Coelenterazine (Marine Bioluminescent Substrate): A Source of Inspiration for the Discovery of Novel Antioxidants

Abstract

Coelenterazine and derivatives were initially considered in the scientific community for their (bio)luminescent properties. Now, another interest of such hetero-bicycles has been pointed out by the discovery of remarkable antioxidative properties, and an unique mode of action as a "cascade": the mother-compound (imidazolopyrazinone) is transformed by ROS into a daughter-compound (2-amino-pyrazine) also endowed with antioxidative properties. This review illustrates the therapeutic potential of synthetic imidazolopyrazinones (coelenterazine analogues): chemical reactivity assays with singulet oxygen, radical anion superoxide, peroxynitrite, and radicals formed during lipid and LDL peroxidation, cellular tests of protection against oxidative stress using keratinocyte, hepatocyte, neuronal and erythrocyte cells, and finally in vivo evaluation in a hamster model of ischemia-reperfusion, are fully described.

In vitro and in vivo studies of 6,8-(diaryl)imidazo[1,2-a]pyrazin-3(7H)-ones as new antioxidants

“…15 The so-produced amides 2, formally derived from aminopyrazines 3, were however inactive in antioxidant tests. 24,25 In the course of chemical and air oxidation studies of coelenterazine (1a), we observed the formation of coelenteramine (3a), in quite significant amounts, together with the expected coelenteramide (2a). This interesting observation was general: the oxidative degradation of imidazopyrazinones 1 led always to both amides 2 and aminopyrazines 3.…”

“…[18][19][20][21][22][23] A few years ago, our research group considered coelenterazine and other imidazopyrazinones 1 as potential leads in the discovery of novel antioxidants for therapeutic use. 24 We showed that imidazopyrazinones have good antioxidant properties as they are highly reactive with radical anion superoxide, lipid radicals, nitrofurantoin-derived radicals and peroxynitrite; LDL protection by compounds 1 has been further demonstrated in vitro. Finally, cellular protection against oxidative stress and UV-irradiation damages has been observed, in the presence of compounds 1, on various cell lines (human keratinocytes, rat hepatocytes, rat neuronal cells, fish erythrocytes).…”

“…Finally, cellular protection against oxidative stress and UV-irradiation damages has been observed, in the presence of compounds 1, on various cell lines (human keratinocytes, rat hepatocytes, rat neuronal cells, fish erythrocytes). 24 During these previous studies, we found that the chemical precursors of imidazopyrazinones synthesis, namely the 2-amino-1,4-pyrazine derivatives 3, are also endowed with remarkable antioxidant properties providing R 3 is a para-phenol (or a catechol) moiety. 25,26 The main metabolite of luciferase-catalyzed oxidation of coelenterazine (1a) is coelenteramide (2a) which is initially produced in the excited state; this species emits light during decay (Scheme 1).…”

Development of a High-Throughput Gaussia Luciferase Reporter Assay for the Activation of the GADD45a Gene by Mutagens, Promutagens, Clastogens, and Aneugens

“…This can be increased by inclusion of hydroxypropyl-β-cyclodextrin. 22 Coelenterazine is also sensitive to oxidative degradation, 23 and previous authors have demonstrated that antioxidants, such as vitamin C, can increase its stability. 24 In this study, we demonstrate that control of pH effectively stabilizes the signal for the duration of data collection.…”

Chemical, biological and evolutionary aspects of beetle bioluminescence

“…39 Recently, Dubuisson et al reviewed the striking antioxidative properties of coelenterazines and derivatives towards singlet oxygen, peroxynitrite, radical anion superoxide and other radicals, thereby affording protection against oxidative injury promoted, for example, by tert-butyl hydroperoxide to cells and ischemia-reperfusion in hamster. 40 These authors emphasize the therapeutic potential of synthetic imidazolopyrazinones (coelenterazine analogs).…”