Department of Molecular and Cellular Biochemistry, Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40506-0509, United States.
J Med Chem. 2011 Mar 10;54(5):1288-97. doi: 10.1021/jm101248v. Epub 2011 Feb 3.
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.
结直肠癌（CRC）是美国癌症相关死亡的第二大主要原因。CRC 是由肿瘤抑制基因 APC 或 β-连环蛋白基因的突变引发的。这些突变稳定了 β-连环蛋白并使 Wnt/β-连环蛋白靶基因（如 c-Myc 和 cyclin D1）持续激活，最终导致癌症。天然存在的二苯乙烯衍生物白藜芦醇和紫檀芪抑制 Wnt 信号并抑制 CRC 细胞增殖，但在低于 10 μM 的浓度下无效。为了了解这些二苯乙烯衍生物中的构效关系，并开发比这些天然产物更有效的 Wnt 抑制剂，我们合成并评估了一系列氟化 N,N-二烷基氨基二苯乙烯。在该组中，（E）-4-（2,6-二氟苯乙烯基）-N,N-二甲基苯胺（4r）以纳摩尔水平抑制 Wnt 信号，并以 20 mg/kg 的剂量抑制人 CRC 细胞异种移植物在裸鼠中的生长。这些氟化 N,N-二烷基氨基二苯乙烯似乎抑制了 β-连环蛋白下游的 Wnt 信号，可能在转录水平上。
