State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China.
Department of Chemistry, Tongji University, Siping Road 1239, Shanghai, 200092, China.
Eur J Med Chem. 2018 Dec 5;160:133-145. doi: 10.1016/j.ejmech.2018.10.017. Epub 2018 Oct 10.
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 (IC) 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.
色氨酸 2,3-双加氧酶（TDO）因其参与癌症和神经退行性疾病而成为有前途的治疗靶点。开发有效的 TDO 抑制剂是疾病治疗的主要策略。然而，缺乏 TDO 抑制剂生物测定系统减缓了 TDO 抑制剂研究的进展。在此，在最佳表达条件下制备了活性重组人 TDO（hTDO），优化了酶测定法，并开发了两种 TDO 活性的细胞测定法。然后，评估了 9 种色氨酸衍生物（5a-5i）的潜在 TDO 抑制活性，并测量了抑制常数（Ki）、酶和细胞半数最大抑制浓度（IC），并确定了抑制类型。色氨酸具有不同水平的 TDO 抑制活性；在 8 位具有取代基的色氨酸比其他衍生物具有更强的抑制活性。此外，除了 5g 和 5h 之外，大多数化合物的抑制活性均优于先前报道的 TDO 抑制剂 LM10。此外，化合物 5c 和 5d 的分子对接研究表明，色氨酸环的 O 原子通过强配位相互作用定向朝向 hTDO 的血红素铁（Fe）。这些发现表明色氨酸及其衍生物有可能被开发为用于 TDO 相关靶标治疗的有前途的分子。
