Discovery and structure-activity relationship studies of 1-aryl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione derivatives as potent dual inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) and trytophan 2,3-dioxygenase (TDO)

Pan, Shulei; Zhou, Yangli; Wang, Qiusheng; Wang, Yanlin; Tian, Chuanshan; Wang, Tianqi; Huang, Luyi; Nan, Jinshan; Li, Linli; Yang, Shengyong

doi:10.1016/j.ejmech.2020.112703

Cited by 24 publications

(9 citation statements)

References 89 publications

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“…Accordingly, compound 64b could be taken as a lead molecule for further development of potent anti-lung cancer therapeutic agents. In LL2 (Lewis lung cancer, bearing a high expression level of IDO1) and Hepa1-6-xenografted mouse models, compound 65 (30 mg/kg, intraperitoneally) demonstrates moderate in vivo anticancer efficacy with TGI rates of 62.5% and 80%, and the potency is higher than that of epacdostat (TGI: 50.0%) (Pan et al, 2020). Moreover, in vivo experiments reveal no obvious body weight change, implying its excellent safety profile.…”

Section: Miscellaneous 123-triazole-containing Compoundsmentioning

confidence: 99%

1,2,3-Triazole-Containing Compounds as Anti–Lung Cancer Agents: Current Developments, Mechanisms of Action, and Structure–Activity Relationship

Liang

Sun

et al. 2021

Front. Pharmacol.

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Lung cancer is the most common malignancy and leads to around one-quarter of all cancer deaths. Great advances have been achieved in the treatment of lung cancer with novel anticancer agents and improved technology. However, morbidity and mortality rates remain extremely high, calling for an urgent need to develop novel anti–lung cancer agents. 1,2,3-Triazole could be readily interact with diverse enzymes and receptors in organisms through weak interaction. 1,2,3-Triazole can not only be acted as a linker to tether different pharmacophores but also serve as a pharmacophore. This review aims to summarize the recent advances in 1,2,3-triazole–containing compounds with anti–lung cancer potential, and their structure–activity relationship (SAR) together with mechanisms of action is also discussed to pave the way for the further rational development of novel anti–lung cancer candidates.

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Section: Miscellaneous 123-triazole-containing Compoundsmentioning

confidence: 99%

1,2,3-Triazole-Containing Compounds as Anti–Lung Cancer Agents: Current Developments, Mechanisms of Action, and Structure–Activity Relationship

Liang

Sun

et al. 2021

Front. Pharmacol.

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“…It remains unclear whether the proposed non-enzymatic activity of IDO2 will compensate for inhibition of the enzyme [32]. Dual inhibitors of both enzymes are under active investigation and may prove even more suitable [31][32][33][34][35][36][37].…”

Section: Ido and Immunological Tolerancementioning

confidence: 99%

Interactions of IDO and the Kynurenine Pathway with Cell Transduction Systems and Metabolism at the Inflammation–Cancer Interface

Stone

Williams

2023

Cancers

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The mechanisms underlying a relationship between inflammation and cancer are unclear, but much emphasis has been placed on the role of tryptophan metabolism to kynurenine and downstream metabolites, as these make a substantial contribution to the regulation of immune tolerance and susceptibility to cancer. The proposed link is supported by the induction of tryptophan metabolism by indoleamine-2,3-dioxygenase (IDO) or tryptophan-2,3-dioxygenase (TDO), in response to injury, infection or stress. This review will summarize the kynurenine pathway and will then focus on the bi-directional interactions with other transduction pathways and cancer-related factors. The kynurenine pathway can interact with and modify activity in many other transduction systems, potentially generating an extended web of effects other than the direct effects of kynurenine and its metabolites. Conversely, the pharmacological targeting of those other systems could greatly enhance the efficacy of changes in the kynurenine pathway. Indeed, manipulating those interacting pathways could affect inflammatory status and tumor development indirectly via the kynurenine pathway, while pharmacological modulation of the kynurenine pathway could indirectly influence anti-cancer protection. While current efforts are progressing to account for the failure of selective IDO1 inhibitors to inhibit tumor growth and to devise means of circumventing the issue, it is clear that there are wider factors involving the relationship between kynurenines and cancer that merit detailed consideration as alternative drug targets.

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“…Kynurenic acid could directly repress the function of effector T cells and enhance the inhibitory activities of regulatory T cells (Tregs), and at the same time Trp depletion in the microenvironment also suppresses T cell proliferation, thus an immunosuppressive effect was exerted via multiple pathways [19] . Many cancer cells highly express IDO1, and the IDO1-mediated Trp metabolic pathway is considered as an important cause leading to tumor immune escape [20] . Therefore, IDO1 inhibition modulates the Trp content of the tumor microenvironment, avoids the suppression of T cell proliferation in the tumor microenvironment, and activates or improves the body immune function, suggesting that IDO1 might serve as a cancer immunotherapy target [21] .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and activity study of novel theophylline derivatives as IDO1 inhibitors

Hou

Lou

et al. 2023

Preprint

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Indoleamine 2,3-dioxygenase 1 (IDO1), an immunomodulatory enzyme associated with tumor immune escape. Numerous studies have shown that it is an attractive therapeutic target for cancer diseases. To identify holo-IDO1 inhibitors with novel skeleton structures, a series of theophylline derivatives with 1,2,3-triazole groups were designed and synthesized by condensingtheophylline acetic acid and 4-aminophenylacetylene.In the IDO1 enzymatic activity assay, we found that compound 3c exhibited the best inhibitory effect(IC50 = 10.07µM). Molecular docking and affinity prediction analysis further elucidated the binding ability and mode of the dominant compounds. Our study suggested that the theophylline derivatives are potential holo-IDO1 inhibitors for future development.

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Discovery and structure-activity relationship studies of 1-aryl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione derivatives as potent dual inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) and trytophan 2,3-dioxygenase (TDO)

Cited by 24 publications

References 89 publications

1,2,3-Triazole-Containing Compounds as Anti–Lung Cancer Agents: Current Developments, Mechanisms of Action, and Structure–Activity Relationship

1,2,3-Triazole-Containing Compounds as Anti–Lung Cancer Agents: Current Developments, Mechanisms of Action, and Structure–Activity Relationship

Interactions of IDO and the Kynurenine Pathway with Cell Transduction Systems and Metabolism at the Inflammation–Cancer Interface

Synthesis and activity study of novel theophylline derivatives as IDO1 inhibitors

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