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

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.

• Authors: Guoshun Luo, Zhichao Tang, Kejing Lao, Xinyu Li, Qidong You, Hua Xiang
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 150 Pg. 783-795 (Apr 25 2018) ISSN: 1768-3254 [Electronic] France
• PMID: 29587221 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• ESR1 protein, human
• Estrogen Receptor alpha
• Ligands
• Pyrimidines
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Estrogen Receptor alpha (antagonists & inhibitors, metabolism)
• Female
• Humans
• Ligands
• MCF-7 Cells
• Molecular Structure
• Neovascularization, Pathologic (drug therapy, metabolism, pathology)
• Pyrimidines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors, metabolism)