2. Academic Validation
  3. Structure-activity relationships of 2, 4-disubstituted pyrimidines as dual ERα/VEGFR-2 ligands with anti-breast cancer activity

Structure-activity relationships of 2, 4-disubstituted pyrimidines as dual ERα/VEGFR-2 ligands with anti-breast cancer activity

  • Eur J Med Chem. 2018 Apr 25:150:783-795. doi: 10.1016/j.ejmech.2018.03.018.
Guoshun Luo 1,  Zhichao Tang 1,  Kejing Lao 2,  Xinyu Li 1,  Qidong You 1,  Hua Xiang 3
Affiliations

Affiliations

  • 1 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.
  • 2 Institute of Basic and Translational Medicine, School of Basic Medical Science, Xi'an Medical University, No.1 Xinwang Road, Xi'an, 710021, China.
  • 3 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. Electronic address: xianghua@cpu.edu.cn.
PMID: 29587221 DOI: 10.1016/j.ejmech.2018.03.018
Abstract

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 (IC50 = 1.64 μM) as well as excellent VEGFR-2 inhibition (IC50 = 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.

Keywords

2, 4-disubstituted pyrimidines; Anti-Breast cancer; Antiangiogenesis; ERα; VEGFR-2.

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