Covalent reactions of Wortmannin under physiological conditions

被引：33

作者：

Yuan, Hushan

Barnes, Katie R.

Weissleder, Ralph

Cantley, Lewis

Josephson, Lee

机构：

[1] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA

[2] Harvard Univ, Sch Med, Charlestown, MA 02129 USA

[3] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA

[4] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02115 USA

来源：

CHEMISTRY & BIOLOGY | 2007年 / 14卷 / 03期

关键词：

D O I：

10.1016/j.chembiol.2007.02.007

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：321 / 328

页数：8

共 29 条

[21] ANTIINFLAMMATORY ACTIVITY OF NEW MOLD METABOLITE 11-DEACETOXY-WORTMANNIN AND OF SOME OF ITS DERIVATIVES [J].