Journal
CHEMISTRY & BIOLOGY
Volume 14, Issue 3, Pages 321-328Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2007.02.007
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Funding
- NCI NIH HHS [T32 CA079443, P50CA86355] Funding Source: Medline
- NIBIB NIH HHS [R01EB00662] Funding Source: Medline
- NIGMS NIH HHS [GM041890, R01 GM041890] Funding Source: Medline
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Wortmannin (Wm), a steroid-like molecule of 428.4 Da, appears to be unstable in biological fluids (apparent chemical instability), yet it exhibits an anti proliferative activity in assays employing a 48 hr incubation period (prolonged bioactivity), a situation we refer to as the wortmannin paradox. Under physiological conditions, Wm covalently reacts with nucleophiles such as the side chains of cysteine, N-methyl hexanoic acid, lysine, or proline at the C20 position on the furan ring. Like Wm, WmC20 amino acid derivatives had significant anti proliferative activities. Three Wm derivatives, WmC20-proline, WmC20-cysteine, and a WmC20-N-methyl hexanoic acid, generated Wm that then reacted with lysine in an exchange-type reaction. This unusual, reversible, covalent reaction of Wm with nucleophiles under physiological conditions provides an explanation for the wortmannin paradox.
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