Novel SERMs based on 3-aryl-4-aryloxy-2H-chromen-2-one skeleton - A possible way to dual ERα/VEGFR-2 ligands for treatment of breast cancer

There is considerable interest in developing new SERMs as multifunctional agents in women's health. Development of dual selective Estrogen Receptor modulators/VEGFR-2 inhibitors (SERMs/V-2I) has been an attractive strategy for the discovery of new breast Cancer therapeutic agents. Our previous efforts led to the preparation of a series of 3-aryl-4-anilino-2H-chromen-2-ones endowed with potent Estrogen Receptor binding affinity and anti-proliferative efficacy. In this study, various structurally related 3-aryl-4-anilino/aryloxy-2H-chromen-2-one analogues were rationally designed, synthesized and evaluated as a new chemo-type of dual ERα and VEGFR-2 inhibitors. Most of the derivatives exhibited potent activities in both enzymatic and cellular assays. SAR investigation revealed that introducing of bioisosteric O atom at the C-4 position of coumarin scaffold is beneficial to improve the inhibitory potency, especially in ERα binding affinity assay. Furthermore, most of the piperidyl substituted compounds showed better inhibitory activity against MCF-7 and Ishikawa cells than lead compounds BL-18d, tamoxifen and Vandetanib. Optimization of the hit compound, identified in an ERα binding affinity assay, led to compound 42d, exhibiting an IC₅₀ for ERα binding affinity of 2.19 μM while retaining an excellent inhibition on VGFR-2 as well as a potent suppression on the growth of angiogenesis-related cells. In RT-PCR assay, 42d exerted significantly antiestrogenic property via suppressing the expression of Progesterone Receptor (PgR) mRNA in MCF-7 cells, which was consistent with the ERα antagonistic property of a selective Estrogen receptor Modulator. Further mechanism investigation demonstrated that compound 42d could inhibit the activation of VEGFR-2 and subsequent signaling transduction of Raf-1/MAPK/ERK pathway in MCF-7 cells. All these results together with molecular modeling studies open a new avenue for the development of multifunctional agents targeting ERα and VEGFR-2 in the therapy of some breast cancers.

Anti-breast cancer; Coumarin; Docking studies; Estrogen receptor; VEGFR-2.