Fluoropyrimidin-2,4-dihydroxy-5-isopropylbenzamides as antitumor agents against CRC and NSCLC cancer cells

Wu, Wei‐Cheng; Liu, Yimin; Liao, Yu-Hsuan; Hsu, Kai‐Cheng; Lien, Ssu-Ting; Chen, I-Chung; Lai, Mei-Jung; Li, Yu-Hsuan; Pan, Shiow‐Lin; Chen, Mei-Chuan; Liou, Jing‐Ping

doi:10.1016/j.ejmech.2020.112540

Cited by 9 publications

(6 citation statements)

References 48 publications

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“…AUY-922, as a positive prodrug control, performed favorable anti-NSCLC activity on NSCLC cell lines H460, A549 and H1975 ( 33 ). Herein, the effects of NVP-AUY922 on cell viability, cell cycle progression and cell apoptosis of another NSCLC cell line H1299 were analyzed.…”

Section: Resultsmentioning

confidence: 99%

Complex Crystal Structure Determination of Hsp90N-NVP-AUY922 and In Vitro Anti-NSCLC Activity of NVP-AUY922

Guo

et al. 2022

Front. Oncol.

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New targeted chemotherapy agents greatly improved five-year survival in NSCLC patients, but which were susceptible to drug resistance. NVP-AUY922, terminated in phase II clinical trials, exhibited promising anti-NSCLC (non-small-cell lung cancer) activity targeting to Hsp90N (heat shock protein), which demonstrated advantages in overcoming drug resistance as a broad-spectrum anti-cancer target. It was expected to develop novel anti-NSCLC drugs to overcome drug resistance by the structural optimization of NVP-AUY922. However, the absence of high-resolution complex crystal structure of Hsp90N-NVP-AUY922 blocked the way. Herein, 1.59 Å-resolution complex crystal structure of Hsp90N-NVP-AUY922 (PDB ID 6LTI) was successfully determined by X-ray diffraction. Meanwhile, there was a strong binding capability between NVP-AUY922 and its target Hsp90N verified by TSA (ΔTm, −15.56 ± 1.78°C) and ITC (Kd, 5.10 ± 2.10 nM). Results by the complex crystal structure, TSA and ITC verified that NVP-AUY922 well accommodated in the ATP-binding pocket of Hsp90N to disable the molecular chaperone activity of Hsp90. Therefore, NVP-AUY922 exhibited approving inhibitory activity on NSCLC cell line H1299 (IC50, 2.85 ± 0.06 μM) by inhibiting cell proliferation, inducing cell cycle arrest and promoting cell apoptosis. At the basis of the complex crystal structure and molecular interaction analysis, thirty-two new NVP-AUY922 derivatives were further designed, and among which twenty-eight new ones display enhanced binding force with Hsp90N by molecular docking evaluation. The results would promote anti-NSCLC new drug development to overcome drug resistance based on the lead compound NVP-AUY922.

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Section: Resultsmentioning

confidence: 99%

Complex Crystal Structure Determination of Hsp90N-NVP-AUY922 and In Vitro Anti-NSCLC Activity of NVP-AUY922

Guo

et al. 2022

Front. Oncol.

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“…Apoptosis is a self-destructive process of cell stress, resulting in cell death and reduced cell viability, especially in tumor cells. Some biomarkers are used to monitor the process of apoptosis, including caspases (23), mitochondrial potential (24), and sub G1 group (25). Studies have shown that the main internal and external causes of apoptosis are related to caspases, including caspase-3 and/or caspase-9 (26).…”

Section: Discussionmentioning

confidence: 99%

Neferine induces p38 MAPK/JNK1/2 activation to modulate melanoma proliferation, apoptosis, and oxidative stress

