Synthesis and evaluation of oxindoles as promising inhibitors of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1

Paul, Soumen; Roy, Arijit; Deka, Suman Jyoti; Panda, Subhankar; Srivastava, Gopal N.; Trivedi, Vishal; Manna, Debasis

doi:10.1039/c7md00226b

Cited by 16 publications

(17 citation statements)

References 58 publications

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“…The measured EC 50 values of the potent compounds were within the range of 60–422 nM (Table 3 and S10). Control compound, 4-amino- N -(3-chloro-4-fluorophenyl)- N ′-hydroxy-1,2,5-oxadiazole-3- carboximidamide and MMG-0358, showed EC 50 values of 63 and 120 nM, under similar experimental conditions, which are in agreement with the reported values 18,28,30,31 . However, smaller variations in the compound’s IDO1 inhibitory activities between the two activity assay systems, against the purified enzyme and under the cellular conditions, could be primarily due to the obstacles in regulating the redox activity of the enzyme and/or environmental effect on the assay systems.…”

Section: Resultssupporting

confidence: 89%

“…5 and S2; Table S6). Where, V and [S] represent the initial reaction rate and the substrate concentration, respectively 28,30,34 . Nevertheless, this calculated competitive mode of IDO1 inhibition by the selected compounds may not exhibit their true-mode of enzyme inhibition.…”

Section: Resultsmentioning

confidence: 99%

“…Detailed mechanistic studies of the IDO1 assisted catabolism of L-Trp in demonstrating that the generation of ferric-superoxide intermediate is the prime necessity for the subsequent oxidation process, suggesting both O 2 and L-Trp as substrate for the enzyme. Henceforth, supplementary enzyme kinetic studies regarding O 2 are required to recognize the precise mode of IDO1 enzyme inhibition 8,26–28,30 .

Figure 5Determination of mode of IDO1 inhibition of the selected compounds. The plot of 1/V against 1/[S] at different concentrations of the compounds 3i ( A ), 4i ( B ), and 4k ( C ).…”

Section: Resultsmentioning

confidence: 99%

“…The efficacy of the compound’s direct binding to the enzyme active site was measured by UV-Vis spectroscopic analysis 26–28,30 . All the measurements were performed at room temperature using 100 mM KPB (pH 6.5), purified hIDO1 enzyme (3 µM), and selected compounds (20 µM.…”

Section: Methodsmentioning

confidence: 99%

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4,5-Disubstituted 1,2,3-triazoles: Effective Inhibition of Indoleamine 2,3-Dioxygenase 1 Enzyme Regulates T cell Activity and Mitigates Tumor Growth

Panda

Pradhan

Chatterjee

et al. 2019

Sci Rep

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The improvement of body’s own immune system is considered one of the safest approaches to fight against cancer and several other diseases. Excessive catabolism of the essential amino acid, L-tryptophan (L-Trp) assists the cancer cells to escape normal immune obliteration. The formation of disproportionate kynurenine and other downstream metabolites suppress the T cell functions. Blocking of this immunosuppressive mechanism is considered as a promising approach against cancer, neurological disorders, autoimmunity, and other immune-mediated diseases. Overexpression of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme is directly related to the induction of immunosuppressive mechanisms and represents an important therapeutic target. Several classes of small molecule-based IDO1 inhibitors have been already reported, but only few compounds are currently being evaluated in various stages of clinical trials as adjuvants or in combination with chemo- and radiotherapies. In the quest for novel structural class(s) of IDO1 inhibitors, we developed a series of 4,5-disubstituted 1,2,3-triazole derivatives. The optimization of 4,5-disubstituted 1,2,3-triazole scaffold and comprehensive biochemical and biophysical studies led to the identification of compounds, 3i, 4i, and 4k as potent and selective inhibitors of IDO1 enzyme with IC50 values at a low nanomolar level. These potent compounds also showed strong IDO1 inhibitory activities in MDA-MB-231 cells with no/negligible level of cytotoxicity. The T cell activity studies revealed that controlled regulation of IDO1 enzyme activity in the presence of these potent compounds could induce immune response against breast cancer cells. The compounds also showed excellent in vivo antitumor efficacy (of tumor growth inhibition = 79–96%) in the female Swiss albino mice. As a consequence, this study describes the first example of 4,5-disubstituted 1,2,3-triazole based IDO1 inhibitors with potential applications for immunotherapeutic studies.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Figure 5Determination of mode of IDO1 inhibition of the selected compounds. The plot of 1/V against 1/[S] at different concentrations of the compounds 3i ( A ), 4i ( B ), and 4k ( C ).…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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4,5-Disubstituted 1,2,3-triazoles: Effective Inhibition of Indoleamine 2,3-Dioxygenase 1 Enzyme Regulates T cell Activity and Mitigates Tumor Growth

