دورية أكاديمية
From EGFR kinase inhibitors to anti-inflammatory drugs: Optimization and biological evaluation of (4-(phenylamino)quinazolinyl)-phenylthiourea derivatives as novel NF-κB inhibitors.
| العنوان: | From EGFR kinase inhibitors to anti-inflammatory drugs: Optimization and biological evaluation of (4-(phenylamino)quinazolinyl)-phenylthiourea derivatives as novel NF-κB inhibitors. |
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| المؤلفون: | Wagdy RA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt., Chen PJ; Department of Medical Research, E-Da Hospital, Kaohsiung 824005, Taiwan., Hamed MM; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University Campus, 66123 Saarbrücken, Germany., Darwish SS; Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt; School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, New Administrative Capital, 11578 Cairo, Egypt., Chen SH; School of Nursing, Fooyin University, Kaohsiung 831, Taiwan., Abadi AH; Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt., Abdel-Halim M; Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt., Hwang TL; Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Research Center for Chinese Herbal Medicine, Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; Department of Chemical Engineering, Ming Chi University of Technology, New Taipei City 243, Taiwan. Electronic address: htl@mail.cgu.edu.tw., Engel M; Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany. Electronic address: ma.engel@mx.uni-saarland.de. |
| المصدر: | Bioorganic chemistry [Bioorg Chem] 2022 Oct; Vol. 127, pp. 105977. Date of Electronic Publication: 2022 Jun 18. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 1303703 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2120 (Electronic) Linking ISSN: 00452068 NLM ISO Abbreviation: Bioorg Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Amsterdam : Elsevier Original Publication: New York, London, Academic Press. |
| مواضيع طبية MeSH: | NF-kappa B*/metabolism , Phenylthiourea*, Anti-Inflammatory Agents/pharmacology ; ErbB Receptors/metabolism ; Lipopolysaccharides ; Phosphorylation |
| مستخلص: | The transcription factor NF-κB is a pivotal mediator of chronic inflammatory and autoimmune diseases. Based on our previously published dual EGFR/NF-κB inhibitors, we designed and synthesized new thiourea quinazoline derivatives that retained only the NF-κB inhibitory activity. Several congeners displayed a strong suppression of NF-κB activity in a reporter gene assay, yet low cytotoxicity, and were further evaluated in differentiated macrophage-like THP-1 cells. The compounds exhibited a strong inhibition of IL-6 and, less potently, of TNFα release, which was accompanied by a selective induction of macrophage cell death. The mode of action was investigated with a selected inhibitor, 18, revealing that the translocation of p65/RelA to the nucleus but not its release from the IκB complex was inhibited. Eventually, 18 was identified as the first small molecule inhibitor affecting only the phosphorylation of p65-Ser468 but not of Ser536, which may be causally related to the retention of NF-κB in the cytoplasm. Altogether, our novel NF-κB inhibitors seem applicable for the suppression of cytokine release and the additional selective depletion of activated macrophages in various inflammatory diseases. (Copyright © 2022 Elsevier Inc. All rights reserved.) |
| فهرسة مساهمة: | Keywords: 4-Aminoquinazolines; IL-6; Inflammation; Macrophage targeting; NF-κB inhibitor; TNFα |
| المشرفين على المادة: | 0 (Anti-Inflammatory Agents) 0 (Lipopolysaccharides) 0 (NF-kappa B) 6F82C6Q54C (Phenylthiourea) EC 2.7.10.1 (ErbB Receptors) |
| تواريخ الأحداث: | Date Created: 20220702 Date Completed: 20220815 Latest Revision: 20220816 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1016/j.bioorg.2022.105977 |
| PMID: | 35779404 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1090-2120 |
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| DOI: | 10.1016/j.bioorg.2022.105977 |