Murias Marek, Jäger Walter, Handler Norbert, Erker Thomas, Horvath Zsuzsanna, Szekeres Thomas, Nohl Hans, Gille Lars
Institute of Pharmaceutical Chemistry, University of Vienna, A-1090 Vienna, Austria.
Biochem Pharmacol. 2005 Mar 15;69(6):903-12. doi: 10.1016/j.bcp.2004.12.001.
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 O(2)(*-) (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 (IC(50): 2.69microM; k(9): 443000M(-1)s(-1)), 3,4,4',5-tetrahydroxystilbene (IC(50): 41.5microM; k(9): 882000M(-1)s(-1)) and 3,3',4,4',5,5'-hexahydroxystilbene (IC(50): 5.02microM), 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.
白藜芦醇（反式 - 3,4',5 - 三羟基芪）是一种天然存在的羟基芪，被认为是红葡萄酒中具有化学预防特性的重要抗氧化成分。然而，据报道白藜芦醇及其代谢产物piceatannol也具有细胞生长抑制活性。为了弄清楚这是否与这些化合物的抗氧化特性有关，我们合成了其他五种多羟基化白藜芦醇类似物，并研究了前体/抗氧化特性与细胞毒性之间的构效关系。用超氧阴离子（O(2)(*-)）（5,5 - 二甲基 - 1 - 吡咯啉 - N - 氧化物/电子自旋共振（DMPO/ESR））和2,2 - 二苯基 - 1 - 苦基肼（DPPH）（光度法）进行的自由基清除实验表明，3,3',4',5 - 四羟基芪（IC(50)：2.69微摩尔；k(9)：443000M(-1)s(-1)）、3,4,4',5 - 四羟基芪（IC(50)：41.5微摩尔；k(9)：882000M(-1)s(-1)）和3,3',4,4',5,5'-六羟基芪（IC(50)：5.02微摩尔）的抗自由基活性比白藜芦醇及其另外两种类似物高6600倍以上。此外，在HL - 60白血病细胞中，与具有其他取代模式的羟基芪相比，具有邻位羟基的羟基芪表现出高三倍以上的细胞生长抑制活性。在微粒体模型系统中，邻位羟基芪的氧化导致邻位半醌的存在，这通过ESR光谱观察到。进一步的实验表明，这些中间体进行氧化还原循环，从而消耗额外的氧气并形成细胞毒性氧自由基。与具有其他取代模式的化合物不同，具有一个或两个间苯二酚基团的羟基芪（化合物1和3）没有显示出额外的氧气消耗或半醌形成。这些发现表明，邻位羟基芪细胞毒性的增加与代谢或自氧化过程中形成的邻位半醌的存在有关。
