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

• Published in: European journal of medicinal chemistry Vol. 150; pp. 783 - 795
• Main Authors: Luo, Guoshun, Tang, Zhichao, Lao, Kejing, Li, Xinyu, You, Qidong, Xiang, Hua
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 25.04.2018; Elsevier
• Subjects: 2, 4-disubstituted pyrimidines; Anti-Breast cancer; Antiangiogenesis; Chemistry, Medicinal; ERα; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; VEGFR-2; Anti-Breast cancer; ERα; VEGFR-2; Antiangiogenesis; 2, 4-disubstituted pyrimidines; DESIGN; ESTROGEN-RECEPTOR MODULATORS; ER MODULATORS; ALPHA; MECHANISMS; DISCOVERY; ANGIOGENESIS INHIBITORS; BIOLOGICAL EVALUATION; AGENTS; ER alpha
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.03.018

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. [Display omitted] •Twenty-one pyrimidines were evaluated as dual ERα/VEGFR-2 ligands.•II-9OH exhibited potent activities in both enzymatic and cellular assays.•II-9OH induced apoptosis and inhibited migration on MCF-7 cells.•In vivo anti-angiogenic activity of II-9OH was determined using CAM assay.•Synergetic effect of II-9OH on ERα and VEGFR-2/Raf-1/MAPK/ERK pathway.