2-(2-(2,4-dioxopentan-3-ylidene)hydrazineyl)benzonitrile as novel inhibitor of receptor tyrosine kinase and PI3K/AKT/mTOR signaling pathway in glioblastoma

Nerve growth factor receptor (NGFR), a member of kinase protein, is emerging as an important target for Glioblastoma (GBM) treatment. Overexpression of NGFR is observed in many metastatic cancers including GBM, promoting tumor migration and invasion. Hydrazones have been reported to effectively interact with receptor tyrosine kinases (RTKs). We report herein the synthesis of 23 arylhydrazones of active methylene compounds (AHAMCs) compounds and their anti-proliferative activity against GBM cell lines, LN229 and U87. Compound R234, 2-(2-(2,4-dioxopentan-3-ylidene)hydrazineyl)benzonitrile, was identified as the most active anti-neoplastic compound, with the IC 50 value ranging 87 μM - 107 μM. Molecular docking simulations of the synthesized compounds into the active site of tyrosine receptor kinase A (TrkA), demonstrated a strong binding affinity with R234 and concurs well with the obtained biological results. R234 was found to be a negative regulator of PI3K/Akt/mTOR pathway and an enhancer of p53 expression. In addition, R234 treated GBM cells exhibited the downregulation of cyclins, cyclin-dependent kinases and other key molecules involved in cell cycle such as CCNE, E2F, CCND, CDK6, indicating that R234 induces cell cycle arrest at G1/S. R234 also exerted its apoptotic effects independent of caspase3/7 activity, in both cell lines. In U87 cells, R234 induced oxidative effects whereas LN229 cells annulled oxidative stress. The study thus concludes that R234, being a negative modulator of RTKs and cell cycle inhibitor, may represent a novel class of anti-GBM drugs. © 2019 Elsevier Masson SAS

Authors
Viswanathan A.1 , Kute D.1 , Musa A.2 , Konda Mani S. , Sipilä V.1 , Emmert-Streib F.2 , Zubkov F.I. 4 , Gurbanov A.V. 5, 6 , Yli-Harja O.7, 8 , Kandhavelu M.1
Journal
European Journal of Medicinal Chemistry
Publisher
Elsevier Masson SAS
Language
English
Pages
291-303
Status
Published
Link
External link
DOI
10.1016/J.EJMECH.2019.01.021
Year
2019
Organizations
  • 1 Molecular Signaling Lab, Faculty of Medicine and Health Technology, Tampere University and BioMediTech, P.O. Box 553, Tampere, 33101, Finland
  • 2 Predictive Medicine and Data Analytics Lab, Faculty of Medicine and Health Technology, Tampere University and BioMediTech, P.O. Box 553, Tampere, 33101, Finland
  • 3 Centre of Advanced Study in Crystallography & Biophysics, University of Madras, Chennai, 600 025, India
  • 4 Organic Chemistry Department, Faculty of Science, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St., Moscow, 117198, Russian Federation
  • 5 Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, Lisbon, 1049–001, Portugal
  • 6 Department of Chemistry, Baku State University, Z. Xalilov Str. 23, Baku, Az 1148, Azerbaijan
  • 7 Computaional Systems Biology Group, Faculty of Medicine and Health Technology, Tampere University and BioMediTech, P.O. Box 553, Tampere, 33101, Finland
  • 8 Institute for Systems Biology, 1441N 34th Street, Seattle, WA 98103-8904, United States
Keywords
2 [2 (2,4 dioxopentan 3 ylidene)hydrazineyl]benzonitrile; antimitotic agent; benzonitrile; caspase 3; caspase 7; cisplatin; cyclin D; cyclin dependent kinase 6; cyclin E; hydrazine derivative; mammalian target of rapamycin; neurotrophin; phosphatidylinositol 3 kinase; protein kinase B; protein kinase Mer; protein p53; protein serine threonine kinase inhibitor; protein tyrosine kinase A; protein tyrosine kinase inhibitor; reactive oxygen metabolite; transcription factor E2F; unclassified drug; antineoplastic agent; benzonitrile; nitrile; phosphatidylinositol 3 kinase; protein kinase B; protein kinase inhibitor; protein tyrosine kinase; target of rapamycin kinase; Akt signaling; antiproliferative activity; Article; binding affinity; cell cycle progression; cell proliferation; cell viability; comparative study; controlled study; cytotoxicity; diazotization; DNA repair; down regulation; drug protein binding; drug receptor binding; drug synthesis; enzyme active site; enzyme activity; enzyme inhibition; G1 phase cell cycle checkpoint; gene expression; glioblastoma; glioblastoma cell line; human; human cell; IC50; LN-229 cell line; molecular docking; neuroapoptosis; oxidation reduction potential; oxidative stress; protein expression; S phase cell cycle checkpoint; u87 cell line; antagonists and inhibitors; apoptosis; cell survival; chemistry; drug effect; gene expression regulation; glioblastoma; metabolism; pathology; signal transduction; tumor cell line; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; G1 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Nitriles; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Receptor Protein-Tyrosine Kinases; S Phase Cell Cycle Checkpoints; Signal Transduction; TOR Serine-Threonine Kinases
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