Structure–activity relationship and enzyme kinetic studies on 4-aryl-1H-1,2,3-triazoles as indoleamine 2,3-dioxygenase (IDO) inhibitors

Huang, Qiang; Zheng, Maofa; Yang, Shuangshuang; Kuang, Chunxiang; Yu, Cunjing; Yang, Qing

doi:10.1016/j.ejmech.2011.08.044

Cited by 66 publications

(44 citation statements)

References 29 publications

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“… 76 A switch from a non-competitive mechanism to an uncompetitive mechanism of inhibition was noticed in biochemical assays for some imidazole-based compounds and triazole-based derivatives with respect to the parent compound 4-PI ( 14 ). 73 , 75 This observation was tentatively explained with these compounds showing a similar binding affinity towards both the inactive ferric form and the active ferrous form of IDO1. 73 …”

Section: Structure–activity Relationships Of Ido1 Inhibitorsmentioning

confidence: 76%

“…The imidazole group replacement of 4-PI ( 14 ) with the triazole ring was also exploited in subsequent studies to generate focused libraries of 4-aryl-1,2,3-triazoles as IDO1 inhibitors. 75 , 76 While results confirmed that substitutions at the para position of the phenyl ring were generally detrimental for IDO1 inhibitor activity, they further suggested some substituents that are allowed at the meta position of the phenyl ring such as chlorine (IC 50 = 1.2 μM; P815B IC 50 = 0.62 μM) and bromine (IC 50 = 2.0 μM; P815B IC 50 = 0.94 μM). Germane to the ortho position, it was again suggested that a small polar moiety such as the hydroxyl group improves the inhibitor potency (IC 50 = 15 μM; P815B IC 50 = 1.7 μM), while large bulky groups are detrimental for the activity.…”

Section: Structure–activity Relationships Of Ido1 Inhibitorsmentioning

confidence: 88%

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Advances in indoleamine 2,3-dioxygenase 1 medicinal chemistry

et al. 2017

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Section: Structure–activity Relationships Of Ido1 Inhibitorsmentioning

confidence: 76%

Section: Structure–activity Relationships Of Ido1 Inhibitorsmentioning

confidence: 88%

Advances in indoleamine 2,3-dioxygenase 1 medicinal chemistry

et al. 2017

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“…Our initial experiments showed that resting MSCs, negative for the IDO protein, were able to demonstrate robust upregulation of the downstream AHR signaling pathway in response to 1MT. However, it is conceivable that IDO+ cells might occupy equivalents of 1MT in the active site of the IDO protein, leaving none available to activate the AHR response [ 26 ]. To address this, we pre-treated MSCs with IFN-γ for 24h, which is sufficient to induce robust IDO protein expression [ 16 ].…”

Section: Resultsmentioning

confidence: 99%

The IDO inhibitor 1-methyl tryptophan activates the aryl hydrocarbon receptor response in mesenchymal stromal cells

et al. 2017

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The catabolism of tryptophan (Trp) by indoleamine 2,3-dioxygenase (IDO) is a key step in tolerance effected by a variety of cell types, including mesenchymal stromal cells (MSCs). Trp catabolism generates molecules known as kynurenines, whose tolerance mechanisms involve activation of the Aryl Hydrocarbon Receptor (AHR). A synthetic analog of Trp, 1-methyl tryptophan (1MT), is a selective inhibitor of IDO enzymatic activity being utilized in cancer immunotherapy trials. We hypothesized 1MT might activate AHR independently of its effects on IDO. We demonstrate MSCs express AHR protein, and that in vitro treatment with 1MT causes AHR nucleotranslocation. Upon analyzing mRNA, we observed transcriptional upregulation of cytochrome p450 1a1 and 1b1 by 1MT racemic mixture (R-MT), consistent with AHR-activation. RNA-sequencing identified Nrf2, MAPK12 and IL-1a as downstream targets of 1MT. We demonstrate 1a1 and 1b1 activation by 1MT in IDO+ MSC following interferon-γ (IFN-γ) activation, suggesting AHR signaling is uncoupled from IDO catalytic function. Such a mechanism of action for 1MT may extend its usage to a wider range of patients, irrespective of tumor IDO expression. These observations support a novel paradigm by which AHR-activating compounds like 1MT can be used in cancer immunotherapy to stimulate a pro-inflammatory response.

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“…In the present study, galanal was found to possess more IDO1 inhibitory potency than either the most-commonly used 1-MT or other previously-published inhibitors (Table. 1) [14] [28] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43]. Since the IC 50 value of inhibitor depends on the IDO1 enzyme activity in each experiment, we could not unconditionally compare the previous results.…”

Section: Discussionmentioning

confidence: 99%

Effects of Various Phytochemicals on Indoleamine 2,3-Dioxygenase 1 Activity: Galanal Is a Novel, Competitive Inhibitor of the Enzyme

Yamamoto

Imai

et al. 2014

PLoS ONE

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Indoleamine 2,3-dioxygenase (IDO) 1, that catalyzes the first and rate-limiting step in the degradation of L-tryptophan, has an important immunomodulatory function. The activity of IDO1 increases in various inflammatory diseases, including tumors, autoimmune diseases, and different kinds of inflammation. We evaluated the suppressive effect of plant extracts or phytochemicals on IDO1 induction and activity; sixteen kinds of plants extracts and fourteen kinds of phytochemicals were examined. As a result, the methanol extracts of Myoga flower buds, which are traditional Japanese foods, and labdane-type diterpene galanal derived from Myoga flowers significantly suppressed IDO1 activity. The Lineweaver-Burk plot analysis indicated that galanal is a competitive inhibitor. Galanal attenuated L-kynurenine formation with an IC50 value of 7.7 µM in the assay system using recombinant human IDO1, and an IC50 value of 45 nM in the cell-based assay. Further, mechanistic analysis revealed that galanal interfered with the transcriptional function of the nuclear factor-κB and the interferon-γ signaling pathway. These effects of galanal are important for immune response. Because the inhibitory effect of galanal on IDO1 activity was stronger than that of 1-methyl tryptophan, a tryptophan analog, galanal may have great potential as the novel drug for various immune-related diseases.

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Structure–activity relationship and enzyme kinetic studies on 4-aryl-1H-1,2,3-triazoles as indoleamine 2,3-dioxygenase (IDO) inhibitors

Cited by 66 publications

References 29 publications

Advances in indoleamine 2,3-dioxygenase 1 medicinal chemistry

Advances in indoleamine 2,3-dioxygenase 1 medicinal chemistry

The IDO inhibitor 1-methyl tryptophan activates the aryl hydrocarbon receptor response in mesenchymal stromal cells

Effects of Various Phytochemicals on Indoleamine 2,3-Dioxygenase 1 Activity: Galanal Is a Novel, Competitive Inhibitor of the Enzyme

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