Please use this identifier to cite or link to this item: https://doi.org/10.3389/fphar.2018.01125
Title: N-substituted pyrido-1,4-Oxazin-3-ones induce apoptosis of hepatocellular carcinoma cells by targeting NF-?B signaling pathway
Authors: Mohan, C.D
Bharathkumar, H
Dukanya, Department of Studies in Organic Chemistry, University of Mysore, Mysore, India
Rangappa, S
Shanmugam, M.K 
Chinnathambi, A
Alharbi, S.A
Alahmadi, T.A
Bhattacharjee, A
Lobie, P.E 
Deivasigamani, A
Hui, K.M
Sethi, G 
Basappa, Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Bangalore, India, Department of Studies in Organic Chemistry, University of Mysore, Mysore, India
Rangappa, K.S
Kumar, A.P 
Keywords: 2 [3 (3 oxo 2h pyrido[3,2 b][1,4]oxazin 4(3h) yl)propyl]isoindoline 1,3 dione
4 (2,6 dichlorobenzyl) 2h pyrido[3,2 b][1,4]oxazin 3(4h) one
4 (4 isopropylbenzyl) 2h pyrido[3,2 b][1,4]oxazin 3(4h) one
4 (4 nitrobenzyl) 2h pyrido [3,2 b][1,4]oxazin 3(4h) one
4 (cyclohexylmethyl) 2h pyrido[3,2 b][1,4]oxazin 3(4h) one
4 [(3 oxo 2h pyrido[3,2 b][1,4]oxazin 4(3h) yl)methyl]benzonitrile
4 [(6,6 dimethyl 4 phenyl 5,6 dihydro 4h 1,2 oxazin 3 yl)methyl] 2h pyrido[3,2 b][1,4]oxazin 3(4h) one
4 [4 (tert butyl)benzyl] 2h pyrido[3,2 b][1,4]oxazin 3(4h) one
4 [[4 (4 chlorophenyl) 6,6 dimethyl 5,6 dihydro 4h 1,2 oxazin 3 yl]methyl] 2h pyrido[3,2 b][1,4]oxazin 3(4h) one
4' [(3 oxo 2h pyrido[3,2 b][1,4]oxazin 4(3H) yl)methyl] [1,10 biphenyl] 2 carbonitrile
antineoplastic agent
DNA
immunoglobulin enhancer binding protein
liver protective agent
luciferase
transcription factor RelA
unclassified drug
animal experiment
animal model
animal tissue
antiproliferative activity
apoptosis
Article
cancer inhibition
cell viability
computer model
controlled study
dose response
down regulation
drug effect
drug efficacy
drug identification
drug potency
drug synthesis
female
gene expression regulation
HCCLM3 cell line
Hep-G2 cell line
Huh-7 cell line
IC50
liver cell carcinoma
luciferase gene
molecularly targeted therapy
mouse
nonhuman
pharmacological parameters
protein DNA binding
protein expression
protein phosphorylation
time dependence
tumor volume
Issue Date: 2018
Citation: Mohan, C.D, Bharathkumar, H, Dukanya, Department of Studies in Organic Chemistry, University of Mysore, Mysore, India, Rangappa, S, Shanmugam, M.K, Chinnathambi, A, Alharbi, S.A, Alahmadi, T.A, Bhattacharjee, A, Lobie, P.E, Deivasigamani, A, Hui, K.M, Sethi, G, Basappa, Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Bangalore, India, Department of Studies in Organic Chemistry, University of Mysore, Mysore, India, Rangappa, K.S, Kumar, A.P (2018). N-substituted pyrido-1,4-Oxazin-3-ones induce apoptosis of hepatocellular carcinoma cells by targeting NF-?B signaling pathway. Frontiers in Pharmacology 9 (NOV) : 1125. ScholarBank@NUS Repository. https://doi.org/10.3389/fphar.2018.01125
Rights: Attribution 4.0 International
Abstract: Hepatocellular carcinoma (HCC) is a fatal disease and ranked fifth in cancer related mortality. Persistent activation of NF-?B is responsible for the oncogenesis, metastasis, tumor evasion, anti-apoptosis, angiogenesis and proliferation in HCC. Therefore, designing of chemically novel, biologically potent small molecules that target NF-?B signaling cascade have gained prominent clinical interest. Herein we synthesized a novel class of 4-(substituted)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one by reacting 2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one with various alkyl halides by using combustion derived bismuth oxide. We evaluated the antiproliferative efficacy of newly synthesized compounds against HCC cells and identified 4-(4-nitrobenzyl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (NPO) as lead anticancer agent. In addition, we investigated the effect of NPO on the DNA binding ability of NF-?B and NF-?B regulated luciferase expression in HCC cells. The results demonstrated that NPO can induce significant growth inhibitory effects in HepG2, HCCLM3 and Huh-7 cells in dose and time-dependent manner. Interestingly, NPO induced significant downregulation in p65 DNA binding ability, p65 phosphorylation and subsequent expression of NF-?B dependent luciferase gene expression in diverse HCC cell lines. Further, in silico docking analysis suggested that NPO can show direct physical interaction with NF-?B. Finally, NPO was found to significantly abrogate tumor growth at a dose of 50 mg/kg in an orthotopic mouse model. Thus, we report the potential anticancer effects of NPO as a novel inhibitor of NF-?B signaling pathway in HCC. Copyright © 2018 Mohan, Bharathkumar, Dukanya, Rangappa, Shanmugam.
Source Title: Frontiers in Pharmacology
URI: https://scholarbank.nus.edu.sg/handle/10635/181171
ISSN: 16639812
DOI: 10.3389/fphar.2018.01125
Rights: Attribution 4.0 International
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