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      Synthesis, biological evaluation, and structure−activity relationships of dithiolethiones as inducers of cytoprotective phase 2 enzymes

      Munday, Rex; Zhang, Yuesheng; Paonessa, Joseph D.; Munday, Christine M.; Wilkins, Alistair L.; Babu, Jacob
      DOI
       10.1021/jm100425v
      Link
       pubs.acs.org
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      Citation
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      Munday, R., Zhang, Y., Paonessa, J.D., Munday, C.M., Wilkins, A.L. & Babu, J. (2010). Synthesis, biological evaluation, and structure−activity relationships of dithiolethiones as inducers of cytoprotective phase 2 enzymes. Journal of Medicinal Chemistry, 53(12), 4761-4767.
      Permanent Research Commons link: https://hdl.handle.net/10289/4119
      Abstract
      Dithiolethiones are a family of promising cancer chemopreventive agents, and induction of phase 2 enzymes is key to their chemopreventive activities. Two dithiolethiones have been evaluated in humans for cancer prevention. While some chemopreventive activities were detected in several human studies, potential side effects are a concern. Herein, we report structure−activity relationships of 25 dithiolethiones. Several compounds show exceedingly potent and bladder specific activity in phase 2 enzyme induction. Structural features responsible for such activity, as well as those inhibiting the activity, are discussed. Moreover, the compounds activate and depend on Nrf2 for their inductive activities. Nrf2 is a major transcriptional stimulator of cytoprotective genes and is critical for cancer prevention. Thus, several new dithiolethiones that are highly promising for bladder cancer prevention have been identified. Because the compounds act specifically in the bladder, the likelihood of potential systemic toxicity may be low.
      Date
      2010
      Type
      Journal Article
      Publisher
      American Chemical Society
      Collections
      • Science and Engineering Papers [3122]
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