wortmannin and viridin

Naturally occurring furanosteroids such as viridin and wortmannin have long been known as potent inhibitors of the lipid kinase PI-3K. We have been interested in directly accessing analogs of these complex natural products from abundant steroid feedstock materials. In this communication, we describe the synthesis of viridin/wortmannin hybrid molecules from readily available building blocks that function as PI-3K inhibitors and maintain their electrophilic properties. The compounds also show anti-proliferative effects against a breast cancer line.

Topics: Androstadienes; Androstenes; Bacteriocins; Binding Sites; Breast Neoplasms; Cell Survival; Crystallography, X-Ray; Female; Humans; MCF-7 Cells; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Protein Structure, Tertiary; Steroids; Wortmannin

When the viridin wortmannin (Wm) is modified by reaction with certain nucleophiles at the C20 position, the compounds obtained exhibit an improved antiproliferative activity even though a covalent reaction between C20 and a lysine in the active site of PI3 kinase is essential to Wm's ability to inhibit this enzyme. Here we show that this improved potency results from an intramolecular attack by the C6 hydroxyl group that slowly converts these inactive prodrugs to the active species Wm over the 48 h duration of the antiproliferative assay. Our results provide a guide for selecting Wm-like compounds to maximize kinase inhibition with the variety of protocols used to assess the role of PI3 kinase in biological systems, or for achieving optimal therapeutic effects in vivo . In addition, the slow self-activation of WmC20 derivatives provides a mechanism that can be exploited to obtain kinase inhibitors endowed with physical and pharmacokinetic properties far different from man-made kinase inhibitors because they do not bind to kinase active sites.

Topics: Androstadienes; Androstenes; Bacteriocins; Cell Line, Tumor; Cell Proliferation; Humans; Models, Molecular; Molecular Structure; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Prodrugs; Protein Binding; Protein Kinase Inhibitors; Structure-Activity Relationship; Time Factors; Wortmannin