The first pharmacophore model for potent NF-κB inhibitors

Tsai, Keng‐Chang; Teng, Li Wei; Shao, Yi; Chen, Yu Chen; Lee, Yu Ching; Li, Minyong; Hsiao, Nai-Wan

doi:10.1016/j.bmcl.2009.08.021

Cited by 11 publications

(5 citation statements)

References 38 publications

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“…HRMS (EI), M + 1 calculated for C 16 H 14 ClN 3 , 284.0949, found 284.0950. These experimental results are consistent with previous reports [ 18 – 20 ].…”

Section: Methodssupporting

confidence: 94%

Syntheses and Structure–Activity Relationships of N-Phenethyl-Quinazolin-4-yl-Amines as Potent Inhibitors of Cytochrome bd Oxidase in Mycobacterium tuberculosis

et al. 2021

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The development of cytochrome bd oxidase (cyt-bd) inhibitors are needed for comprehensive termination of energy production in Mycobacterium tuberculosis (Mtb) to treat tuberculosis infections. Herein, we report on the structure-activity-relationships (SAR) of 22 new N-phenethyl-quinazolin-4-yl-amines that target cyt-bd. Our focused set of compounds was synthesized and screened against three mycobacterial strains: Mycobacterium bovis BCG, Mycobacterium tuberculosis H37Rv and the clinical isolate Mycobacterium tuberculosis N0145 with and without the cytochrome bcc:aa3 inhibitor Q203 in an ATP depletion assay. Two compounds, 12a and 19a, were more active against all three strains than the naturally derived cyt-bd inhibitor aurachin D.

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“…HRMS (EI), M + 1 calculated for C 16 H 14 ClN 3 , 284.0949, found 284.0950. These experimental results are consistent with previous reports [ 18 – 20 ].…”

Section: Methodssupporting

confidence: 94%

Syntheses and Structure–Activity Relationships of N-Phenethyl-Quinazolin-4-yl-Amines as Potent Inhibitors of Cytochrome bd Oxidase in Mycobacterium tuberculosis

et al. 2021

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“…DU145 cells were incubated with 6-Amino quinazoline and isohelenin, potent inhibitors of NF-κB transcriptional activation (30, 31), SC-514, a reversible and highly selective inhibitor of IKK-2 and wedelolactone, a irreversible inhibitor of IKKα and β kinase activity (32) or DMSO (control) for 24h. Under the conditions tested, only SC-514 and 6-Amino quinazoline strongly inhibited proliferation (Figure 4d) demonstrating that pharmacological NF-κB inhibitors are potent inhibitors of cell proliferation.…”

Section: Resultsmentioning

confidence: 99%

The receptor tyrosine kinase Axl is an essential regulator of prostate cancer proliferation and tumor growth and represents a new therapeutic target

et al. 2012

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Deregulation of the receptor tyrosine kinase Axl has been implicated in the progression of several human cancers. However, the role of Axl in prostate cancer remains poorly understood, and the therapeutic efficacy of Axl targeting remains untested. In this report we identified Axl as a new therapeutic target for prostate cancer. Axl is consistently overexpressed in prostate cancer cell lines and human prostate tumors. Interestingly, the blockage of Axl gene expression strongly inhibits proliferation, migration, invasion, and tumor growth. Furthermore, inhibition of Axl expression by small interfering RNA regulates a transcriptional program of genes involved in cell survival, strikingly all connected to the NF-κB pathway. Additionally, blockage of Axl expression leads to inhibition of Akt, IKKα and IκBα phosphorylation, increasing IκBα expression and stability. Furthermore, induction of Akt phosphorylation by IGF1 in Axl knockdown cells restores Akt activity and proliferation. Taken together our results establish an unambiguous role for Axl in prostate cancer tumorigenesis with implications for prostate cancer treatment.

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“…Another possibility would be the interaction with transcription factor(s), or a direct pathway inhibition at the TLR, for which dihydro-pyrrolo [2,3-d]pyrimidines have been recently demonstrated to be effective [34]. Concerning a possible interaction with transcription factor Nf-κB, it would be interesting to use the results presented here as a test set for already existing in silico screening systems for small molecule immune-modulators, as published by Tsai and colleagues for NF-κB [35]. Here, the authors focused on the pgLPS-induced release of IL-8 as a key cytokine of the immune response in HGF-1 cells.…”

Section: Discussionmentioning

confidence: 97%

“…Figure A2), 11 (Figure A3), 15 (Figure A4), and 16 (Figure A5), as well as NMR data and purities of all synthesized compounds, are presented in Appendix A. Synthetic dihydrochalcones were tested alongside well-characterized natural compounds (2-5, 8, 9, and 18)[13,35,[39][40][41] for a more comprehensive evaluation of the anti-inflammatory effect.…”

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confidence: 99%

Identification of Interleukin-8-Reducing Lead Compounds Based on SAR Studies on Dihydrochalcone-Related Compounds in Human Gingival Fibroblasts (HGF-1 cells) In Vitro

et al. 2020

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Background: In order to identify potential activities against periodontal diseases, eighteen dihydrochalcones and structurally related compounds were tested in an established biological in vitro cell model of periodontal inflammation using human gingival fibroblasts (HGF-1 cells). Methods: Subsequently to co-incubation of HGF-1 cells with a bacterial endotoxin (Porphyromonas gingivalis lipopolysaccharide, pgLPS) and each individual dihydrochalcone in a concentration range of 1 µM to 100 µM, gene expression of interleukin-8 (IL-8) was determined by qPCR and cellular interleukin-8 (IL-8) release by ELISA. Results: Structure–activity analysis based on the dihydrochalcone backbone and various substitution patterns at its aromatic ring revealed moieties 2′,4,4′,6′-tetrahydroxy 3-methoxydihydrochalcone (7) to be the most effective anti-inflammatory compound, reducing the pgLPS-induced IL-8 release concentration between 1 µM and 100 µM up to 94%. In general, a 2,4,6-trihydroxy substitution at the A-ring and concomitant vanilloyl (4-hydroxy-3-methoxy) pattern at the B-ring revealed to be preferable for IL-8 release inhibition. Furthermore, the introduction of an electronegative atom in the A,B-linker chain led to an increased anti-inflammatory activity, shown by the potency of 4-hydroxybenzoic acid N-vanillylamide (13). Conclusions: Our data may be feasible to be used for further lead structure designs for the development of potent anti-inflammatory additives in oral care products.

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The first pharmacophore model for potent NF-κB inhibitors

Cited by 11 publications

References 38 publications

Syntheses and Structure–Activity Relationships of N-Phenethyl-Quinazolin-4-yl-Amines as Potent Inhibitors of Cytochrome bd Oxidase in Mycobacterium tuberculosis

Syntheses and Structure–Activity Relationships of N-Phenethyl-Quinazolin-4-yl-Amines as Potent Inhibitors of Cytochrome bd Oxidase in Mycobacterium tuberculosis

The receptor tyrosine kinase Axl is an essential regulator of prostate cancer proliferation and tumor growth and represents a new therapeutic target

Identification of Interleukin-8-Reducing Lead Compounds Based on SAR Studies on Dihydrochalcone-Related Compounds in Human Gingival Fibroblasts (HGF-1 cells) In Vitro

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