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Chemical Modification of the Tryptophan Residue in a Recombinant Ca2+-ATPase N-domain for Studying Tryptophan-ANS FRET
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Chemical Modification of the Tryptophan Residue in a Recombinant Ca2+-ATPase N-domain for Studying Tryptophan-ANS FRET

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Tryptophan 2,3-dioxygenase inhibitory activities of tryptanthrin derivatives

Shengnan Zhang1, Fangfei Qi1, Xin Fang1

  • 1State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China.

European Journal of Medicinal Chemistry
|October 16, 2018
PubMed

Insights

Tryptophan 2,3-dioxygenase (TDO) inhibitors are crucial for treating cancer and neurodegenerative diseases. This study developed new bioassays and found that tryptanthrin derivatives show potent TDO inhibitory activity, offering potential therapeutic strategies.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Medicinal Chemistry

Background:

  • Tryptophan 2,3-dioxygenase (TDO) is a key enzyme implicated in cancer and neurodegenerative diseases.
  • Developing effective TDO inhibitors is critical for therapeutic intervention.
  • A lack of robust bioassay systems has hindered TDO inhibitor research.

Purpose of the Study:

  • To develop and optimize bioassay systems for TDO activity.
  • To evaluate the TDO inhibitory potential of nine tryptanthrin derivatives.
  • To characterize the inhibitory mechanism and potency of active compounds.

Main Methods:

  • Preparation of active recombinant human TDO (hTDO).
  • Optimization of enzymatic and development of cellular TDO activity assays.
  • In vitro evaluation of tryptanthrin derivatives' inhibitory activity, including IC50 and Ki determination.
  • Molecular docking studies to elucidate binding interactions.

Main Results:

  • Established functional enzymatic and cellular assays for TDO activity.
  • Identified nine tryptanthrin derivatives with varying TDO inhibitory effects.
  • Tryptanthrins with 8-position substituents demonstrated enhanced inhibitory activity.
  • Most compounds showed superior inhibition compared to the known inhibitor LM10.
  • Molecular docking revealed coordination interactions between tryptanthrin derivatives and hTDO's heme iron.

Conclusions:

  • Tryptanthrin derivatives represent a promising class of compounds for TDO inhibition.
  • The developed bioassays facilitate further research in TDO inhibitor discovery.
  • These findings support the potential development of tryptanthrins for TDO-targeted therapies in relevant diseases.
Keywords:
TDO activity assayTDO inhibitorTryptanthrin derivativesTryptophan 2,3-dioxygenase

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