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Inami K.,University of Tokyo | Inami K.,Tokyo University of Science | Iizuka Y.,University of Tokyo | Furukawa M.,University of Tokyo | And 7 more authors.
Bioorganic and Medicinal Chemistry | Year: 2012

Synthetic 6-chromanol derivatives were prepared with several chlorine substitutions, which conferred both electron-withdrawing inductive effects and electron-donating resonance effects. A trichlorinated compound (2), a dichlorinated compound (3), and three monochlorinated compounds (4, 5, and 6) were synthesized; compounds 2, 3, and 6 were novel. The antioxidant activities of the compounds, evaluated in terms of their capacities to scavenge galvinoxyl radical, were associated with the number and positioning of chlorine atoms in the aromatic ring of 6-chromanol. The activity of compound 1 (2,2-dimethyl-6-chromanol) was slightly higher than the activities of compounds 2 (2,2-dimethyl-5,7-dichloro-6-chromanol) or 3 (2,2-dimethyl-5,7,8-trichloro-6- chromanol), in which the chlorine atoms were ortho to the phenolic hydroxyl group of 6-chromanol. The scavenging activity of compound 3 was slightly higher than that of 2, which contained an additional chlorine substituted in the 8 position. The activities of polychlorinated compounds 2 and 3 were higher than the activities of any of the monochlorinated compounds (4-6). Compound 6, in which a chlorine was substituted in the 8 position, exhibited the lowest activity. Substitution of a chlorine atom meta to the hydroxyl group of 6-chromanol (compounds 2 and 6) decreased galvinoxyl radical scavenging activity, owing to the electron-withdrawing inductive effect of chlorine. Positioning the chloro group ortho to the hydroxyl group (compounds 4 and 5) retained antioxidant activity because the intermediate radical was stabilized by the electron-donating resonance effect of chlorine in spite of the electron-withdrawing inductive effect of chlorine. Antioxidant activities of the synthesized compounds were evaluated for correlations with the O-H bond dissociation energies (BDEs) and the ionization potentials. The BDEs correlated with the second-order rate constants (k) in the reaction between galvinoxyl radical and the chlorinated 6-chromanol derivatives in acetonitrile. This indicated that the antioxidant mechanism of the synthesized compounds consisted of a one-step hydrogen atom transfer from the phenolic OH group rather than an electron transfer followed by a proton transfer. The synthesized compounds also exhibited hydroxyl radical scavenging capacities in aqueous solution. © 2012 Elsevier Ltd. All rights reserved.

Kawashima T.,Radio Redox Response Research Team | Manda S.,Radio Redox Response Research Team | Uto Y.,Tokushima University | Ohkubo K.,Osaka University | And 11 more authors.
Bulletin of the Chemical Society of Japan | Year: 2012

The kinetics for the reaction of the 2,2-diphenyl-1-picrylhydrazyl radical (DPPḢ) with artepillin C, a prenylated phenylpropanoid found specifically in Brazilian propolis, and its analogues was examined in deaerated acetonitrile (MeCN) to shed light on the mechanism for the radical-scavenging reaction of phenolic antioxidants as well as on the structureactivity relationship. Among the examined analogues, a compound having a catechol moiety is found to have the largest second-order rate constant (k) for the DPPḢ-scavenging reaction. The deuterium kinetic isotope effect of 1.6 was observed for the DPPḢ-scavenging reaction of artepillin C in the presence of 0.13M CD 3OD or CH 3OH in deaerated MeCN at 298 K. The log k values were found to be linearly correlated with calculated energy difference values (DHT, HT: hydrogen transfer) between the artepillin C analogues and the corresponding phenoxyl radicals, while such a linear correlation cannot be observed between the log k values and calculated ionization potentials (IP), DHT 1 IP, or experimental one-electron-oxidation potentials of the artepillin C analogues. These results together with a calculated structure of the transition state for the reaction between the artepillin C analogue and DPPḢ suggest that the DPPḢ- scavenging reaction of the artepillin C analogues in deaerated MeCN proceeds via a one-step hydrogen-atom transfer from the phenolic OH group to DPPḢ rather than an electron transfer followed by proton transfer. © 2012 The Chemical Society of Japan.

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