Development of Sulfamoylated 4‑(1-Phenyl‑1<i>H</i>‑1,2,3-triazol-4-yl)phenol Derivatives as Potent Steroid Sulfatase Inhibitors for Efficient Treatment of Breast Cancer

We present here the advances achieved in the development of new sulfamoylated 4-(1-phenyl-1H-1,2,3-triazol-4-yl)­phenol derivatives as potent steroid sulfatase (STS) inhibitors for the treatment of breast cancer. Prompted by promising biological results and in silico analysis, the initial series of similar compounds were extended, appending a variety of m-substituents at the outer phenyl ring. The inhibition profiles of the newly synthesized compounds were evaluated using a radioisotope enzymatic assay and, together with the preceding reported derivatives, using a radioisotope assay in MCF-7 cells. The most active compound, 5l, demonstrated an extraordinary STS inhibitory potency in MCF-7 cells with an IC50 value improved 5-fold compared to that of the reference Irosustat (0.21 vs 1.06 nM). The five most potent compounds were assessed in vivo in a 67NR mouse mammary gland cancer model, with 4b measured to induce up to 51% tumor growth inhibition at 50 mg/kg with no evidence of side effects and toxicity.本研究报道了新型磺酰化4-(1-苯基-1H-1,2,3-三唑-4-基)苯酚衍生物的研发进展，该类化合物作为强效类固醇硫酸酯酶（steroid sulfatase, STS）抑制剂，可用于乳腺癌的治疗。受前期颇具前景的生物学活性结果与计算机模拟分析的启发，研究团队对初始同系列化合物进行了结构拓展，在外苯环上引入了多种间位取代基。通过放射性同位素酶促测定法评估了新合成化合物的抑制活性，并结合此前已报道的衍生物，在MCF-7细胞中采用放射性同位素测定法完成了活性测试。活性最优的化合物5l在MCF-7细胞中展现出极强的STS抑制活性，其半最大抑制浓度（IC50）相较于对照药物依洛司他（Irosustat）提升了5倍（0.21 nM 对比 1.06 nM）。研究选取5种活性最强的化合物，在67NR小鼠乳腺癌模型中开展了体内评价，其中化合物4b在50 mg/kg给药剂量下可实现最高51%的肿瘤生长抑制率，且未观察到任何不良反应与毒性。