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Design, synthesis and evaluation of alkylphosphocholine-gefitinib conjugates as multitarget anticancer agents

Md Maqusood Alam1, Ahmed H E Hassan2,3, Yeong Ho Kwon1

  • 1Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea.

Archives of Pharmacal Research
|November 3, 2017
PubMed

Insights

New anticancer agents combining alkylphosphocholines and gefitinib show promise. These multitarget agents overcome resistance by inhibiting Akt phosphorylation and EGFR tyrosine kinases, offering improved efficacy against various cancers.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • Drug resistance to current chemotherapies necessitates novel anticancer agents with improved efficacy and reduced side effects.
  • Polypharmacology, targeting multiple signaling pathways with a single molecule, offers a more effective strategy than single-target approaches.
  • Alkylphosphocholines inhibit Akt phosphorylation, while quinazoline derivatives target epidermal growth factor receptor (EGFR) tyrosine kinases, both demonstrating anticancer potential.

Purpose of the Study:

  • To design and synthesize novel alkylphosphocholine-gefitinib conjugates as multitarget anticancer agents.
  • To evaluate the antiproliferative and cytotoxic activities of these conjugates against various human cancer cell lines.
  • To assess the compounds' ability to inhibit key cancer-related signaling pathways: Akt phosphorylation and EGFR tyrosine kinases.

Main Methods:

  • Synthesis of novel alkylphosphocholine-gefitinib conjugates with varying linker lengths.
  • In vitro antiproliferative assays using lung, breast, liver, and skin cancer cell lines.
  • Biochemical assays to determine the inhibition of Akt phosphorylation and EGFR tyrosine kinase activity.

Main Results:

  • The synthesized conjugates demonstrated significant antiproliferative activity across tested cancer cell lines.
  • Conjugates with longer linker chains exhibited enhanced antiproliferative effects and Akt phosphorylation inhibition.
  • These long-chain conjugates maintained EGFR tyrosine kinase inhibitory activity and showed superior or comparable cytotoxicity to erlotinib and miltefosine.

Conclusions:

  • Alkylphosphocholine-gefitinib conjugates represent a promising class of multitarget anticancer agents.
  • Linker length critically influences the bioactivity of these conjugates, with longer linkers enhancing efficacy.
  • These novel compounds offer a potential strategy to overcome drug resistance and improve cancer treatment outcomes.
Keywords:
Akt phosphorylation inhibitorsAlkylphosphocholinesAntiproliferartive agentsEGFR tyrosine kinase inhibitorsGefitinib

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