| Peter Wipf1, Robert J. Halter1, Daniel J. Minion1, Nathan T. Ihle2, Ryan Williams2, Sherry Chow2, Wade Chew2, Gillian Paine-Murrieta2, Robert Abraham3, Lynn Kirkpatrick4, and Garth Powis2. (1) Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, (2) Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, (3) Burnham Institute, La Jolla, CA 92037, (4) ProlX Pharmaceuticals, Tucson, AZ 85701 |
| A library of 95 wortmannin analogs was prepared via nucleophilic ring opening of wortmannin by a variety of amines, amino acids and thiols. Wortmannin, a metabolite of Pencillium wortmanni, has a wide array of biological activity, including anti-inflammatory, anti-fungal and anti-cancer activity. Wortmannin is widely used in biological assays as a selective inhibitor of PI-3 kinase. Unfortunately, it also exhibits a high degree of liver toxicity, rendering it unsuitable for clinical development. The di-allyl amine derived analog, PX-866, exhibited nanomolar activity against PI-3-kinase and three human cancer cell lines and was selected for further animal studies. The biological activity of wortmannin inspired us to pursue synthetic efforts toward the thiophene analog (1). Our progress toward this goal, starting from 3,4-dibromothiophene will also be presented. 
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