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

Both ER alpha 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 ER alpha/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 ER alpha-binding affinity. The most potent compound II-90H, an analog of 2-(4-hydroxylphenyl)pyrimidine, was 19-fold more efficacious than tamoxifen in MCF-7 cancer cells and exhibited the best ERa binding affinity (IC50= 1.64 mu M) as well as excellent VEGFR-2 inhibition (IC50 = 0.085 mu M). Furthermore, this dual targeted compound II-90H 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-90H, suggesting that II-90H is a promising candidate for the development of multifunctional agents targeting ERa and VEGFR-2 in the therapy of some breast cancers. (C) 2018 Elsevier Masson SAS. All rights reserved.