Synthesis of A83586C analogs with potent anticancer and beta-catenin/ TCF4/osteopontin inhibitory effects and insights into how A83586C modulates E2Fs and pRb.
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).
Hale
Karl J
KJ
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.
Manaviazar
Soraya
S
Lazarides
Linos
L
George
Jonathan
J
Walters
Marcus A
MA
Cai
Jiaqiang
J
Delisser
Vern M
VM
Bhatia
Gurpreet S
GS
Peak
S Andrew
SA
Dalby
Stephen M
SM
Lefranc
Amandine
A
Chen
Ying-Nan P
YN
Wood
Alexander W
AW
Crowe
Paul
P
Erwin
Pauline
P
El-Tanani
Mohamed
M
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*
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