title: Synthesis of A83586C analogs with potent anticancer and beta-catenin/ TCF4/osteopontin inhibitory effects and insights into how A83586C modulates E2Fs and pRb.
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 beta-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).
authors.affiliation: The School of Chemistry & Chemical Engineering and the Centre for Cancer Research and Cell Biology (CCRCB), Queen's University Belfast (QUB), Stranmillis Road, Belfast BT9 5AG, UK.
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Hale
authors.forename: Soraya
authors.initials: S
authors.lastname: Manaviazar
authors.forename: Linos
authors.initials: L
authors.lastname: Lazarides
authors.forename: Jonathan
authors.initials: J
authors.lastname: George
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Walters
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Cai
authors.forename: Vern M
authors.initials: VM
authors.lastname: Delisser
authors.forename: Gurpreet S
authors.initials: GS
authors.lastname: Bhatia
authors.forename: S Andrew
authors.initials: SA
authors.lastname: Peak
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Dalby
authors.forename: Amandine
authors.initials: A
authors.lastname: Lefranc
authors.forename: Ying-Nan P
authors.initials: YN
authors.lastname: Chen
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Wood
authors.forename: Paul
authors.initials: P
authors.lastname: Crowe
authors.forename: Pauline
authors.initials: P
authors.lastname: Erwin
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Tanani
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D050684:E2F Transcription Factors / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D051176:beta Catenin / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D047630:Depsipeptides; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin; C056791:A 83586C