Antioxidant activity of 4-methylcoumarins

Abstract

Polyphenolic coumarins are known to act as antioxidants in biological systems, but it is difficult to distinguish their antioxidant activity from the many other effects they produce in cells. We have determined the radical scavenging capacity of 22 structurally related natural and synthetic 4-methylcoumarins, by measuring their reaction with radicals, galvinoxyl and 2,2-diphenyl-1-picrylhydrazyl, using electron paramagnetic resonance spectroscopy. Efficient antioxidant activity of 4-methylcoumarins in cells was verified using the DCF fluorescent probe assay for determination of intracellular reactive oxygen species levels. As expected, the o-dihydroxysubstituted coumarins were found to be excellent radical scavengers and better than the m-dihydroxysubstituted or monohydroxysubstituted analogues, but surprisingly the corresponding o-diacetoxy derivatives also turned out to be good scavengers, even in the absence of an esterase. Another unexpected result was that the antioxidant efficiency of 4-methylcoumarins could be modulated by introducing an ethoxycarbonylethyl substituent at the C-3 position; this effect cannot be explained by simple electron donating/withdrawing properties. Coumarin concentrations of 10 microM or less were used in all experiments, corresponding to the levels relevant for therapeutic purposes. Considering that 4-methylcoumarins, in contrast to many other coumarins, are not metabolized to toxic epoxide intermediates, these results indicate promising new strategies for the design of non-toxic antioxidant coumarin-based drugs.

Structure–activity relationship studies of 4-methylcoumarin derivatives as anticancer agents

“…They are present at high levels in cinnamon and many fruits and vegetables (Krieger et al, 2013;Ribeiro da Silva et al, 2014). Different derivatives of these compounds possess a wide range of biological activities (Venugopala et al, 2013) such as antioxidant (Morabito et al, 2010;Natella et al, 2010;Pedersen et al, 2007), anti-inflammatory (Togna et al, 2014), antimicrobial (Gupta et al, 2012), and in vitro (Macakova et al, 2012) and in vivo platelet anti-aggregation effects .…”

4-Methylcoumarin Derivatives with Anti-inflammatory Effects in Activated Microglial Cells

“…23,26) 4-Methylcoumarin derivatives bearing 7,8-dihydroxy and 7,8-diacetoxy moieties have been reported to be potent antioxidant compounds. [12][13][14] Most of these reports have suggested that 7,8-dihydroxy confers higher activity compared to 7,8-diacetoxy, 13,14) probably due the important contribution of catechol moiety to the antioxidant activity. However, in some papers this difference seems to be minimal.…”

“…9,11,15,16) 4-Methylcoumarins bearing 7,8-ortho-dihydroxy or 7,8-orthodiacetoxy moieties have been found to be better radical scavengers and antioxidants. 12,17) On the other hand, the insertion of ethoxycarbonylmethyl moiety at C3 position does not lower the activity of these compounds and may increase the lipophilicity. 14) Increased lipophilicity is a very important physicochemical property that enables the compound to cross the cell membranes and reach its intracellular targets.…”

“…6) Recently, much attention has been focused on the anti-inflammatory activity of coumarin derivatives. [7][8][9][10] 4-Methylcoumarins, a subclass of coumarin compounds, are effective antioxidant [11][12][13][14] and anti-inflammatory agents. 9,11,15,16) 4-Methylcoumarins bearing 7,8-ortho-dihydroxy or 7,8-orthodiacetoxy moieties have been found to be better radical scavengers and antioxidants.…”

New compounds able to control hepatic cholesterol metabolism: Is it possible to avoid statin treatment in aged people?

“…Coumarins and their derivatives have attracted intense interest in recent years because of their diverse pharmacological properties: many coumarin derivatives have the special ability to scavenge reactive ROS and to influence processes involving free radical injury. In particular both esculetin and a novel synthetic 4-methylcoumarin, 4-methylesculetin (ESC), possess two hydroxyl moieties on their benzene rings, and these were the two most effective radical scavengers among the coumarins selected for a structure-activity relationship study in cell culture [41] . Beyond its antioxidant activity, ESC is able to lower HMGR activity reducing PP2A protein levels leading to HMGR hyperphosphorylation.…”