163239-22-3

Usage

Uses

Used in Pigmentation Studies:
680C91 is used as a tryptophan 2,3 dioxygenase (TDO) inhibitor for studying its effects on pigmentation in Doryteuthis pealeii embryos. The inhibition of TDO by 680C91 can help researchers understand the role of TDO in pigmentation processes and potentially lead to the development of new treatments for pigmentation-related disorders.
Used in Cancer Research:
680C91 is used as a TDO inhibitor to study its effects on esophageal squamous cell carcinoma in xenograft tumor assays. By inhibiting TDO, researchers can investigate the role of TDO in tumor growth and progression, as well as the potential therapeutic benefits of TDO inhibition in cancer treatment.
Used in Toxic Fragment Formation Studies:
680C91 is used as a tryptophan 2,3 dioxygenase 2 (TDO2) inhibitor to study its effects on toxic fragment formation in human embryonic kidney cells. This application can provide insights into the role of TDO2 in the formation of toxic fragments and contribute to the development of strategies to mitigate their harmful effects.

Biochem/physiol Actions

680C91 is a potent inhibitor of the enzyme tryptophan 2,3-dioxygenase (TDO), which directs the conversion of trypophan to kynurenin. Kynurenin has recently been identified as an endogenous lignd of the arylhydrocarbon receptor (AHR). TDO is highly expressed in glioma cells, and contributes to AHR-mediated glioma cell survival and suppression of anti-tumor immune responses.

References

1) Schwarcz and Pellicciari (2002),?Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities; J. Pharmacol. Exp. Therap.,?303?1 2) Salter?et al. (1995),?The effects of a novel and selective inhibitor of tryptophan 2,3-dioxygenase on tryptophan and serotonin metabolism; Biochem. Pharmacol,?49?1435 3) Salter?et al. (1995),?The effects of an inhibitor of tryptophan 2,3-dioxygenase and a combined inhibitor of tryptophan 2,3-dioxygenase and 5-HT reuptake in the rat; Neuropharmacology,?34?217 4) Opitz?et al. (2011),?An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor; Nature,?478197

Upstream product

• 2795-41-7 6-fluoro-1H-indole-3-carbaldehyde 
• 6419-36-9 3-pyridineacetic acid hydrochloride 
• 501-81-5 pyridyl-3-yl-acetic acid 
• 96631-90-2 N,N-dimethyl-2-(4-fluoro-2-nitrophenyl)ethenylamine 
• 446-10-6 2-nitro-4-fluorotoluene 
• 399-51-9 6-fluoro-1H-indole 

Relevant academic research and scientific papers

Novel tryptophan dioxygenase inhibitors and combined tryptophan dioxygenase/5-HT reuptake inhibitors

Tryptophan dioxygenase (TDO) is a liver enzyme that is responsible for the majority of the metabolism of tryptophan. A series of novel 3-(2-pyridylethenyl)indoles are shown to be potent inhibitors of TDO with selected members of the series also having 5-hydroxy tryptamine (5-HT) reuptake inhibitory activity. These compounds are shown to provide significant increases in the levels of tryptophan and 5-HT in the cerebrospinal fluid and are thus of interest for antidepressant therapy.

The Effects of a Novel and Selective Inhibitor of Tryptophan 2,3-Dioxygenase on Tryptophan and Serotonin Metabolism in the Rat

The effects of a novel inhibitor 680C91 ((E)-6-fluoro-3-[2-(3-pyridyl)vinyl]-1H-indole) of the key enzyme of tryptophan catabolism tryptophan 2,3-dioxygenase (TDO) (EC 1.13.11.11), were examined on tryptophan catabolism in vitro and in vivo and on brain levels of tryptophan, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA). 680C91 was a potent (Ki = 51nM) and selective TDO inhibitor with no inhibitory activity against indoleamine 2,3-dioxygenase (EC 1.13.11.17), monoamine oxidase A and B, 5-HT uptake and 5-HT1A,1D,2A and 2C receptors at a concentration of 10 μM. 680C91 has no effect on the binding of tryptophan to serum albumin in plasma and inhibited TDO competitively with respect to its substrate tryptophan. 680C91 inhibited the catabolism of tryptophan by rat liver cells and rat liver perfused in situ. The catabolism of L-[ring-2-14C]-tryptophan and a load dose of tryptophan (100 mg/kg) in vivo were inhibited by prior administration of 680C91. Administration of 680C91 alone produced marked increases in brain tryptophan, 5-HT and 5-HIAA. A load dose of tryptophan (100 mg/kg), producing increases in brain tryptophan 4-fold greater than that seen with 680C91, did not increase brain 5-HT and 5-HIAA to levels greater than those seen with 680C91 and produced a shorter-lasting increase in these parameters. These data therefore demonstrate the importance of TDO as a regulator of whole-body tryptophan catabolism and brain levels of tryptophan and 5-HT and suggest that a greater antidepressant efficacy might be achieved with inhibitors of TDO than tryptophan administration alone.

Tryptophan 2,3-dioxygenase (TDO) inhibitors. 3-(2-(pyridyl)ethenyl)indoles as potential anticancer immunomodulators

Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance. IDO inhibition is thus an active area of research in drug development. Recently, our group has shown that tryptophan 2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is also expressed in many tumors and that this expression prevents tumor rejection by locally depleting tryptophan. Herein, we report a structure-activity study on a series of 3-(2-(pyridyl)ethenyl)indoles. More than 70 novel derivatives were synthesized, and their TDO inhibitory potency was evaluated. The rationalization of the structure-activity relationships (SARs) revealed essential features to attain high TDO inhibition and notably a dense H-bond network mainly involving His55 and Thr254 residues. Our study led to the identification of a very promising compound (58) displaying good TDO inhibition (Ki = 5.5 μM), high selectivity, and good oral bioavailability. Indeed, 58 was chosen for preclinical evaluation.