Xie¹,

Chen²,

Cong³

2020

Ann Transl Med

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Background: Melanoma is a malignant skin cancer that has a poor prognosis in advanced patients. The aim of the present study was to investigate the antitumor role of neferine in melanoma.Methods: A375 and C32 cells were selected as research vectors in vitro. Cell counting Kit-8, 5-ethynyl-2'deoxyuridine staining, transwell, and flow cytometry assay were used to examined cell malignant phenotypes. Mitochondrial dysfunction was detected by 5,50,6,60-tetrachloro-1,10,3,30-tetraethyl-imidacarbocyanine iodide staining and enzyme-linked immunosorbent assay. Reactive oxygen species (ROS) generation was measured using oxidation sensitive fluorescent probe. The phosphorylation activity of p38 and Jun-Nterminal kinase (JNK) 1/2 were examined by Western blot. A xenograft model was established via the subcutaneous injection of A375 cells into the right flank of BALB/c mice in vivo.Results: Neferine (2.5, 5, or 10 μM) treatment inhibited proliferation, invasion, and enhanced apoptotic rate of A375 and C32 cells. Neferine treatment induced abnormal changes in mitochondrial membrane potential. Further studies showed that neferine could significantly increase the production of reactive oxygen species (ROS) and 3,4-methylenedioxyamphetamine (MDA) content, decreased the superoxide dismutase (SOD) level. Neferine (5, 10, or 20 mg/kg) obviously suppressed the weight and size of the xenograft tumor, the number of apoptotic cells in vivo, and the expression of Ki67 + and survivin + decreased. Notably, neferine also activated the phosphorylation of p38 and JNK1/2. Conclusions: Neferine inhibits the proliferative and invasion ability of melanoma cells and promotes their apoptosis, ameliorating the malignant progression of melanoma, likely achieved by upregulating the phosphorylation levels of p38 mitogen-activated protein kinase and JNK1/2.

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“…5.1.10. Synthesis of Methyl 7-((3-((Methyl(prop-2-yn-1-yl)amino)methyl)phenyl)amino)-7-oxoheptanoate (43). The title compound 43 was synthesized using 3-((methyl(prop-2-yn-1-yl)amino)methyl)aniline (38) and 7-methoxy-7-oxoheptanoic acid in a manner similar to that described for compound 40 in 78% yield.…”

Section: Methodsmentioning

confidence: 99%

“…Protein lysates from cells (1 × 10 6 ) were separated by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate and then transferred onto a PVDF membrane. After the transfer, the membrane was used for Western blotting analysis according to a method described previously …”

Section: Experimental Sectionmentioning

confidence: 99%

Installation of Pargyline, a LSD1 Inhibitor, in the HDAC Inhibitory Template Culminated in the Identification of a Tractable Antiprostate Cancer Agent

et al. 2021

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Pragmatic insertion of pargyline, a LSD1 inhibitor, as a surface recognition part in the HDAC inhibitory pharmacophore was planned in pursuit of furnishing potent antiprostate cancer agents. Resultantly, compound 14 elicited magnificent cell growth inhibitory effects against the PC-3 and DU-145 cell lines and led to remarkable suppression of tumor growth in human prostate PC-3 and DU-145 xenograft nude mouse models. The outcome of the enzymatic assays ascertained that the substantial antiproliferative effects of compound 14 were mediated through HDAC6 isoform inhibition as well as selective MAO-A and LSD1 inhibition. Moreover, the signatory feature of LSD1 inhibition by 14 in the context of H3K4ME2 accumulation was clearly evident from the results of western blot analysis. Gratifyingly, hydroxamic acid 14 demonstrates good human hepatocytic stability and good oral bioavailability in rats and exhibits enough promise to emerge as a therapeutic for the treatment of prostate cancer in the near future.

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Fluoropyrimidin-2,4-dihydroxy-5-isopropylbenzamides as antitumor agents against CRC and NSCLC cancer cells

Cited by 9 publications

References 48 publications

Complex Crystal Structure Determination of Hsp90N-NVP-AUY922 and In Vitro Anti-NSCLC Activity of NVP-AUY922

Complex Crystal Structure Determination of Hsp90N-NVP-AUY922 and In Vitro Anti-NSCLC Activity of NVP-AUY922

Neferine induces p38 MAPK/JNK1/2 activation to modulate melanoma proliferation, apoptosis, and oxidative stress

Installation of Pargyline, a LSD1 Inhibitor, in the HDAC Inhibitory Template Culminated in the Identification of a Tractable Antiprostate Cancer Agent

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