New quinoline/chalcone hybrids as anti-cancer agents: Design, synthesis, and evaluations of cytotoxicity and PI3K inhibitory activity

Samar H. Abbas, Amer Ali Abd El-Hafeez, Mai E. Shoman, Monica M. Montano, Heba A. Hassan

Research output: Contribution to journalArticle

Abstract

A series of quinoline-chalcone hybrids was designed as potential anti-cancer agents, synthesized and evaluated. Different cytotoxic assays revealed that compounds experienced promising activity. Compounds 9i and 9j were the most potent against all the cell lines tested with IC50 = 1.91–5.29 µM against A549 and K-562 cells. Mechanistically, 9i and 9j induced G2/M cell cycle arrest and apoptosis in both A549 and K562 cells. Moreover, all PI3K isoforms were inhibited non selectively with IC50s of 52–473 nM when tested against the two mentioned compounds with 9i being most potent against PI3K-γ (IC50 = 52 nM). Docking of 9i and 9j showed a possible formation of H-bonding with essential valine residues in the active site of PI3K-γ isoform. Meanwhile, Western blotting analysis revealed that 9i and 9j inhibited the phosphorylation of PI3K, Akt, mTOR, as well as GSK-3β in both A549 and K562 cells, suggesting the correlation of blocking PI3K/Akt/mTOR pathway with the above antitumor activities. Together, our findings support the antitumor potential of quinoline-chalcone derivatives for NSCLC and CML by inhibiting the PI3K/Akt/mTOR pathway.

LanguageEnglish (US)
Pages360-377
Number of pages18
JournalBioorganic Chemistry
Volume82
DOIs
StatePublished - Feb 1 2019

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Chalcone
Cytotoxicity
Phosphatidylinositol 3-Kinases
Apoptosis
Neoplasms
K562 Cells
Inhibitory Concentration 50
Protein Isoforms
Cells
G2 Phase Cell Cycle Checkpoints
Emitter coupled logic circuits
Phosphorylation
Valine
quinoline
Assays
Catalytic Domain
Western Blotting
Derivatives
Cell Line

Keywords

  • Apoptosis
  • Cancer
  • Chalcone
  • G/M arrest
  • PI3K pathway
  • Quinoline

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

Cite this

New quinoline/chalcone hybrids as anti-cancer agents : Design, synthesis, and evaluations of cytotoxicity and PI3K inhibitory activity. / Abbas, Samar H.; Abd El-Hafeez, Amer Ali; Shoman, Mai E.; Montano, Monica M.; Hassan, Heba A.

In: Bioorganic Chemistry, Vol. 82, 01.02.2019, p. 360-377.

Research output: Contribution to journalArticle

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