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Related Experiment Videos

Wortmannin-C20 conjugates generate wortmannin.

Hushan Yuan1, Ji Luo, Ralph Weissleder

  • 1Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.

Journal of Medicinal Chemistry
|January 20, 2006
PubMed
Summary
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New wortmannin conjugates create phosphoinositol-3-OH kinase (PI3K) inhibitors. These compounds release wortmannin (Wm) internally, enabling targeted PI3K inhibition with potentially reduced toxicity.

Area of Science:

  • Medicinal Chemistry
  • Biochemistry
  • Pharmacology

Background:

  • Wortmannin (Wm) is a potent inhibitor of phosphoinositol-3-OH kinase (PI3K).
  • Wm exhibits anti-inflammatory and anti-proliferative activities but possesses significant toxic effects.
  • Targeted delivery or slow-release formulations of Wm could improve its therapeutic index.

Purpose of the Study:

  • To develop novel wortmannin conjugates as targeted or slow-release PI3K inhibitors.
  • To investigate the mechanism of PI3K inhibition by these conjugates.
  • To explore the potential for reduced toxicity compared to parent wortmannin.

Main Methods:

  • Synthesis of C20-6-(N-methylamino)hexanoic conjugates of wortmannin.
  • Characterization of conjugates featuring a tertiary enamine at the C20 position.

Related Experiment Videos

  • In vitro assessment of wortmannin (Wm) generation and PI3K inhibition.

    • Main Results:

    • The developed wortmannin conjugates generate active wortmannin (Wm) via intramolecular attack.
    • These conjugates inhibit PI3K without needing to bind to the ATP pocket.
    • Conjugation to carriers like BSA, IgG, or beads is feasible for targeted delivery.

    Conclusions:

    • Wortmannin conjugates offer a strategy for designing PI3K inhibitors with improved targeting or controlled release.
    • This approach may lead to more selective PI3K inhibition in specific tissues, potentially mitigating systemic toxicity.
    • The design allows for wortmannin-based inhibitors that do not rely on ATP-pocket binding.