Design, synthesis and biological evaluation of pyrazolyl-nitroimidazole derivatives as potential EGFR/HER-2 kinase inhibitors

Tao, Xiang-Xiang; Duan, Yongtao; Chen, Longwang; Tang, Dan-Jie; Yang, Meng-Ru; Wang, Pengfei; Xu, Chen; Zhu, Hai‐Liang

doi:10.1016/j.bmcl.2015.11.040

Cited by 54 publications

(17 citation statements)

References 24 publications

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“…Since the specific ligand to HER2 receptor is unidentified, and HER2 may function as didiemer more with EGFR in HepG2 cells, cell proliferation ability was assessed through EGF stimulation in serum free medium. Trastuzumab with the high concentrations of 30 and 100 g/mL suppressed slightly (10%‐20%) the proliferation of HepG2, JM1, and HER2‐transfected McA cells, ( F = 3.422, 17.174, and 10.001, P = 0.029, 0.001, and 0.001) (Figure B), indicating HER2 may function as a proliferation receptor through receptor dimerization with EGFR after EGF stimulation.…”

Section: Resultsmentioning

confidence: 99%

Recognition of HER2 expression in hepatocellular carcinoma and its significance in postoperative tumor recurrence

et al. 2019

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Background The ERBB2 oncogene hypothesis is challenged in hepatocellular carcinoma (HCC) with the conflicting evidences of human epidermal growth factor receptor 2 (HER2) overexpression. HER2 could be a new target as a treatment option for HCC as well as tumor recurrence after surgery. HER2 in HCC biology needs further explorations. Methods Clinical and mRNA data of HCC patients were obtained from TCGA HCC cohort, GSE89377 and GSE115018. Western Blotting and immunohistochemistry were employed to test expression of HER2, E‐cadherin, and Vimentin. In HepG2, JM1, HER2‐transfected McA cells, and TGF‐β cocultured JM1 cells, HCC biology, including cell survival, proliferation, and epithelial‐to‐mesenchymal transition (EMT) phenotypes were evaluated. Results ERBB2 mRNA amplification was found in HCC datasets, and its expression was downregulated in high grade HCC with a worse overall survival. HER2 overexpression was identified in H4IIE, HepG2, JM1 cells, and 82% (14/17) HCC samples, and tumor stage was correlated with expression of HER2, E‐cadherin, and Vimentin (P < 0.05). Trastuzumab with the high concentrations suppressed proliferation of HER2‐positive hepatoma cells (P < 0.05); in the coculture model to induce EMT of JM1 cells, HER2 expression increased with downregulated E‐cadherin and upregulated Vimentin. Trastuzumab intravenous injection inhibited in vivo tumor size and metastases (P < 0.05). Signal analysis revealed that HER2 functioned through upregulation of β‐catenin and inhibition of SMAD3. Conclusion HER2 expression pattern is linked with tumor stage and overall survival; the transforming function of HER2 is found more relevant through β‐catenin and SMAD3. HER2‐targeted treatment is recommended to suppress the HER2‐mediated tumor growth during postoperative liver regeneration.

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Section: Resultsmentioning

confidence: 99%

Recognition of HER2 expression in hepatocellular carcinoma and its significance in postoperative tumor recurrence

et al. 2019

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“…It had been reported that anticancer compounds such as 3-alkoxy-1H-pyrazolo [3,4-d]pyrimidines analogues (3A-1-PP, Figure 1) showed potent EGFR kinase inhibitory activity, with IC50 values reaching single digit nanomolar values [16]. Compounds a, b, c and d (Figure 1) displayed the most potent EGFR inhibitory activity, with IC50 values of 0.07, 0.24, 0.06 and 0.26 μM respectively, which were comparable to the positive control erlotinib (IC50 = 0.03 μM) [17][18][19][20]. Compound e containing the dihydropyrazole and naphthalene ring showed the highest inhibitory EGFR activity (IC50 = 0.12 μM) [21].…”

Section: Introductionmentioning

confidence: 90%

Design, Synthesis and Biological Evaluation of Benzohydrazide Derivatives Containing Dihydropyrazoles as Potential EGFR Kinase Inhibitors

Wang

Yan

et al. 2016

Molecules

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A series of novel benzohydrazide derivatives containing dihydropyrazoles have been synthesized as potential epidermal growth factor receptor (EGFR) kinase inhibitors and their biological activities as potential antiproliferative agents have been evaluated. Among these compounds, compound H20 exhibited the most potent antiproliferative activity against four cancer cell line variants (A549, MCF-7, HeLa, HepG2) with IC 50 values of 0.46, 0.29, 0.15 and 0.21 µM respectively, which showed the most potent EGFR inhibition activities (IC 50 = 0.08 µM for EGFR). Molecular modeling simulation studies were performed in order to predict the biological activity and activity relationship (SAR) of these benzohydrazide derivatives. These results suggested that compound H20 may be a promising anticancer agent.

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“… 4 , 18 Over the years, electron-deficient nitroaromatic compounds have been investigated for use in cancer treatment and, likely, the nitroimidazole derivatives have been reported as potent mitogen-activated protein (MAP) kinase inhibitors. 19 , 20 A perusal of literature reveals that oximes act as a core structural motif of myriad chemotypes endowed with anticancer activities including kinase inhibition. 21 − 23 Designing hybrid molecules in which two or more pharmacophores are covalently linked is a rationally attractive approach toward the development of effective therapeutic molecules.…”

Section: Introductionmentioning

confidence: 99%

Design and Development of Small-Molecule Arylaldoxime/5-Nitroimidazole Hybrids as Potent Inhibitors of MARK4: A Promising Approach for Target-Based Cancer Therapy

et al. 2020

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Microtubule affinity-regulating kinase 4 (MARK4), a member of the serine/threonine kinase family, is an emerging therapeutic target in anticancer drug discovery paradigm due to its involvement in regulation of microtubule dynamics, cell cycle regulation, and cancer progression. Therefore, to identify the novel chemical architecture for the design and development of novel MARK4 inhibitors with concomitant radical scavenging property, a series of small-molecule arylaldoxime/5-nitroimidazole conjugates were designed and synthesized via multistep chemical reactions following the pharmacophoric hybridization approach. Compound 4h was identified as a promising MARK4 inhibitor with high selectivity toward MARK4 inhibition as compared to the panel of screened 30 kinases pertaining to the serine/threonine family, which was validated by molecular docking and fluorescence binding studies. The comprehensive cell-based examination divulged the promising apoptotic, antiproliferative, and antioxidant potential for the chemotype 4h . The compound 4h was endowed with the K a value of 3.6 × 10 3 M –1 for human serum albumin, which reflects its remarkable transportation and delivery properties to the target site via blood. The present study impedes that in the future, such compounds may stand as optimized pharmacological lead candidates in drug discovery for targeting cancer via MARK4 inhibition with a remarkable anticancer profile.

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Design, synthesis and biological evaluation of pyrazolyl-nitroimidazole derivatives as potential EGFR/HER-2 kinase inhibitors

Cited by 54 publications

References 24 publications

Recognition of HER2 expression in hepatocellular carcinoma and its significance in postoperative tumor recurrence

Recognition of HER2 expression in hepatocellular carcinoma and its significance in postoperative tumor recurrence

Design, Synthesis and Biological Evaluation of Benzohydrazide Derivatives Containing Dihydropyrazoles as Potential EGFR Kinase Inhibitors

Design and Development of Small-Molecule Arylaldoxime/5-Nitroimidazole Hybrids as Potent Inhibitors of MARK4: A Promising Approach for Target-Based Cancer Therapy

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