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 (Win) through an intramolecular attack. The generation of Win by these conjugates permits the design of Wm based PI3K inhibitors that need not fit into the ATP pocket of PI3K, including Win conjugates of BSA, IgG, or beads. Win generating WmC20-N(Me)-hexanoate conjugates offer an approach to the design of targeted or slow release forms of Win which may inhibit PI3K in tissues more selectively than the parent Win, a compound which has desirable anti-inflammatory and anti-proliferative activities but which also has a variety of toxic effects.