2. Academic Validation
  3. Tryptophan 2,3-dioxygenase inhibitory activities of tryptanthrin derivatives

Tryptophan 2,3-dioxygenase inhibitory activities of tryptanthrin derivatives

  • Eur J Med Chem. 2018 Dec 5:160:133-145. doi: 10.1016/j.ejmech.2018.10.017.
Shengnan Zhang 1,  Fangfei Qi 2,  Xin Fang 3,  Dan Yang 4,  Hairong Hu 5,  Qiang Huang 6,  Chunxiang Kuang 7,  Qing Yang 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China. Electronic address: 15210700072@fudan.edu.cn.
  • 2 State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China. Electronic address: 16210700114@fudan.edu.cn.
  • 3 State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China. Electronic address: 16210700065@fudan.edu.cn.
  • 4 State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China. Electronic address: 16110700083@fudan.edu.cn.
  • 5 State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China. Electronic address: hrhu@fudan.edu.cn.
  • 6 State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China. Electronic address: huangqiang@fudan.edu.cn.
  • 7 Department of Chemistry, Tongji University, Siping Road 1239, Shanghai, 200092, China. Electronic address: kuangcx@tongji.edu.cn.
  • 8 State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China. Electronic address: yangqing68@fudan.edu.cn.
PMID: 30321802 DOI: 10.1016/j.ejmech.2018.10.017
Abstract

Tryptophan 2,3-dioxygenase (TDO) is becoming a promising therapeutic target due to its involvement in Cancer and neurodegenerative diseases. Development of efficient TDO inhibitors is a prime strategy in disease treatment. However, the lack of a TDO inhibitor bioassay system slows the progress of TDO inhibitor research. Herein, an active recombinant human TDO (hTDO) was prepared under optimal expression conditions, an enzymatic assay was optimized, and two cellular assays of TDO activity were developed. Then, the potential TDO inhibitory activities of nine tryptanthrin derivatives (5a-5i) were evaluated, and the inhibitory constants (Ki), enzymatic and cellular half maximal inhibitory concentrations (IC50) were measured, and the type of inhibition was determined. The tryptanthrins had various levels of TDO inhibitory activities; tryptanthrins with a substituent at 8-position had stronger inhibitory activities than the Other derivatives. Moreover, most of the compounds, except 5g and 5h, exhibited better inhibitory activities than the previously reported TDO inhibitor LM10. Furthermore, the molecular docking study of compounds 5c and 5d revealed that the O atom of the tryptanthrin ring is directed toward the heme iron (Fe) of hTDO via strong coordination interactions. These findings suggest that tryptanthrin and its derivatives have the potential to be developed as promising molecules for TDO-related target therapy.

Keywords

TDO activity assay; TDO inhibitor; Tryptanthrin derivatives; Tryptophan 2,3-dioxygenase.

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