Novel SERMs based on 3-aryl-4-aryloxy-2H-chromen-2-one skeleton - A possible way to dual ER alpha/VEGFR-2 ligands for treatment of breast cancer
Novel SERMs based on 3-aryl-4-aryloxy-2H-chromen-2-one skeleton - A possible way to dual ER alpha/VEGFR-2 ligands for treatment of breast cancer
复制标题
基于 3-芳基-4-芳氧基-2H-chromen-2-one 骨架的新型 SERM - ER α/VEGFR-2 双配体治疗乳腺癌的可能方法
DOI：
10.1016/j.ejmech.2017.09.015
复制
发表时间：
2017
影响因子：
6.7
通讯作者：
Xiang Hua
中科院分区：
文献类型：
--
作者：
Luo Guoshun;Li Xinyu;Zhang Guoqing;Wu Chengzhe;Tang Zhengpu;Liu Linyi;You Qidong;Xiang Hua
人们对开发新的 SERM 作为女性健康的多功能制剂非常感兴趣。开发双选择性雌激素受体调节剂/VEGFR-2 抑制剂 (SERM/V-2I) 一直是发现新乳腺癌治疗药物的一个有吸引力的策略。我们之前的努力导致制备了一系列具有有效雌激素受体结合亲和力和抗增殖功效的3-芳基-4-苯胺基-2H-色烯-2-酮。在这项研究中，合理设计、合成了各种结构相关的3-芳基-4-苯胺基/芳氧基-2H-chromen-2-one类似物，并作为一种新的化学类型的ERα和VEGFR-2双重抑制剂进行了评估。大多数衍生物在酶和细胞测定中都表现出有效的活性。 SAR研究表明，在香豆素支架的C-4位引入生物等排O原子有利于提高抑制效力，特别是在ERα结合亲和力测定中。此外，大多数哌啶基取代的化合物对MCF-7和Ishikawa细胞表现出比先导化合物BL-18d、他莫昔芬和凡德他尼更好的抑制活性。对 ERα 结合亲和力测定中鉴定的命中化合物进行优化，得到化合物 42d，其对 ERα 结合亲和力的 IC50 为 2.19 μM，同时保留对 VGFR-2 的出色抑制作用以及对血管生成相关细胞生长的有效抑制作用。在 RT-PCR 测定中，42 通过抑制 MCF-7 细胞中孕激素受体 (PgR) mRNA 的表达，发挥显着的抗雌激素特性，这与选择性雌激素受体调节剂的 ERα 拮抗特性一致。进一步的机制研究表明，compound42d 可以抑制 MCF-7 细胞中 VEGFR-2 的激活以及随后 Raf-1/MAPK/ERK 通路的信号转导。所有这些结果与分子模型研究一起为开发针对 ERα 和 VEGFR-2 的多功能药物治疗某些乳腺癌开辟了新途径。
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 compoundsBL-18d, tamoxifen and Vandetanib. Optimization of the hit compound, identified in an ERα binding affinity assay, led to compound42d, exhibiting an IC50for 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,42dexerted 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 compound42dcould 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.