Structural aspects of antioxidant activity of substituted pyridoindoles

Abstract

Stobadine and its two structural analogues, dehydrostobadine and N-acetylated stobadine were used to examine how structural alteration in the close proximity of the indolic nitrogen would influence the antioxidant activity of the substituted pyridoindoles. The compounds were tested for their efficiency to scavenge stable free radicals of alpha,alpha'-diphenyl-beta-picrylhydrazyl as well as for their ability to prevent 2,2'-azobis-(2-amidinopropane)hydrochloride induced peroxidation of dioleoyl phosphatidylcholine liposomes. The results proved that the substituted pyridoindoles can act as potent scavengers of peroxyl radicals both in aqueous and lipid phases, the antioxidant activity being comparable with that of Trolox. Structural changes in the proximity of the indolic nitrogen were found crucial for the radical scavenging efficiency: aromatisation of the pyridoindole skeleton in dehydrostobadine lowered the antioxidant activity, while acetylation of the indolic nitrogen completely abolished the ability to scavenge peroxyl radicals. The results are in agreement with the notion that the antioxidant activity of stobadine and of the related pyridoindoles may be mediated via the indolic nitrogen centre. When stobadine and Trolox were present simultaneously in liposomal incubations, Trolox spared stobadine in a dose-dependent manner; a direct interaction of Trolox with stobadinyl radical appears to be a plausible explanation with possible consequences for the antioxidant capacity of stobadine under in vivo conditions, where re-cycling of stobadine by vitamin E might occur.

Substituted derivatives of indole acetic acid as aldose reductase inhibitors with antioxidant activity: structure-activity relationship

“…All compounds studied, with exception of 1-indole acetic acid, were found to have higher antiradical activity in comparison with melatonin, a 3-substituted indole derivative used as a structurally related reference antioxidant. The absence of the scavenging ability of 1-indole acetic acid is in compliance with the notion according to which the prerequisite of the antiradical activity of the indole derivatives is the presence of free hydrogen at this nitrogen (Rackova et al 2002). By its splitting, resonance stabilized indolyl radical is created, the stability of which is affected by the presence of aromatic substituents.…”

Stobadine – An Indole Type Alternative to the Phenolic Antioxidant Reference Trolox

“…In the ethanolic solution, trolox scavenged 1,1`-diphenyl-2-picrylhydrazyl (DPPH) radical more efficiently than did stobadine, based on the initial velocity measurements (Rackova et al, 2002). The finding was corroborated by the respective rate constants (Rackova et al, 2004) as shown in Table 2.…”

“…Indeed, Steenken et al (1992) in their pulse radiolytic study demonstrated the ability of trolox to recycle stobadine from its one-electron oxidation product, to give a corresponding trolox phenoxyl radical. When stobadine and trolox were present simultaneously in oxidatively stressed liposomes, trolox spared stobadine in the system in a dose-dependent manner (Rackova et al, 2002). Direct interaction of trolox with the stobadinyl radical resulting in the recovery of parent stobadine molecule appears to be a plausible mechanism.…”

“…As a result of the acidobasic equilibrium, the corresponding distribution ratios at pH 7 of trolox and stobadine, D = 0.33 (Barclay et al, 1995) and 3.72 (Kagan et al, 1993), respectively, clearly favour partitioning of stobadine into the lipid phase, yet not that of trolox. This may explain the profound drop of the apparent antioxidant efficiency of trolox in experimental models involving membranous systems (Horakova et al, 2003;Juskova et al, 2010;Rackova et al, 2002;Rackova et al, 2004;Stefek et al, 2008).…”

Antioxidant action of the hexahydropyridoindole SMe1EC2 in the cellular system of isolated red blood cellsin vitro

“…[5][6][7] Modification of the stobadine molecule by aromatic electron-donating substitution was reported to enhance the intrinsic free radical scavenging activity, while variations of the N2 substituent afforded a synthetically accessible way to modulate the biological availability by affecting both lipophilicity and basicity of the molecule, without changing significantly the free radical scavenging activity. [5][6][7] Among the novel derivatives, the compound (±)-cis-8-methoxy-2,3,4,4a,5,9b-hexahydro-1H-pyrido [4,3-b] indole-2-carboxylic acid ethyl ester (SMe1EC2) (Fig. 1) has been subject of extensive preclinical studies.…”