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Synthesis, biological evaluation and molecular docking of new sulfonamide-based indolinone derivatives as multitargeted kinase inhibitors against leukemia.

Abstract
Series of novel sulfonamide-based 3-indolinones 3a-m and 4a-f were designed, synthesized and then their cytotoxic activity was evaluated against a panel of sixty cancer cell lines. This screening indicated that 4-(2-(5-fluoro-2-oxoindolin-3-ylidene)acetyl)phenyl benzenesulfonate (4f) possessed promising cytotoxicity against CCRF-CEM and SR leukemia cell lines with IC50 values 6.84 and 2.97 µM, respectively. Further investigation of the leukemic cytotoxicity of compound 4f was carried out by performing PDGFRα, VEGFR2, Aurora A/B and FLT3 enzyme assays and CCRF-CEM and SR cell cycle analysis. These investigations showed that compound 4f exhibited pronounced dual inhibition of both kinases PDGFRα and Aurora A with potency of 24.15 and 11.83 nM, respectively. The in vitro results were supported by molecular docking studies in order to explore its binding affinity and its key amino acids interactions. This work represents compound 4f as a promising anticancer agent against leukemia.
AuthorsMarwa El-Hussieny, Naglaa F El-Sayed, Marwa A Fouad, Ewies F Ewies
JournalBioorganic chemistry (Bioorg Chem) Vol. 117 Pg. 105421 (12 2021) ISSN: 1090-2120 [Electronic] United States
PMID34666258 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2021 Elsevier Inc. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • Oxindoles
  • Protein Kinase Inhibitors
  • Sulfonamides
  • Phosphotransferases
Topics
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Oxindoles (chemical synthesis, chemistry, pharmacology)
  • Phosphotransferases (antagonists & inhibitors, metabolism)
  • Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
  • Structure-Activity Relationship
  • Sulfonamides (chemical synthesis, chemistry, pharmacology)

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