Synthesis of A83586C analogs with potent anticancer and beta-catenin/ TCF4/osteopontin inhibitory effects and insights into how A83586C modulates E2Fs and pRb.

Karl J Hale, S. Manaviazar, L. Lazarides, J. George, M.A. Walters, J. Cai, V.M. Delisser, G.S. Bhatia, S.A. Peak, S.M. Dalby, A. Lefranc, Y.P. Chen, A.W. Wood, Paul Crowe, Pauline Erwin, Mohamed El-Tanani

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Abstract

The synthesis of three potent new antitumor agents is described: the A83586C-citropeptin hybrid (1), the A83586C-GE3 hybrid (2), and l-Pro-A83586C (3). Significantly, compounds 1 and 2 function as highly potent inhibitors of ß-catenin/TCF4 signaling within cancer cells, while simultaneously downregulating osteopontin (Opn) expression. A83586C antitumor cyclodepsipeptides also inhibit E2F-mediated transcription by downregulating E2F1 expression and inducing dephosphorylation of the oncogenic hyperphosphorylated retinoblastoma protein (pRb).
Original languageEnglish
Pages (from-to)737-740
Number of pages4
JournalOrganic Letters
Volume11
Issue number3
DOIs
Publication statusPublished - 05 Feb 2009

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