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Synthesis and PI3 Kinase Inhibition Activity of a Wortmannin-Leucine Derivative.

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.

SUBMITTER: Cantrell W

PROVIDER: S-EPMC6100554 | biostudies-other | 2018 Jul

REPOSITORIES: biostudies-other

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Synthesis and PI3 Kinase Inhibition Activity of a Wortmannin-Leucine Derivative.

Cantrell William W Huang Yue Y Menchaca Antonio A AA Kulik George G Welker Mark E ME

Molecules (Basel, Switzerland) 20180720 7

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 pathwa ...[more]

PMID: 30036994

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