Natural and newly synthesized hydroxy-1-aryl-isochromans: A class of potential antioxidants and radical scavengers

Abstract

We investigated the antioxidant and radical scavenging activity of polyphenolic isochromans. To assess the relation between structure and scavenging properties the natural occurring 1-(3′-methoxy-4′-hydroxy)phenyl-6,7-dihydroxy-isochroman (ISO-3, three OH groups) was compared with three newly synthesized derivatives that differ in their degree of hydroxylation by substitution with methoxy-groups (ISO-4: four OH groups; ISO-2: two OH groups and ISO-0: fully methoxylated). We found that ISO-4 is a 2-fold better scavenger for the artificial radical 1,1-diphenyl-2-picrylhydrazyl (DPPH, 100 μM) with an EC₅₀=10.3 μM compared to the natural ISO-3 (EC₅₀=22.4 μM) and to ISO-2 (EC₅₀=25.1 μM), while ISO-0 did not react with DPPH. The scavenging capacity for superoxide enzymatically generated in a hypoxanthin-xanthinoxidase reaction was the highest for ISO-4 (EC₅₀=34.3 μM) compared to those of ISO-3 (EC₅₀=84.0 μM) and ISO-2 (EC₅₀=91.8 μM), while ISO-0 was inactive. In analogy, ISO-4 scavenged peroxynitrite (ONOO⁻, EC₂₅=23.0 μM) more effective than ISO-3, ISO-2 and ISO-0.

When C6 rat glioma cells loaded with the reactive oxygen/nitrogen (ROS/RNS)-sensitive fluorochrome 2,7-dichlorodihydrofluorescein, were exposed to hydrogen peroxide, the lowest stress level as indicated by the fluorescence signal was detected when the cells were pretreated with ISO-4 or ISO-2 but to a much lesser extent with ISO-3, while ISO-0 did not show any effect. All tested hydroxyisochromans superceded the scavenging effect of trolox.

The excellent radical and ROS/RNS scavenging features of the hydroxy-1-aryl isochromans and their simple synthesis let these compounds appear to be interesting candidates for pharmaceutical interventions that protect against the deleterious action of ROS/RNS.

• Hydroxyisochromans
• reactive oxygen species
• hydrogen peroxide
• reactive nitrogen species
• peroxynitrite
• astrocytes