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Design of Novel Hypoxia-Targeting IDO Hybrid Inhibitors Conjugated with an Unsubstituted L-TRP as an IDO Affinity Moiety

  • Hitomi Nakashima
  • Kazuhiro Ikkyu
  • Kouichiro Nakashima
  • Keiichiro Sano
  • Yoshihiro Uto
  • Eiji Nakata
  • Hideko Nagasawa
  • Hiroshi Sugimoto
  • Yoshitsugu Shiro
  • Yoshinori Nakagawa
  • Hitoshi Hori
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 662)

Abstract

We presented here design, syntheses and inhibitory activities of novel hypoxia-targeting IDO hybrid inhibitors conjugated with an unsubstituted L-Trp as an IDO affinity moiety without inhibitor 1MT, such as L-Trp-TPZ hybrids 1 (TX-2274), 2 (UTX-3), 3 (UTX-4), and 4 (UTX-2). TPZ-monoxide hybrids 1 and 3 were good competitive IDO inhibitors, while TPZ hybrids 2 and 4 were uncompetitive IDO inhibitors. Among them TPZ-monoxide hybrid 1 have the strongest IDO inhibitory activity. It suggests that TPZ-monoxide hybrids 1 and 3 are able to bind the active site of IDO, TPZ hybrids 2 and 4 are able to bind the enzyme-substrate complex. We proposed the possible mechanism of action of TPZ hybrid 2 that may first affect as a hypoxic cytotoxin, and then metabolized to TPZ-monoxide hybrid 1, which may do as an IDO inhibitor more effectively than its parent TPZ hybrid 2.

Keywords

Heme Iron Kynurenine Pathway Conjugation Reaction Uncompetitive Inhibition Indole Moiety 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The authors thank Ms. M. Nakamura, Ms. K. Yamashita, Ms. E. Okayama and the staff of our Faculty for measurement of NMR, MS and elemental analyses.

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Hitomi Nakashima
    • 1
  • Kazuhiro Ikkyu
    • 1
  • Kouichiro Nakashima
    • 1
  • Keiichiro Sano
    • 1
  • Yoshihiro Uto
    • 1
  • Eiji Nakata
    • 1
  • Hideko Nagasawa
    • 2
  • Hiroshi Sugimoto
    • 3
  • Yoshitsugu Shiro
    • 3
  • Yoshinori Nakagawa
    • 4
  • Hitoshi Hori
    • 1
  1. 1.Department of Life System, Institute of Technology and ScienceGraduate School, The University of TokushimaTokushimaJapan
  2. 2.Laboratory of Pharmaceutical ChemistryGifu Pharmaceutical UniversityGifuJapan
  3. 3.Biometal Science Laboratory, RIKEN SPring-8 Center, Harima InstituteHyogoJapan
  4. 4.Morita Pharmaceutical Ind. Ltd, FukuyamaHiroshimaJapan

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