Synthesis of A83586C Analogs with Potent Anticancer and β-Catenin/ TCF4/Osteopontin Inhibitory Effects and Insights Into How A83586C Modulates E2Fs and pRb

• Published in: Organic letters Vol. 11; no. 3; pp. 737 - 740
• Main Authors: Hale, Karl J, Manaviazar, Soraya, Lazarides, Linos, George, Jonathan, Walters, Marcus A, Cai, Jiaqiang, Delisser, Vern M, Bhatia, Gurpreet S, Peak, S. Andrew, Dalby, Stephen M, Lefranc, Amandine, Chen, Ying-Nan P, Wood, Alexander W, Crowe, Paul, Erwin, Pauline, El-Tanani, Mohamed
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 05.02.2009; Amer Chemical Soc
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; beta Catenin - antagonists & inhibitors; Chemistry; Chemistry, Organic; Depsipeptides - chemical synthesis; Depsipeptides - chemistry; Depsipeptides - pharmacology; DNA-Binding Proteins - antagonists & inhibitors; Drug Screening Assays, Antitumor; E2F Transcription Factors - metabolism; E2F1 Transcription Factor - metabolism; Humans; Inhibitory Concentration 50; Physical Sciences; Science & Technology; Transcription Factor 4; Transcription Factors - antagonists & inhibitors; OSTEOPONTIN GENE; GE3; HUMAN BREAST-CANCER; EXPRESSION; CYCLODEPSIPEPTIDE
• ISSN: 1523-7060; 1523-7052
• DOI: 10.1021/ol802818f

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 β-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).