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Design, synthesis of phenstatin/isocombretastatin-oxindole conjugates as antimitotic agents

G Bharath Kumar1, V Lakshma Nayak1, Ibrahim Bin Sayeed1

  • 1Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.

Bioorganic & Medicinal Chemistry
|March 14, 2016
PubMed

Insights

New phenstatin/isocombretastatin-oxindole conjugates show potent anticancer activity. Compounds 5c and 5d effectively inhibit cancer cell proliferation, induce cell cycle arrest, and disrupt tubulin polymerization, offering promising therapeutic leads.

Area of Science:

  • Medicinal Chemistry
  • Cancer Biology
  • Pharmacology

Background:

  • Developing novel anticancer agents is crucial for improving patient outcomes.
  • Phenstatins and isocombrestatins are known for their antimitotic properties.
  • Oxindole derivatives have shown potential in cancer therapy.

Purpose of the Study:

  • To synthesize and evaluate novel phenstatin/isocombretastatin-oxindole conjugates for cytotoxic activity.
  • To investigate the mechanism of action of potent conjugates.
  • To explore their potential as anticancer therapeutics.

Main Methods:

  • Synthesis of phenstatin/isocombretastatin-oxindole conjugates.
  • In vitro cytotoxicity assays against human cancer cell lines (prostate, lung, colon, breast, liver).
  • Cell cycle analysis, Annexin V-FITC assay, mitochondrial membrane potential assessment, tubulin polymerization assay, and molecular docking.

Main Results:

  • Synthesized conjugates exhibited cytotoxic activity with IC50 values ranging from 0.049 to 38.90 μM.
  • Conjugates 5c and 5d demonstrated significant antiproliferative effects on lung and colon cancer cells (IC50 values in nM range).
  • Compounds 5c and 5d induced G2/M phase arrest, apoptosis, and inhibited tubulin polymerization (IC50 values in μM range), binding to the colchicine site.

Conclusions:

  • Phenstatin/isocombrestatatin-oxindole conjugates represent a promising class of anticancer agents.
  • Compounds 5c and 5d exhibit potent and broad-spectrum anticancer activity through tubulin inhibition and apoptosis induction.
  • These findings warrant further investigation for clinical development.
Keywords:
Annexin V-FITC and mitochondrial membrane depolarizationPhenstatin/isocombretastatin-oxindoleTubulin depolymerization

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