Antioxidant activity of 4-methylcoumarins.
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.
Pedersen
Jens Z
JZ
Department of Biology, University of Rome Tor Vergata, Italy. jzp@ofir.dk
Oliveira
Cristina
C
Incerpi
Sandra
S
Kumar
Vineet
V
Fiore
Anna Maria
AM
De Vito
Paolo
P
Prasad
Ashok K
AK
Malhotra
Sanjay V
SV
Parmar
Virinder S
VS
Saso
Luciano
L
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D001559:Benzhydryl Compounds / Q000737:chemistry / Q000494:pharmacology; D001713:Biphenyl Compounds; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D015394:Molecular Structure; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010851:Picrates / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013871:Thiones / Q000737:chemistry / Q000494:pharmacology
D000975:Antioxidants; D001559:Benzhydryl Compounds; D001713:Biphenyl Compounds; D003374:Coumarins; D016166:Free Radical Scavengers; D010851:Picrates; D017382:Reactive Oxygen Species; D013871:Thiones; C004931:1,1-diphenyl-2-picrylhydrazyl; C020338:galvinoxyl