title: Wortmannin-C20 conjugates generate wortmannin.
abstract: 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.
authors.affiliation: Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Hushan
authors.initials: H
authors.lastname: Yuan
authors.forename: Ji
authors.initials: J
authors.lastname: Luo
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Lewis
authors.initials: L
authors.lastname: Cantley
authors.forename: Lee
authors.initials: L
authors.lastname: Josephson
mesh_terms: 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
chemical_list: 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