derivatives, were attributed to the flattening effect of the 5-gem-dimethyl group on the azepine ring, which should enhance nitrone reactivity and/or increase stability of the radical adducts. In contrast, owing to steric hindrance, a methyl group to C-1 diminishes the {radical dot}OH-scavenging activity of the nitrone group. All the assayed compounds were more potent than PBN as inhibitors of 6-OHDA-induced lipid peroxidation (LPO) and protein carbonylation (PCO), taken as an indicator of mitochondrial protein oxidative damage. The most promising antioxidant (compound 11), bearing 5-gem-dimethyl and spiro C-3 cyclohexyl groups, highlighted in this study as the best features, inhibited LPO and PCO with IC50 values of 20 and 48 μM, respectively, showing a potency improvement over PBN of two order magnitude. Both LPO and PCO inhibition potency data were found primarily related to the {radical dot}OH-scavenging activities, whereas lipophilicity plays a role in improving the LPO (but not PCO) inhibition, as a statistically valuable two-parameter equation proved. © 2008 Elsevier Inc. All rights reserved.

Soto-Otero R.1 , Méndez-Álvarez E.1 , Sánchez-Iglesias S.1 , Zubkov F.I. 2 , Voskressensky L.G. 2 , Varlamov A.V. 2 , De Candia M. , Altomare C.3
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  • 1 Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Santiago de Compostela, Santiago de Compostela, Spain
  • 2 Organic Chemistry Department, the Russian Peoples Friendship University, Moscow, Russian Federation
  • 3 Dipartimento Farmaco-chimico, Facoltà di Farmacia, Università degli Studi di Bari, Via E. Orabona 4, I-70125 Bari, Italy
Ключевые слова
2-Benzazepine nitrones; 6-Hydroxydopamine; Lipid peroxidation; Neuroprotection; Protein carbonylation; Radical scavengers
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