Luo Guoshun, Tang Zhichao, Lao Kejing, Li Xinyu, You Qidong, Xiang Hua
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
Institute of Basic and Translational Medicine, School of Basic Medical Science, Xi'an Medical University, No.1 Xinwang Road, Xi'an, 710021, China.
Eur J Med Chem. 2018 Apr 25;150:783-795. doi: 10.1016/j.ejmech.2018.03.018. Epub 2018 Mar 7.
Both ERα and VEGFR-2 are important targets for cancer therapies. Here a series of 2, 4-disubstituted pyrimidine derivatives were designed, synthesized and evaluated as dual ERα/VEGFR-2 ligands. Most of the derivatives exhibited potent activities in both enzymatic and cellular assays. Structure-activity relationship studies showed that a hydrogen-bonding interaction in the head section is important factors for the enhancement of ERα-binding affinity. The most potent compound II-9OH, an analog of 2-(4-hydroxylphenyl)pyrimidine, was 19-fold more efficacious than tamoxifen in MCF-7 cancer cells and exhibited the best ERα binding affinity (IC = 1.64 μM) as well as excellent VEGFR-2 inhibition (IC = 0.085 μM). Furthermore, this dual targeted compound II-9OH exerted significantly antiestrogenic property via suppressing the expression of progesterone receptor (PgR) mRNA in MCF-7 cells and also showed obvious in vivo angiogenesis inhibitory effects in CAM assay. An induction of apoptosis and a decrease in cell migration, accompanied by transduction inhibition of Raf-1/MAPK/ERK pathway, were observed in MCF-7 cells after treatment with II-9OH, suggesting that II-9OH is a promising candidate for the development of multifunctional agents targeting ERα and VEGFR-2 in the therapy of some breast cancers.
雌激素受体α（ERα）和血管内皮生长因子受体2（VEGFR-2）都是癌症治疗的重要靶点。在此，设计、合成并评估了一系列2,4-二取代嘧啶衍生物作为ERα/VEGFR-2双靶点配体。大多数衍生物在酶学和细胞实验中均表现出强效活性。构效关系研究表明，头部区域的氢键相互作用是增强ERα结合亲和力的重要因素。最具活性的化合物II-9OH是2-(4-羟基苯基)嘧啶的类似物，在MCF-7癌细胞中的效力比他莫昔芬高19倍，具有最佳的ERα结合亲和力（IC = 1.64 μM）以及出色的VEGFR-2抑制作用（IC = 0.085 μM）。此外，这种双靶点化合物II-9OH通过抑制MCF-7细胞中孕激素受体（PgR）mRNA的表达发挥显著的抗雌激素特性，并且在鸡胚绒毛尿囊膜（CAM）实验中也显示出明显的体内血管生成抑制作用。用II-9OH处理MCF-7细胞后，观察到细胞凋亡诱导和细胞迁移减少，同时伴有Raf-1/MAPK/ERK信号通路转导抑制，这表明II-9OH是开发用于治疗某些乳腺癌的靶向ERα和VEGFR-2的多功能药物的有前景的候选物。
