Acid-promoted reaction of the stilbene antioxidant resveratrol with nitrite ions: mild phenolic oxidation at the 4'-hydroxystiryl sector triggering nitration, dimerization, and aldehyde-forming routes.
In 0.1 M phosphate buffer, pH 3.0, and at 37 degrees C, resveratrol ((E)-3,4',5-trihydroxystilbene, 1a), an antioxidant and cancer chemopreventive phytoalexin, reacted smoothly at 25 microM or 1 mM concentration with excess nitrite ions (NO2(-)) to give a complex pattern of products, including two novel regioisomeric alpha-nitro (3a) and 3'-nitro (4) derivatives along with some (E)-3,4',5-trihydroxy-2,3'-dinitrostilbene (5), four oxidative breakdown products, 4-hydroxybenzaldehyde, 4-hydroxy-3-nitrobenzaldehyde, 3,5-dihydroxyphenylnitromethane, and 3,5-dihydroxybenzaldehyde, two dimers, the resveratrol (E)-dehydrodimer 6 and restrytisol B (7), and the partially cleaved dimer 2. The same products were formed in the absence of oxygen. 1H,15N HMBC and LC/MS analysis of the crude mixture obtained by reaction of 1a with Na (15)NO2 suggested the presence of 3,4',5,beta-tetrahydroxy-alpha-nitro-alpha,beta-dihydrostilbene (8) as unstable intermediate which escaped isolation. Under similar conditions, the structurally related catecholic stilbene piceatannol ((E)-3,3',4,5'-tetrahydroxystilbene, 1b) gave, besides (E)-3,3',4,5'-tetrahydroxy-beta-nitrostilbene (3b), 3,4-dihydroxybenzaldehyde and small amounts of 3,5-dihydroxybenzaldehyde. Mechanistic experiments were consistent with the initial generation of the phenoxyl radical of 1a at 4'-OH, which may undergo free radical coupling with NO2 at the alpha- or 3'-position, to give eventually nitrated derivatives and/or oxidative double bond fission products, or self-coupling, to give dimers. The oxygen-independent, NO2(-)-mediated oxidative fission of the double bond under mild, physiologically relevant conditions is unprecedented in stilbene chemistry and is proposed to involve breakdown of hydroxynitro(so) intermediates of the type 8.
Panzella
Lucia
L
Department of Organic Chemistry and Biochemistry, delle Piante e dell'Ambiente, University of Naples Federico II, Naples, Italy.
De Lucia
Maria
M
Amalfitano
Carmine
C
Pezzella
Alessandro
A
Evidente
Antonio
A
Napolitano
Alessandra
A
d'Ischia
Marco
M
D000143:Acids / Q000737:chemistry*; D000447:Aldehydes / Q000138:chemical synthesis*; D000975:Antioxidants / Q000737:chemistry*; D019281:Dimerization; D007477:Ions / Q000737:chemistry; D015394:Molecular Structure; D009573:Nitrites / Q000737:chemistry*; D010084:Oxidation-Reduction; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry*
D000143:Acids; D000447:Aldehydes; D000975:Antioxidants; D007477:Ions; D009573:Nitrites; D013267:Stilbenes; D000077185:Resveratrol