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

Baburajeev, C. P.; Mohan, Chakrabhavi Dhananjaya; Patil, Govindagouda S.; Rangappa, Shobith; Pandey, Vijay; Anusha, Sebastian; Fuchs, Julian E.; Bender, Andreas; Lobie, Peter E.; Basappa, Basappa; Rangappa, Kanchugarakoppal S.

doi:10.1039/c6ra01906d

Cited by 22 publications

(17 citation statements)

References 44 publications

(52 reference statements)

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“…EMT can be modulated by diverse transcription factors including zinc-finger E-box-binding (ZEB), Twist, Snail, and Slug [16] , [17] , [18] . STAT3 is frequently overactivated in different tumors including hepatocellular carcinoma (HCC) and can positively correlate with tumorigenicity, EMT, antiapoptosis, and metastasis [19] , [20] , [21] , [22] . IL-6 activates STAT3 to promote EMT through the induction of Snail expression in cancers [8] , [23] .…”

Section: Introductionmentioning

confidence: 99%

Brusatol suppresses STAT3-driven metastasis by downregulating epithelial-mesenchymal transition in hepatocellular carcinoma

Lee

Mohan

Deivasigamani

et al. 2020

Journal of Advanced Research

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118

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Section: Introductionmentioning

confidence: 99%

Brusatol suppresses STAT3-driven metastasis by downregulating epithelial-mesenchymal transition in hepatocellular carcinoma

Lee

Mohan

Deivasigamani

et al. 2020

Journal of Advanced Research

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118

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“…2-ethoxy-4,5-diphenyl-1,3-oxazine-6-one is a small molecule reported to decrease the levels of nuclear NF-κB in lipopolysaccharide (LPS)-induced NGF-differentiated PC12 cells [ 16 ]. Given the relevance with aforementioned reports and in continuation of our effort to synthesize various heterocycles to explore their medicinal properties [ 17 – 24 ], herein we prepared the series of oxazine derivatives and evaluated their effect on HCT116 cells. The lead compounds 2-((2-acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-oxazin-3-yl)methyl)isoindoline-1,3-dione (API) and dimethyl 2-((2-acetyl-4-(4-methoxyphenyl)-6,6-dimethyl-5,6-dihydro-2H-1,2-oxazin-3-yl)methyl)malonate (DMO) were chosen and evaluated for their NF-κB DNA binding inhibitory activity and NF-κB dependent luciferase expression studies.…”

Section: Introductionmentioning

confidence: 99%

Novel Synthetic Oxazines Target NF-κB in Colon Cancer In Vitro and Inflammatory Bowel Disease In Vivo

et al. 2016

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Aberrant activation of nuclear factor kappa B (NF-κB) has been linked with the pathogenesis of several proinflammatory diseases including number of cancers and inflammatory bowel diseases. In the present work, we evaluated the anticancer activity of 1,2-oxazines derivatives against colorectal cancer cell lines and identified 2-((2-acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-oxazin-3-yl)methyl)isoindoline-1,3-dione (API) as the lead anticancer agent among the tested compounds. The apoptosis inducing effect of API was demonstrated using flow cytometry analysis and measuring the caspase 3/7 activity in API treated cells. Based on the literature on inhibition of NF-κB by oxazines, we evaluated the effect of 1,2-oxazines against the ability of NF-κB binding to DNA, NF-κB-dependent luciferase expression and IκBα phosphorylation. We found that, API abrogate constitutive activation of NF-κB and inhibits IκBα phosphorylation in HCT116 cells. Our in silico analysis revealed the binding of oxazines to the hydrophobic cavity that present between the interface of p65 and IκBα. Given the relevance with aberrant activation of NF-κB in inflammation bowel disease (IBD), we evaluated the effect of API on dextran sulphate sodium-induced IBD mice model. The treatment of IBD induced mice with API decreased the myeloperoxidase activity in colonic extract, modulated the colon length and serum levels of pro- and anti-inflammatory cytokines such as TNF-α, IFN-γ, IL-6, IL-1β and IL-10. Furthermore, the histological analysis revealed the restoration of the distorted cryptic epithelial structure of colon in the API treated animals. In conclusion, we comprehensively validated the NF-κB inhibitory efficacy of API that targets NF-κB in in vitro colon cancer and an in vivo inflammatory bowel disease model.

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“…In addition, several studies have demonstrated the persistent phosphorylation of STAT3 in 22-65% of NSCLC [81], and the deregulation of STAT3 has been associated with malignant transformation [86,87]. The phosphorylation of Tyr705 is a critical event in regulating the transcriptional activity of STAT3, and mitigation of phosphorylation can result in a decline in the STAT3 nuclear pool [88]. Therefore, blocking of nuclear translocation of STAT3 by inhibiting its phosphorylation could be a therapeutic approach.…”

Section: Discussionmentioning

confidence: 99%

The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells

et al. 2019

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STAT3 is an oncogenic transcription factor that regulates the expression of genes which are involved in malignant transformation. Aberrant activation of STAT3 has been observed in a wide range of human malignancies and its role in negative prognosis is well-documented.In this report, we performed high-throughput virtual screening in search of STAT3 signaling inhibitors using a cheminformatics platform and identified 2-Amino-6-[2-(Cyclopropylmethoxy)-6-Hydroxyphenyl]-4-Piperidin-4-yl Nicotinonitrile (ACHP) as the inhibitor of the STAT3 signaling pathway. The predicted hit was evaluated in non-small cell lung cancer (NSCLC) cell lines for its STAT3 inhibitory activity. In vitro experiments suggested that ACHP decreased the cell viability and inhibited the phosphorylation of STAT3 on Tyr705 of NSCLC cells. In addition, ACHP imparted inhibitory activity on the constitutive activation of upstream protein tyrosine kinases, including JAK1, JAK2, and Src. ACHP decreased the nuclear translocation of STAT3 and downregulated its DNA binding ability. Apoptosis was evidenced by cleavage of caspase-3 and PARP with the subsequent decline in antiapoptotic proteins, including Bcl-2, Bcl-xl, and survivin. Overall, we report that ACHP can act as a potent STAT3 signaling inhibitor in NSCLC cell lines.

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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

Cited by 22 publications

References 44 publications

Brusatol suppresses STAT3-driven metastasis by downregulating epithelial-mesenchymal transition in hepatocellular carcinoma

Brusatol suppresses STAT3-driven metastasis by downregulating epithelial-mesenchymal transition in hepatocellular carcinoma

Novel Synthetic Oxazines Target NF-κB in Colon Cancer In Vitro and Inflammatory Bowel Disease In Vivo

The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells

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