Synthesis and biological evaluation of tetrahydropyridinepyrazoles (‘PFPs’) as inhibitors of STAT3 phosphorylation

N, Revanna C.; Basappa,; Srinivasa,; Feng, Linyin; Siveen, Kodappully Sivaraman; Dai, Xiaoyun; Swamy, S. Nanjunda; G, Bhadregowda D.; Sethi, Gautam; Mantelingu, Kempegowda; Bender, Andreas; Rangappa, K. S.

doi:10.1039/c3md00119a

Cited by 6 publications

(1 citation statement)

References 25 publications

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“…Additionally, pyrazoles may provide better pharmacological effects, and have also generated a number of drugs such as pyrazofurin, celecoxib, ramifenazone, lonazolac, and rimonabant [26][27][28][29][30]. We reported the synthesis of pyridine-fused pyrazoles as a STAT3 inhibitor and an inhibitor of cancer cell growth [31]. Additionally, the pyrazole-based compound MNS1-Leu inhibited IL-6-induced STAT3 phosphorylation in patient-derived HGG cells without adversely affecting Akt, STAT1, JAK2, or ERK1/2 phosphorylation [32].…”

Section: Introductionmentioning

confidence: 99%

De Novo Design of Imidazopyridine-Tethered Pyrazolines That Target Phosphorylation of STAT3 in Human Breast Cancer Cells

Ravish

Shivakumar

et al. 2023

Bioengineering

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In breast cancer (BC), STAT3 is hyperactivated. This study explored the design of imidazopyridine-tethered pyrazolines as a de novo drug strategy for inhibiting STAT3 phosphorylation in human BC cells. This involved the synthesis and characterization of two series of compounds namely, 1-(3-(2,6-dimethylimidazo [1,2-a]pyridin-3-yl)-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-(4-(substituted)piperazin-1-yl)ethanone and N-substituted-3-(2,6-dimethylimidazo[1,2-a]pyridin-3-yl)-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazoline-1-carbothioamides. Compound 3f with 2,3-dichlorophenyl substitution was recognized among the tested series as a lead structure that inhibited the viability of MCF-7 cells with an IC50 value of 9.2 μM. A dose- and time-dependent inhibition of STAT3 phosphorylation at Tyr705 and Ser727 was observed in MCF-7 and T47D cells when compound 3f was added in vitro. Calculations using density functional theory showed that the title compounds HOMOs and LUMOs are situated on imidazopyridine-pyrazoline and nitrophenyl rings, respectively. Hence, compound 3f effectively inhibited STAT3 phosphorylation in MCF-7 and T47D cells, indicating that these structures may be an alternative synthon to target STAT3 signaling in BC.

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Section: Introductionmentioning

confidence: 99%

De Novo Design of Imidazopyridine-Tethered Pyrazolines That Target Phosphorylation of STAT3 in Human Breast Cancer Cells

Ravish

Shivakumar

et al. 2023

Bioengineering

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Targeting JAK2/STAT3 for the treatment of cancer: A review on recent advancements in molecular development using structural analysis and SAR investigations

Kohal,

Bisht,

Gupta

et al. 2024

Bioorganic Chemistry

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Nano-cuprous oxide catalyzed one-pot synthesis of a carbazole-based STAT3 inhibitor: a facile approach via intramolecular C–N bond formation reactions

et al. 2016

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In this study, we report the one-pot synthesis of substituted carbazole derivatives using nano cuprous oxide as a catalyst via intramolecular C-N bond forming reactions. Among the synthesized carbazoles, 3'-((3-acetyl-6-chloro-9H-carbazol-9-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile (ACB) was identified as lead antiproliferative agent against lung cancer cell lines A549 and LLC with an IC 50 of 13.6 and 16.4 µM respectively. Further, we found that lead compound suppresses the constitutive phosphorylation of STAT3 (Tyr-705) in A549, HCC-2279 and H1975 cells. We analyzed the levels of phospho-STAT3 and LSD1 in the nuclear extract of ACB treated HCC-2279 cells to evaluate the transcriptional activity of STAT3. We found the downregulation of phospho-STAT3 without any change in the expression of LSD1 indicating that ACB downregulates the transcriptional activity of STAT3. Molecular docking

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Synthesis and biological evaluation of tetrahydropyridinepyrazoles (‘PFPs’) as inhibitors of STAT3 phosphorylation

Cited by 6 publications

References 25 publications

De Novo Design of Imidazopyridine-Tethered Pyrazolines That Target Phosphorylation of STAT3 in Human Breast Cancer Cells

De Novo Design of Imidazopyridine-Tethered Pyrazolines That Target Phosphorylation of STAT3 in Human Breast Cancer Cells

Targeting JAK2/STAT3 for the treatment of cancer: A review on recent advancements in molecular development using structural analysis and SAR investigations

Nano-cuprous oxide catalyzed one-pot synthesis of a carbazole-based STAT3 inhibitor: a facile approach via intramolecular C–N bond formation reactions

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