New twelve in silico designed coumarin-based ERα antagonists, namely 3DQ-1a to 3DQ-1е, were synthesized and confirmed as selective ERα antagonists, showing potencies ranging from single-digit nanomolar to picomolar. The hits were confirmed as selective estrogen receptor modulators and validated as antiproliferative agents using MCF-7 breast cancer cell lines exerting from picomolar to low nanomolar potency, at the same time showing no agonistic activity within endometrial cell lines. Their mechanism of action was inspected and revealed to be through the inhibition of the Raf-1/MAPK/ERK signal transduction pathway, preventing hormone-mediated gene expression on either genomic direct or genomic indirect level, and stopping the MCF-7 cells proliferation at G₀/G₁ phase. In vivo experiments, by means of the per os administration to female Wistar rats with pre-induced breast cancer, distinguished six derivatives, 3DQ-4a, 3DQ-2a, 3DQ-1a, 3DQ-1b, 3DQ-2b, and 3DQ-3b, showing remarkable potency as tumor suppressors endowed with optimal pharmacokinetic profiles and no significant histopathological profiles. The presented data indicate the new compounds as potential candidates to be submitted in clinical trials for breast cancer therapy.

新的 12 种计算机设计的基于香豆素的 ERα 拮抗剂，即3DQ-1a至3DQ-1е被合成并确认为选择性 ERα 拮抗剂，显示出从个位数纳摩尔到皮摩尔的效力。这些命中被证实为选择性雌激素受体调节剂，并使用 MCF-7 乳腺癌细胞系验证为抗增殖剂，发挥从皮摩尔到低纳摩尔的效力，同时在子宫内膜细胞系中没有显示激动活性。检查并发现它们的作用机制是通过抑制 Raf-1/MAPK/ERK 信号转导通路，在基因组直接或基因组间接水平上阻止激素介导的基因表达，并阻止 MCF-7 细胞增殖G₀ /G ₁相。在体内实验中，通过对患有预诱导乳腺癌的雌性 Wistar 大鼠进行口服给药，区分了 6 种衍生物：3DQ -4a、3DQ-2a、3DQ-1a、3DQ-1b、3DQ-2b和3DQ-3b，显示出显着的效力，因为肿瘤抑制因子具有最佳的药代动力学特征，并且没有显着的组织病理学特征。所提供的数据表明，新化合物可作为潜在的候选药物提交用于乳腺癌治疗的临床试验。