Investigational New Drugs

, Volume 30, Issue 5, pp 1878–1886 | Cite as

Aza-derivatives of resveratrol are potent macrophage migration inhibitory factor inhibitors

  • Yoshihiko Fujita
  • Rafiqul Islam
  • Kazuko Sakai
  • Hiroyasu Kaneda
  • Kanae Kudo
  • Daisuke Tamura
  • Keiichi Aomatsu
  • Tomoyuki Nagai
  • Hidekazu Kimura
  • Kazuko Matsumoto
  • Marco A. de Velasco
  • Tokuzo Arao
  • Tadashi Okawara
  • Kazuto NishioEmail author


Resveratrol (3, 4′, 5-trihydroxy-trans-stilbene), a natural phytoalexin found in grapes and wine, has anti-proliferative activity on human-derived cancer cells. In our study, we used a conventional condensation reaction between aldehydes and amines to provide a number of aza-resveratrol (3, 4′, 5-trihydroxy-trans- aza-stilbene) derivatives in an attempt to screen for compounds with resveratrol’s action but with increased potency. Aza-resveratrol and its hydroxylated derivative (3, 4, 4′, 5-tetrahydroxy-trans- aza-stilbene) showed a more enhanced anti-proliferative effect than resveratrol in an MCF-7 breast carcinoma cell line. To identify the cellular targets of the aza derivatives of resveratrol, we conjugated the latter aza-stilbene compound with epoxy-activated agarose and performed affinity purification. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, was identified as a major target protein in MCF-7 cell lysates using a matrix-assisted laser desorption/ionization time-of-flight mass spectrometer (MALDI-TOF MS). The aza-resveratrol and its hydroxylated derivative, but not resveratrol, were also found to be potent inhibitors of MIF tautomerase activity, which may be associated with their inhibitory effects on MIF bioactivity for cell growth.


Resveratrol Cancer Macrophage migration inhibitory factor (MIF) Tautomerase, CD74 



We thank Eiko Honda for performing the MALDI-TOF MASS spectrometry, Yoshitaka Horiuchi for the microscopic analysis and Tomoko Kitayama for cell experiments.

Disclosure of potential conflicts of interest

No potential conflicts of interests were disclosed.


This work was supported by funds for the Comprehensive 3rd term of the 10-Year Strategy for Cancer Control, a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (19209018).

Supplementary material

10637_2011_9749_MOESM1_ESM.pdf (40 kb)
Supplementary Fig. 1 Immunoblot analysis of endogenous expression levels of MIF for several cell lines. Subconfluent cells were lysed with buffer containing 0.5% NP-40, 150 mM NaCl, 50 mM Tris–HCl (pH 7.4), 10 mM sodium pyrophosphate and protease inhibitor mix, completeTM (Roche Diagnostics). Thirty μg of protein from each cell line was used for SDS-polyacrylamide gel electrophoresis and transferred onto PVDF membrane, which were then treated with anti-MIF and anti-β-actin antibodies. After incubation with horseradish peroxidase-conjugated secondary antibody, the membrane was visualized using ECL detection system (GE Healthcare Life Science) (PPT 11470 kb)


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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Yoshihiko Fujita
    • 1
  • Rafiqul Islam
    • 2
  • Kazuko Sakai
    • 1
  • Hiroyasu Kaneda
    • 1
  • Kanae Kudo
    • 1
  • Daisuke Tamura
    • 1
  • Keiichi Aomatsu
    • 1
  • Tomoyuki Nagai
    • 1
  • Hidekazu Kimura
    • 1
  • Kazuko Matsumoto
    • 1
  • Marco A. de Velasco
    • 1
  • Tokuzo Arao
    • 1
  • Tadashi Okawara
    • 2
  • Kazuto Nishio
    • 1
    Email author
  1. 1.Department of Genome BiologyKinki University School of MedicineOsakaJapan
  2. 2.Institute of Health ScienceKumamoto Health Science UniversityKumamotoJapan

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