Panda

Pradhan

Chatterjee

et al. 2019

Sci Rep

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“…The isatin–imine hybrids 6 (Figure 4; IC 50 : 7.8–91 μM; 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide [MTT] assay) showed considerable activity against MCF‐7, HepG2, and Jurkat cancer cell lines and the SAR revealed that introduction of benzyl into N‐1 position of isatin moiety was beneficial to the activity. [ 39,40 ] Further study indicated that incorporation of morpholinosulfonyl into the C‐5 position of isatin skeleton was also tolerated and hybrids 7 (IC 50 : 10.39–55.90 μM, SRB assay) displayed potential activity against HepG2, HCT‐116, CACO, and MCF‐7 cancer cell lines, but the activity was not superior to that of doxorubicin (IC 50 : 4.56–8.29 μM). [ 41,42 ] The activity of hybrids 6a,b (IC 50 : 7.8–66 μM) was comparable to or better than that of the references 5‐fluorouracil (IC 50 : 38 to >100 μM) and semaxanib (IC 50 : 41.39 to >100 μM) against the three cancer cell lines and these two hybrids (IC 50 : >100 and 91.53 μM, respectively) were also less toxic than 5‐fluorouracil (IC 50 : 37.87 μM) and semaxanib (IC 50 : 21.86 μM) against normal HFF‐1 cells.…”

Section: Isatin–coumarin Hybridsmentioning

confidence: 99%

Recent advances in isatin hybrids as potential anticancer agents

Ding

Zhou

Zeng

2020

Archiv der Pharmazie

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The isatin framework is a useful template for the development of novel anticancer agents. This is exemplified by the fact that several isatin‐based anticancer agents, such as semaxanib, sunitinib, nintedanib, and hesperadin, are already in use or under clinical trials for the treatment of diverse kinds of cancers. Isatin‐based hybrids could be obtained by incorporating other anticancer pharmacophores into the isatin skeleton and they have the potential to overcome drug resistance with reduced side effects. Thus, isatin‐based hybrids may provide attractive scaffolds for the development of novel anticancer agents. This review covers the recent advances of isatin‐based hybrids with anticancer activity, covering articles published between 2001 and 2019. The anticancer activities of these molecules and the structure–activity relationships are also discussed. The purpose of this review article is to set up the direction for the design and development of isatin‐based hybrids with high efficacy and low toxicity.

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Effect of Molecular Crowding Agents on the Activity and Stability of Immunosuppressive Enzyme Indoleamine 2,3‐Dioxygenase 1

2018

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Indoleamine 2,3-dioxygenase 1 (IDO1) plays pivotal role in regulating the metabolism of L-tryptophan (L-Trp) through kynurenine pathway, which is a well-established therapeutic target for the treatment of diseases associated with immunosuppression. Disproportionate expression of the enzyme and poor prediction of various types of malignancies make the development and clinical trials of IDO1 inhibitors extremely relevant. However, IDO1-based drug development has been hindered due to the use of idealized dilute buffer solution media during the screening and optimization of inhibitors, which do not reflect the highly crowded intracellular environment. In this report, IDO1 enzyme activity and its inhibitory activity against few potent compounds of N'-hydroxyamidine and aryl-substituted pyran scaffolds were investigated under macromolecularly crowded environment. The synthetic crowding agents were used to generate a cellular mimetic condition where IDO1 enzyme was found to retain its activity. A nonlinear relationship between the size and volume of the crowding agent with enzyme kinetic parameters was observed. The results suggest that judicious use of size and volume of the crowding agent could provide cellular mimetic environment. A very similar catalytic efficiency, inhibitory activity along with preservation of secondary structural content of IDO1 enzyme under the selected crowded media makes these crowding agents appropriate for further therapeutic application.

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Synthesis and evaluation of oxindoles as promising inhibitors of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1

Cited by 16 publications

References 58 publications

4,5-Disubstituted 1,2,3-triazoles: Effective Inhibition of Indoleamine 2,3-Dioxygenase 1 Enzyme Regulates T cell Activity and Mitigates Tumor Growth

4,5-Disubstituted 1,2,3-triazoles: Effective Inhibition of Indoleamine 2,3-Dioxygenase 1 Enzyme Regulates T cell Activity and Mitigates Tumor Growth

Recent advances in isatin hybrids as potential anticancer agents

Effect of Molecular Crowding Agents on the Activity and Stability of Immunosuppressive Enzyme Indoleamine 2,3‐Dioxygenase 1

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