Discovery of Tryptanthrin Derivatives as Potent Inhibitors of Indoleamine 2,3-Dioxygenase with Therapeutic Activity in Lewis Lung Cancer (LLC) Tumor-Bearing Mice

Abstract

Indoleamine 2,3-dioxygenase (IDO-1) is emerging as an important new therapeutic target for the treatment of cancer, neurological disorders, and other diseases that are characterized by pathological tryptophan metabolism. However, only a few structural classes are known to be IDO-1 inhibitors. In this study, a natural compound tryptanthrin was discovered to be a novel potent IDO-1 inhibitor by screening of indole-based structures. Three series of 13 tryptanthrin derivatives were synthesized, and the structure-activity analysis was undertaken. The optimization led to the identification of 5c, which exhibited the inhibitory activity at a nanomolar level. In vitro 5c dramatically augmented the proliferation of T cells. When administered to Lewis lung cancer (LLC) tumor-bearing mice, 5c significantly inhibited IDO-1 activity and suppressed tumor growth. In addition, 5c reduced the numbers of Foxp3(+) regulatory T cells (Tregs), which are known to prevent the development of efficient antitumor immune responses.

Exploiting 1,2,3-Triazolium Ionic Liquids for Synthesis of Tryptanthrin and Chemoselective Extraction of Copper(II) Ions and Histidine-Containing Peptides

“…These results clearly demonstrated that ionic liquids 1 and 2 are excellent microwave absorbers, and these ionic solvents outperformed the molecular solvent DMF in the one-pot synthesis of tryptanthrin. Moreover, under our experimental conditions, toluene, a commonly used solvent for the synthesis of tryptanthrin, produced no trace of tryptanthrin (entries 8 and 9, Table 1) [19,[22][23][24][25][26][27][28][29][30]. Although poor isolated yields of tryptanthrin were obtained in the ionic liquid 1 and DMF without the use of any base, ionic liquid 1 nevertheless produced a higher tryptanthrin yield than DMF: 19% versus 6%, respectively (entries 6 and 7, Table 1).…”

“…All these intriguing biological activities from tryptanthrin justify the study for its improved synthesis as a useful scaffold for drug discovery and the advanced development as anti-microbial, anti-inflammatory, and anti-neoplastic agents. Many syntheses of tryptanthrin were reportedly achieved under basic and refluxing conditions (e.g., Et3N in refluxing toluene for 16 h) [19,[22][23][24][25][26][27][28][29][30]. As one example, Srinivasan and co-workers reported the two steps synthesis of tryptanthrin in moderate (54%) isolated yield involving the use of LDA and starting from anthranilic acid, methyl anthranilate, and ethyl orthoformate [26].…”

Fused Heterocyclic Compounds as Potent Indoleamine-2,3-dioxygenase 1 Inhibitors

“…V and [S] represent the initial rate of the reaction and the substrate concentration, respectively. 8,21 However, this observed uncompetitive mode of IDO1 inhibition does not demonstrate their actual mode of enzyme binding. There are several reports of uncompetitive and noncompetitive inhibitors of IDO1 enzyme.…”

Binding properties of different categories of IDO1 inhibitors: a microscale thermophoresis study

“…Tryptanthrin derivative (12) was synthesized in our laboratory following the synthetic scheme already published in the literature [42]. Recombinant human IDO1 (rhIDO1) was purchased from Proteros.…”

“…Tryptanthrin derivatives were reported as potent uncompetitive inhibitors of IDO1 [42]. Among these, compound 12 proved low micromolar K i (= 0.161 μM) and IC 50 (= 0.534 μM) against rhIDO1, while a more potent inhibitory activity was found in HEK 293 cells (IC 50 = 0.023 μM) expressing human IDO1.…”