Wortmannin-C20 conjugates generate wortmannin.
We report on C20-6-(N-methylamino)hexanoic conjugates of wortmannin featuring a tertiary enamine attached to the C20 that inhibit phosphoinositol-3-OH kinase (PI3K) by producing wortmannin (Wm) through an intramolecular attack. The generation of Wm by these conjugates permits the design of Wm based PI3K inhibitors that need not fit into the ATP pocket of PI3K, including Wm conjugates of BSA, IgG, or beads. Wm generating WmC20-N(Me)-hexanoate conjugates offer an approach to the design of targeted or slow release forms of Wm which may inhibit PI3K in tissues more selectively than the parent Wm, a compound which has desirable anti-inflammatory and anti-proliferative activities but which also has a variety of toxic effects.
Yuan
Hushan
H
Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Luo
Ji
J
Weissleder
Ralph
R
Cantley
Lewis
L
Josephson
Lee
L
D000730:Androstadienes / Q000138:chemical synthesis* / Q000737:chemistry; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry; D002208:Caproates / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000077191:Wortmannin
C508804:5-(acetyloxy)-1-((N-(5-carboxypentyl)-N-methylamino)methylene)-4,4a,5,6,6a,8,9,9a-octahydro-11-hydroxy-4-(methoxymethyl)-4a,6a-dimethylcyclopenta(5,6)naphtho(1,2-c)pyran-2,7,10-(1H)-trione; C508805:5-(acetyloxy)-1-((N-(5-carboxypentyl)amino)methylene)-4,4a,5,6,6a,8,9,9a-octahydro-11-hydroxy-4-(methoxymethyl)-4a,6a-dimethylcyclopenta(5,6)naphtho(1,2-c)pyran-2,7,10-(1H)-trione; D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D002208:Caproates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000077191:Wortmannin