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Covalent reactions of wortmannin under physiological conditions

Hushan Yuan1, Katie R Barnes, Ralph Weissleder

  • 1Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA.

Chemistry & Biology
|March 24, 2007
PubMed

Insights

Wortmannin (Wm) is unstable yet active, a paradox explained by its reversible covalent reaction with nucleophiles. This reaction generates active Wm, resolving its prolonged bioactivity in biological fluids.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Chemical Biology

Background:

  • Wortmannin (Wm) exhibits antiproliferative activity despite apparent instability in biological fluids, termed the "wortmannin paradox."
  • Understanding the chemical behavior of Wm in physiological conditions is crucial for explaining its paradoxical bioactivity.

Purpose of the Study:

  • To investigate the chemical mechanism underlying the prolonged bioactivity of Wortmannin (Wm) in biological systems.
  • To elucidate the "wortmannin paradox" by examining Wm's reactivity with biological nucleophiles.

Main Methods:

  • Studied the reaction of Wortmannin (Wm) with various nucleophiles, including amino acid side chains (cysteine, lysine, proline) and N-methyl hexanoic acid, at the C20 position.
  • Synthesized and evaluated the antiproliferative activity of Wm derivatives formed through reactions with amino acids.
  • Investigated the reversibility of covalent reactions between Wm and nucleophiles under physiological conditions.

Main Results:

  • Wortmannin (Wm) undergoes covalent reactions with nucleophiles like cysteine, N-methyl hexanoic acid, lysine, and proline at its C20 position under physiological conditions.
  • Wm derivatives, such as WmC20-proline, WmC20-cysteine, and WmC20-N-methyl hexanoic acid, demonstrated significant antiproliferative activities.
  • Observed an unusual, reversible, covalent reaction mechanism where Wm derivatives can regenerate active Wm, which then reacts with lysine.

Conclusions:

  • The reversible covalent reaction of Wortmannin (Wm) with biological nucleophiles explains its paradoxical prolonged bioactivity and antiproliferative effects.
  • This chemical mechanism provides a resolution to the "wortmannin paradox," highlighting the dynamic interplay between Wm's instability and its functional activity.

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