linoleic-acid and coelenterazine

Coelenterazine is a luciferin found in many marine bioluminescent organisms. This luciferin also possesses high antioxidant properties and an exceptional ability to protect cells exposed to oxidative stress. It has been suggested that coelenterazine's antioxidative mechanisms include the formation of an oxidation product, coelenteramine, also endowed with chain-breaking properties. In this work, coelenterazine analogs were shown to delay the onset of lipid peroxidation in a linoleate micellar solution exposed to free radical initiators. Their consumption was accompanied by the concomitant formation of coelenteramine. This was followed by a reduction in the peroxidation rate coinciding with the consumption of coelenterazine's oxidation product coelenteramine. The addition of coelenteramine to micelles reduced the propagation rate of the oxidative process. When coelenterazine analogs oxidizing into an inactive analog of coelenteramine were applied, the delaying effect but not the reduced peroxidation rate nor the consumption of the aminopyrazine was observed. These results demonstrate the role of the oxidation product coelenteramine in the chain-breaking properties of coelenterazine and analogs.

Topics: Amidines; Antioxidants; Free Radicals; Imidazoles; Linoleic Acid; Lipid Metabolism; Lipid Peroxidation; Micelles; Molecular Structure; Nitriles; Oxidation-Reduction; Pyrazines; Structure-Activity Relationship; Time Factors

Coelenterazine (2-p-hydroxybenzyl-6-(3'-hydroxyphenyl)-8-benzyl-3,7-dihydroimidazolo[1,2-a]pyrazin-3-one, CLZn) and coelenteramine (2-amino-3-benzyl-5-(4'-hydroxyphenyl)-1,4-pyrazine, CLM), first described as luciferin and etioluciferin, respectively, of bioluminescent systems in marine organisms are endowed with antioxidant properties. This study was aimed at understanding the structural basis of their chain-breaking properties and at designing new compounds with improved antioxidative properties. For this, a series of 2-amino-1,4-pyrazine derivatives and their related imidazolopyrazinones were synthesised and examined for their capacity to inhibit lipid peroxidation in linoleate micelles subjected to the peroxidizing action of AAPH. Structure-activity relationship studies indicated that the reduction of the peroxidation rate by CLM is mainly determined by the concomitant presence of 5-p-hydroxyphenyl and 2-amino groups in para position. The lipophilic character of substituents also affected this effect. All imidazolopyrazinones induced a lag-time before the onset of the peroxidation process. The hetero-bicyclic imidazolopyrazinone moiety appears as the main contributor to this activity while phenol groups play little role in it. On the other hand, phenol groups were required for the reduction of the peroxidation rate after the lag-phase. The introduction of a supplementary p-hydroxyphenyl substituent at C8 position did not increase chain-breaking properties. The substitution of the C5-p-hydroxyphenyl with a catechol moiety or the introduction of a second amino group on the pyrazine ring yielded the most active compounds, superior to imidazolopyrazinones and reference antioxidants like epigallocatechin gallate, vitamin E and trolox. The strong antioxidant properties of 2,6-diaminopyrazines are not dependent on the presence of hydroxyl groups indicating that their reaction mechanism differs from that of 2-amino-1,4-pyrazine derivatives.

Topics: Antioxidants; Imidazoles; Linoleic Acid; Lipid Peroxidation; Micelles; Models, Chemical; Oxygen; Pyrazines; Structure-Activity Relationship; Time Factors