1-METHYL-D-TRYPTOPHAN

Description

Indoleamine 2,3-dioxygenase (IDO) metabolizes tryptophan to kynurenine, leading to the production of NAD⁺ via the kynurenine pathway. The overexpression of IDO in tumors and tumor-draining lymph nodes induces immune tolerance and enhances tumor growth in vivo. 1-methyl-D-Tryptophan is an inhibitor of IDO (IC₅₀ = 7 μM) that is effective in vivo. In mice, 1-methyl-D-tryptophan prevents T-cell anergy triggered by dendritic cells overexpressing IDO. It augments the antitumor and antiviral immunoresponse of CD8⁺ T-cells and reduces tumor volume in mice with xenografts overexpressing IDO. 1-methyl-D-Tryptophan, in combination with chemotherapy, causes regression of tumors and prolongs survival. Surprisingly, 1-methyl-D-tryptophan induces the expression of IDO in human ovarian carcinoma SKOV3 cells in culture.

Uses

1-Methyl-D-tryptophan is used in biological studies to determine the effect of IDO2 enzyme (indoleamine-(2,3)-dioxygenase) activity and IDO2-mediated arrest of human T cell proliferation. It reverses IDO-mediated immune suppression

Uses

Indoleamine 2,3-dioxygenase (IDO) metabolizes tryptophan to kynurenine, leading to the production of NAD+ via the kynurenine pathway. The overexpression of IDO in tumors and tumor-draining lymph nodes induces immune tolerance and enhances tumor growth in vivo. 1-methyl-D-Tryptophan is an inhibitor of IDO (IC50 = 7 μM) that is effective in vivo. In mice, 1-methyl-D-tryptophan prevents T-cell anergy triggered by dendritic cells overexpressing IDO. It augments the antitumor and antiviral immunoresponse of CD8+ T-cells and reduces tumor volume in mice with xenografts overexpressing IDO. 1-methyl-D-Tryptophan, in combination with chemotherapy, causes regression of tumors and prolongs survival. Surprisingly, 1-methyl-D-tryptophan induces the expression of IDO in human ovarian carcinoma SKOV3 cells in culture.

reaction suitability

reaction type: solution phase peptide synthesis

Synthesis

73-22-3

74-88-4

21339-55-9

General procedure for the synthesis of acacia alkaloids from L-tryptophan and iodomethane: 10.2 g of L-tryptophan was dissolved in 130 mL of dimethylsulfoxide (DMSO), and 5 g of sodium hydroxide was added in batches over a 30-minute period under nitrogen protection. After addition, the reaction system was stirred at room temperature for 1 h. Subsequently, the reaction system was cooled to 0 °C. A 30 mL solution of DMSO with 7.46 g of iodomethane was slowly added dropwise over 30 min. After the dropwise addition was completed, the reaction was continued for 15 hours. After completion of the reaction, 50 mL of water was added to the system to quench the reaction. The reaction mixture was poured into 400 mL of ether and a large solid was precipitated and filtered. The resulting solid was dissolved in water and the pH was adjusted to 6-7 with concentrated hydrochloric acid, and the solid was again precipitated. Filtering was extracted and dried to give 8.7 g of white powdery product (80% yield, melting point 269°C). The product was analyzed by 1H-NMR, 13C-NMR, IR spectroscopy and mass spectrometry according to the method of Example 1. The results showed that the resulting solid product was 1-methyltryptophan with 100% purity.

in vivo

IC 50

IDO: 19 μM (Ki)

storage

Store at -20°C

References

[1] DE-YAN HOU. Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses.[J]. Cancer research, 2007, 67 2: 792-801. DOI:10.1158/0008-5472.can-06-2925
[2] HATEM SOLIMAN  Scott A  Melanie Mediavilla Varela. Indoleamine 2,3-dioxygenase: is it an immune suppressor?[J]. Cancer journal, 2010, 16 4: 354-359. DOI:10.1097/ppo.0b013e3181eb3343
[3] MARIA FRIBERG. Indoleamine 2,3-dioxygenase contributes to tumor cell evasion of T cell-mediated rejection[J]. International Journal of Cancer, 2002, 101 2: 151-155. DOI:10.1002/ijc.10645
[4] RICHARD METZ. IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: A novel IDO effector pathway targeted by D-1-methyl-tryptophan.[J]. Oncoimmunology, 2012, 1 9: 1460-1468. DOI:10.4161/onci.21716