TY - JOUR
T1 - Antioxidant, prooxidant and cytotoxic activity of hydroxylated resveratrol analogues: Structure-activity relationship
AU - Murias, Marek
AU - Jäger, Walter
AU - Handler, Norbert
AU - Erker, Thomas
AU - Horvath, Zsuzsanna
AU - Szekeres, Thomas
AU - Nohl, Hans
AU - Gille, Lars
N1 - DOI: 10.1016/j.bcp.2004.12.001
Coden: BCPCA
Affiliations: Inst. of Pharmaceutical Chemistry, University of Vienna, A-1090 Vienna, Austria; Clin. Inst. Med. Chem. Lab. D., University of Vienna, A-1090 Vienna, Austria; Res. Inst. Pharmacol. Toxicol. O., Veterinary University of Vienna, A-1210 Vienna, Austria
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Import aus Scopus: 2-s2.0-14644442917
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PY - 2005
Y1 - 2005
N2 - Resveratrol (trans-3,4',5-trihydroxystilbene), a naturally occurring hydroxystilbene, is considered an essential antioxidative constituent of red wine possessing chemopreventive properties. However, resveratrol and even more its metabolite piceatannol were reported to have also cytostatic activities. In order to find out whether this is related to antioxidative properties of those compounds, we synthesized five other polyhydroxylated resveratrol analogues and studied structure-activity relationships between pro-/antioxidant properties and cytotoxicity. Radical scavenging experiments with O2.- (5,5-dimethyl-1-pyrroline-N-oxide/electron spin resonance (DMPO/ESR)) and 2,2-diphenyl-1-picrylhydrazyl (DPPH.) (photometry) revealed that 3,3',4',5-tetrahydroxystilbene (IC50: 2.69 œM; k 9: 443000 M-1 s-1), 3,4,4',5- tetrahydroxystilbene (IC50: 41.5 œM; k9: 882000 M -1 s-1) and 3,3',4,4',5,5'- hexahydroxystilbene (IC50: 5.02 œM), exerted a more than 6600-fold higher antiradical activity than resveratrol and its two other analogues. Furthermore, in HL-60 leukemic cells hydroxystilbenes with ortho-hydroxyl groups exhibited a more than three-fold higher cytostatic activity compared to hydroxystilbenes with other substitution patterns. Oxidation of ortho-hydroxystilbenes in a microsomal model system resulted in the existence of ortho-semiquinones, which were observed by ESR spectroscopy. Further experiments revealed that these intermediates undergo redox-cycling thereby consuming additional oxygen and forming cytotoxic oxygen radicals. In contrast to compounds with other substitution patterns hydroxystilbenes with one or two resorcinol groups (compounds 1 and 3) did not show an additional oxygen consumption or semiquinone formation. These findings suggest that the increased cytotoxicity of ortho-hydroxystilbenes is related to the presence of ortho-semiquinones formed during metabolism or autoxidation. Œ 2004 Elsevier Inc. All rights reserved.
AB - Resveratrol (trans-3,4',5-trihydroxystilbene), a naturally occurring hydroxystilbene, is considered an essential antioxidative constituent of red wine possessing chemopreventive properties. However, resveratrol and even more its metabolite piceatannol were reported to have also cytostatic activities. In order to find out whether this is related to antioxidative properties of those compounds, we synthesized five other polyhydroxylated resveratrol analogues and studied structure-activity relationships between pro-/antioxidant properties and cytotoxicity. Radical scavenging experiments with O2.- (5,5-dimethyl-1-pyrroline-N-oxide/electron spin resonance (DMPO/ESR)) and 2,2-diphenyl-1-picrylhydrazyl (DPPH.) (photometry) revealed that 3,3',4',5-tetrahydroxystilbene (IC50: 2.69 œM; k 9: 443000 M-1 s-1), 3,4,4',5- tetrahydroxystilbene (IC50: 41.5 œM; k9: 882000 M -1 s-1) and 3,3',4,4',5,5'- hexahydroxystilbene (IC50: 5.02 œM), exerted a more than 6600-fold higher antiradical activity than resveratrol and its two other analogues. Furthermore, in HL-60 leukemic cells hydroxystilbenes with ortho-hydroxyl groups exhibited a more than three-fold higher cytostatic activity compared to hydroxystilbenes with other substitution patterns. Oxidation of ortho-hydroxystilbenes in a microsomal model system resulted in the existence of ortho-semiquinones, which were observed by ESR spectroscopy. Further experiments revealed that these intermediates undergo redox-cycling thereby consuming additional oxygen and forming cytotoxic oxygen radicals. In contrast to compounds with other substitution patterns hydroxystilbenes with one or two resorcinol groups (compounds 1 and 3) did not show an additional oxygen consumption or semiquinone formation. These findings suggest that the increased cytotoxicity of ortho-hydroxystilbenes is related to the presence of ortho-semiquinones formed during metabolism or autoxidation. Œ 2004 Elsevier Inc. All rights reserved.
M3 - Article
SN - 0006-2952
VL - 69
SP - 903
EP - 912
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 6
ER -