Design, Synthesis and Antiproliferative Activity of Novel 2-Substituted-4-amino-6-halogenquinolines

Jiang, Nan; Zhai, Xin; Li, Ting; Liu, Difa; Zhang, Tingting; Wang, Bin; Gong, Ping

doi:10.3390/molecules17055870

Cited by 23 publications

(6 citation statements)

References 19 publications

(19 reference statements)

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“…There was no significant difference on Raf-1 kinase activity between NSK-01105 and sorafenib at 10 μmol/L. The quinazoline skeleton is considered to be a promising nucleus for EGFR inhibitors [14]. We further investigated whether NSK-01105 also affected the activation of EGFR.…”

Section: Nsk-01105 Downregulated Bcl-2 and Mcl-1 Levels In Prostate Cmentioning

confidence: 98%

NSK-01105 inhibits proliferation and induces apoptosis of prostate cancer cells by blocking the Raf/MEK/ERK and PI3K/Akt/mTOR signal pathways

Liang

Wang

et al. 2014

Tumor Biol.

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The purposes of this study are to investigate the antitumor activities of NSK-01105, a novel sorafenib derivative, in in vitro and in vivo models, and explore the potential mechanisms. The effects of NSK-01105 on proliferation and apoptosis of prostate cancer cells were established by cytotoxicity assays, apoptosis analysis, flow cytometry analysis, and Western blot analysis. Two xenograft tumor models were used to verify the therapeutic effect of NSK-01105 in vivo. NSK-01105 exhibited broad-spectrum antitumor activity, particularly in prostate cancer cells. Characterization of apoptosis morphology was observed, and the percentage of apoptosis-positive cells significantly increased after NSK-01105 treatment for 24 h. Furthermore, a significant increase of the "sub-G1" population in LNCaP and PC-3 cells after NSK-01105 treatment was determined by cell cycle analysis. Tumor growth was significantly suppressed by once daily oral 30 mg/kg dose of NSK-01105 with the inhibition rates of 63.82% in LNCaP models and 64.29% in PC-3 models, respectively. The activation of Raf-1 kinase and epidermal growth factor receptor was downregulated by NSK-01105 at 10 μmol/L. Consequently, the dual inhibitions of Raf/MEK/ERK and PI3K/Akt/mTOR signal pathways were observed by Western blot analysis. Collectively, our results suggest a role of NSK-01105 in treatment for human prostate tumors by inhibiting cell proliferation and inducing apoptosis. NSK-01105 appears to be a promising orally active anticancer drug and deserves further investigation.

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Section: Nsk-01105 Downregulated Bcl-2 and Mcl-1 Levels In Prostate Cmentioning

confidence: 98%

NSK-01105 inhibits proliferation and induces apoptosis of prostate cancer cells by blocking the Raf/MEK/ERK and PI3K/Akt/mTOR signal pathways

Liang

Wang

et al. 2014

Tumor Biol.

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“…This molecule contains aquinoline ring and a small sulfonamide group. Previous studies also reported 2-sulfolmethyl quinolines showing anti-hepatitis B virus activity [ 38 ] and antiproliferative activity [ 39 ] against HepG2 cancer cells in vitro.…”

Section: Resultsmentioning

confidence: 99%

Targeting DNA Binding for NF-κB as an Anticancer Approach in Hepatocellular Carcinoma

Chung

Lam

Zhou

et al. 2018

Cells

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Quinoline core has been shown to possess a promising role in the development of anticancer agents. However, the correlation between its broad spectrum of bioactivity and the underlying mechanism of actions is poorly understood. The present study, with the use of bioinformatics approaches, reported a series of designed molecules which integrated quinoline core and sulfonyl moiety, with the objective of evaluating the substituent and linker effects on anticancer activities and associated mechanistic targets. We identified potent compounds (1h, 2h, 5 and 8) exhibiting significant anticancer effects towards liver cancer cells (Hep3B) with the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) relative values of cytotoxicity below 0.40, a value in the range of doxorubicin positive control with the value of 0.12. Bulky substituents and the presence of bromine atom, as well as the presence of sulfonamide linkage, are likely the favorable structural components for molecules exerting a strong anticancer effect. To the best of our knowledge, our findings obtained from chemical synthesis, in vitro cytotoxicity, bioinformatics-based molecular docking analysis (similarity ensemble approach, SEA),and electrophoretic mobility shift assay provided the first evidence in correlation to the anticancer activities of the selected compound 5 with the modulation on the binding of transcription factor NF-κB to its target DNA. Accordingly, compound 5 represented a lead structure for the development of quinoline-based NF-κB inhibitors and this work added novel information on the understanding of the mechanism of action for bioactive sulfonyl-containing quinoline compounds against hepatocellular carcinoma.

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“…The quinazoline skeleton is considered to be a promising nucleus for EGFR inhibitors [27] . We further investigated whether NSK-01105 also affected the activities of EGFR.…”

Section: Resultsmentioning

confidence: 99%

NSK-01105, a Novel Sorafenib Derivative, Inhibits Human Prostate Tumor Growth via Suppression of VEGFR2/EGFR-Mediated Angiogenesis

Liang

Wang

et al. 2014

PLoS ONE

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The purpose of this study is to investigate the anti-angiogenic activities of NSK-01105, a novel sorafenib derivative, in in vitro, ex vivo and in vivo models, and explore the potential mechanisms. NSK-01105 significantly inhibited vascular endothelial growth factor (VEGF)-induced migration and tube formation of human umbilical vein endothelial cells at non-cytotoxic concentrations as shown by wound-healing, transwell migration and endothelial cell tube formation assays, respectively. Cell viability and invasion of LNCaP and PC-3 cells were significantly inhibited by cytotoxicity assay and matrigel invasion assay. Furthermore, NSK-01105 also inhibited ex vivo angiogenesis in matrigel plug assay. Western blot analysis showed that NSK-01105 down-regulated VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR2) and the activation of epidermal growth factor receptor (EGFR). Tumor volumes were significantly reduced by NSK-01105 at 60 mg/kg/day in both xenograft models. Immunohistochemical staining demonstrated a close association between inhibition of tumor growth and neovascularization. Collectively, our results suggest a role of NSK-01105 in treatment for human prostate tumors, and one of the potential mechanisms may be attributed to anti-angiogenic activities.

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Design, Synthesis and Antiproliferative Activity of Novel 2-Substituted-4-amino-6-halogenquinolines

Cited by 23 publications

References 19 publications

NSK-01105 inhibits proliferation and induces apoptosis of prostate cancer cells by blocking the Raf/MEK/ERK and PI3K/Akt/mTOR signal pathways

NSK-01105 inhibits proliferation and induces apoptosis of prostate cancer cells by blocking the Raf/MEK/ERK and PI3K/Akt/mTOR signal pathways

Targeting DNA Binding for NF-κB as an Anticancer Approach in Hepatocellular Carcinoma

NSK-01105, a Novel Sorafenib Derivative, Inhibits Human Prostate Tumor Growth via Suppression of VEGFR2/EGFR-Mediated Angiogenesis

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