title: Fluorinated N,N-dialkylaminostilbenes for Wnt pathway inhibition and colon cancer repression.
abstract: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States. CRC is initiated by mutations of the tumor suppressor gene, adenomatous polyposis coli (APC), or β-catenin gene. These mutations stabilize β-catenin and constitutively activate Wnt/β-catenin target genes, such as c-Myc and cyclin D1, ultimately leading to cancer. Naturally occurring stilbene derivatives, resveratrol and pterostilbene, inhibit Wnt signaling and repress CRC cell proliferation but are ineffective at concentrations less than 10 μM. To understand the structure--activity relationship within these stilbene derivatives and to develop more efficacious Wnt inhibitors than these natural products, we synthesized and evaluated a panel of fluorinated N,N-dialkylaminostilbenes. Among this panel, (E)-4-(2,6-difluorostyryl)-N,N-dimethylaniline (4r) inhibits Wnt signaling at nanomolar levels and inhibits the growth of human CRC cell xenografts in athymic nude mice at a dosage of 20 mg/kg. These fluorinated N,N-dialkylaminostilbenes appear to inhibit Wnt signaling downstream of β-catenin, probably at the transcriptional level.
authors.affiliation: Department of Molecular and Cellular Biochemistry, Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40506-0509, United States.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.forename: Vitaliy
authors.initials: V
authors.lastname: Sviripa
authors.forename: Liliia M
authors.initials: LM
authors.lastname: Kril
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Tianxin
authors.initials: T
authors.lastname: Yu
authors.forename: Jiandang
authors.initials: J
authors.lastname: Shi
authors.forename: Piotr
authors.initials: P
authors.lastname: Rychahou
authors.forename: B Mark
authors.initials: BM
authors.lastname: Evers
authors.forename: David S
authors.initials: DS
authors.lastname: Watt
authors.forename: Chunming
authors.initials: C
authors.lastname: Liu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D051153:Wnt Proteins / Q000502:physiology*
chemical_list: D013267:Stilbenes; D051153:Wnt Proteins; C107773:pterostilbene; D000077185:Resveratrol