Structural basis for DNA-cleaving activity of resveratrol in the presence of Cu(II)

Kiyoshi Fukuhara, Maki Nagakawa, Ikuo Nakanishi, Kei Ohkubo, Kohei Imai, Shiro Urano, Shunichi Fukuzumi, Toshihiko Ozawa, Nobuo Ikota, Masataka Mochizuki, Naoki Miyata, Haruhiro Okuda

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

Resveratrol (1, 3,5,4′-trihydroxy-trans-stilbene), a polyphenol found in grapes and other food products, is known as an antioxidant and cancer chemopreventive agent. However, 1 was shown to induce genotoxicity through a high frequency of micronucleus and sister chromatid exchange in vitro and DNA-cleaving activity in the presence of Cu(II). The present study was designed to explore the structure-activity relationship of 1 in DNA strand scission and to characterize the substrate specificity for Cu(II) and DNA binding. When pBR322DNA was incubated with 1 or its analogues differing in the number and positions of hydroxyl groups in the presence of Cu(II), the ability of 4-hydroxystilbene analogues to induce DNA strand scission is much stronger than that of 3-hydroxy analogues. The high binding affinity with both Cu(II) and DNA was also observed by 4-hydroxystilbene analogues. The reduction of Cu(II) which is essential for activation of molecular oxygen proceeded by addition of 1 to the solution of the Cu(II)-DNA complex, while such reduction was not observed with the addition of isoresveratrol, in which the 4-hydroxy group of 1 is changed to the 3-position. The results show that the 4-hydroxystilbene structure of 1 is a major determinant of generation of reactive oxygen species that was responsible for DNA strand scission.

Original languageEnglish
Pages (from-to)1437-1443
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume14
Issue number5
DOIs
StatePublished - 1 Mar 2006

Bibliographical note

Funding Information:
This work was supported partly by a grant (MF-16) from the Organization for Pharmaceutical Safety and Research of Japan, a grant from the Ministry of Health, Labour and Welfare, a Grant-in-Aid for Research of Health Sciences focusing on Drug Innovation (KH51058) from the Japan Health Sciences Foundation, and partly by Grants-in-Aid for Scientific Research (B) (No. 17390033) and for Young Scientist (B) (No. 17790044) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Keywords

  • Antioxidant
  • DNA oxidative damage
  • Polyphenol
  • Resveratrol

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