Original Contribution DNA damage induced by resveratrol and its synthetic analogues in the presence of Cu (II) ions: Mechanism and structure-activity relationship Li-Fang Zheng, Qing-Yi Wei, Yu-Jun Cai, Jian-Guo Fang, Bo Zhou ⁎ , Li Yang, Zhong-Li Liu ⁎ National Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, China Received 2 July 2006; revised 31 August 2006; accepted 8 September 2006 Available online 15 September 2006 Abstract The prooxidant effect of resveratrol (3,5,4′-trihydroxy-trans-stibene) and its synthetic analogues (ArOH), that is, 3,4,4′-trihydroxy-trans- stibene (3,4,4′-THS), 3,4,5-trihydroxy-trans-stibene (3,4,5-THS), 3,4-dihydroxy-trans-stibene (3,4-DHS), 4,4′-dihydroxy-trans-stibene (4,4′- DHS), 2,4-dihydroxy-trans-stilbene (2,4-DHS), 3,5-dihydroxy-trans-stilbene (3,5-DHS) and 3,5,4′-trimethoxy-trans-stibene (3,5,4′-TMS), on supercoiled pBR322 plasmid DNA strand breakage and calf thymus DNA damage in the presence of Cu (II) ions has been studied. It was found that the compounds bearing ortho-dihydroxyl groups (3,4-DHS, 3,4,4′-THS, and 3,4,5-THS) or bearing 4-hydroxyl groups (2,4-DHS, 4,4′-DHS, and resveratrol) exhibit remarkably higher activity in the DNA damage than the ones bearing no such functionalities. Kinetic analysis by UV- visible spectra demonstrates that the formation of ArOH-Cu (II) complexes, the stabilization of oxidative intermediate derived from ArOH and Cu (II)/Cu (I) redox cycles, might be responsible for the DNA damage. This study also reveals a good correlation between antioxidant and prooxidant activity, as well as cytotoxicity against human leukemia (HL-60 and Jurkat) cell lines. The mechanisms and implications of these observations are discussed. © 2006 Elsevier Inc. All rights reserved. Keywords: Resveratrol; DNA damage; Copper; Structure/activity relationship; Reactive oxygen species Introduction Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a naturally occurring phytoalexin present in grapes, nuts, and other plants. It is believed that the high level of this compound in red wine (0.1–15 mg/L) [1] is linked to the low incidence of heart diseases in some regions of France, the so-called “French paradox;” i.e., despite high fat intake, mortality from coronary heart disease is lower due to the regular drinking of wine [2,3]. In addition, resveratrol has been shown to possess cancer chemopreventive activity [4–7]. The metabolism and bioavail- ability of resveratrol have been studied in detail recently [8]. Therefore, the past several years have witnessed intense research devoted to the biological activity, especially the antioxidative activity, of this compound [9–12], since free radical-induced oxidative damage of cell membranes, DNA, and protein is considered to play a causative role in aging and several degenerative diseases, such as cancer and atherosclerosis [13– 16]. On the other hand, it was reported that an antioxidant might become a prooxidant to accelerate lipid peroxidation and/or induce DNA damage under special conditions [17–27]. α- Tocopherol (vitamin E), a well-known antioxidant, was reported to be able to accelerate low-density lipoprotein (LDL) peroxidation via the tocopherol-mediated peroxidation (TMP) [17,18], and to induce DNA damage in the presence of cupric ions [19]. Other polyphenolic antioxidants, including quercetin [20], curcumin [21], tea cathechins [22], salsolinol [23], and Free Radical Biology & Medicine 41 (2006) 1807 – 1816 www.elsevier.com/locate/freeradbiomed Abbreviations: resveratrol, 3,5,4′-trihydroxy-trans-stibene; ArOH, synthetic analogues of resveratrol; 3,4,4′-THS, 3,4,4′-trihydroxy-trans-stibene; 3,4,5- THS, 3,4,5-trihydroxy-trans-stibene; 3,4-DHS, 3,4-dihydroxy-trans-stibene; 4,4′-DHS, 4,4′-dihydroxy-trans-stibene; 2,4-DHS, 2,4-dihydroxy-trans-stil- bene; 3,5-DHS, 3,5-dihydroxy-trans-stilbene; 3,5,4′-TMS, 3,5,4′-trimethoxy- trans-stibene; BCDS, bathocuproinedisulfonic acid; PBS, phosphate-buffered saline; EB, ethidium bromide; ROS, reactive oxygen species. ⁎ Corresponding authors. Fax: +86 931 8625657. E-mail address: bozhou@lzu.edu.cn (B. Zhou). 0891-5849/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.freeradbiomed.2006.09.007