Covalent reactions of wortmannin under physiological conditions.
Wortmannin (Wm), a steroid-like molecule of 428.4 Da, appears to be unstable in biological fluids (apparent chemical instability), yet it exhibits an antiproliferative 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 antiproliferative 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.
Yuan
Hushan
H
Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA.
Barnes
Katie R
KR
Weissleder
Ralph
R
Cantley
Lewis
L
Josephson
Lee
L
D000596:Amino Acids; D000730:Androstadienes / Q000737:chemistry*; D004121:Dimethyl Sulfoxide; D004355:Drug Stability; D007700:Kinetics; D008968:Molecular Conformation; D009183:Mycotoxins / Q000737:chemistry; D012997:Solvents; D019789:Tetraethylammonium; D000077191:Wortmannin
D000596:Amino Acids; D000730:Androstadienes; D009183:Mycotoxins; D012997:Solvents; D019789:Tetraethylammonium; D000077191:Wortmannin; D004121:Dimethyl Sulfoxide