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Published on: July 10, 2019
Synthesis and PI3 Kinase Inhibition Activity of a Wortmannin-Leucine Derivative
William Cantrell1, Yue Huang2, Antonio A Menchaca3
1Medicinal and Process Chemistry, Pharmaceutical Development and Biomaterials Department, Chemistry and Chemical Engineering Division, Southwest Research Institute, P.O. Drawer 28510, San Antonio, TX 78228, USA. william.cantrell@swri.org.
Abstract:
Wortmannin is a potent covalent inhibitor of PI3K that shows substantial in vivo toxicity and thus is unsuitable for systemic therapeutic applications. One possible approach to minimize systemic toxicity is to generate a latent wortmannin pro-drug that will be selectively activated in target tissues. To test this approach, a wortmannin derivative with a leucine linker attached to C20 has been synthesized and tested for inhibition of PI3K activity in prostate cancer cells. Analysis of PI3K pathway inhibition by Wormannin-Leu (Wn-L) and intact Wortmannin (Wn) showed that attachment of Leu at C-20 decreased potency of PI3K pathway inhibition 10-fold compared to intact wortmannin, yet exceeded the potency of a competitive PI3K inhibitor LY294002.
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