设计并合成 3-苄基氨基香豆素-7-O-磺胺酯衍生物作为甾体硫酸酯酶抑制剂。
Design and synthesis of 3-benzylaminocoumarin-7-O-sulfamate derivatives as steroid sulfatase inhibitors.
机构信息
School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
出版信息
Bioorg Chem. 2020 Mar;96:103618. doi: 10.1016/j.bioorg.2020.103618. Epub 2020 Jan 27.
Steroid sulfatase (STS) is a sulfatase enzyme that catalyzes the conversion of sulfated steroid precursors to free steroid. The inhibition of STS could abate estrogenic steroids that stimulate the proliferation and development of breast cancer, and therefore STS is a potential target for adjuvant endocrine therapy. In this study, a series of 3-benzylaminocoumarin-7-O-sulfamate derivatives targeting STS were designed and synthesized. Structure-relationship activities (SAR) analysis revealed that attachment of a benzylamino group at the 3-position of coumarin improved inhibitory activity. Compound 3j was found to have the highest inhibition activity against human placenta isolated STS (IC 0.13 μM) and MCF-7 cell lines (IC 1.35 µM). Kinetic studies found compound 3j to be an irreversible inhibitor of STS, with K and k value of 86.9 nM and 158.7 min, respectively.
甾体硫酸酯酶（STS）是一种硫酸酯酶，能够催化将磺化甾体前体转化为游离甾体。STS 的抑制作用可以减少刺激乳腺癌增殖和发展的雌激素类甾体，因此 STS 是辅助内分泌治疗的潜在靶点。在本研究中，设计并合成了一系列靶向 STS 的 3-苄氨基香豆素-7-O-磺酰胺衍生物。构效关系分析表明，香豆素 3 位连接苄氨基可提高抑制活性。化合物 3j 对人胎盘分离 STS（IC 0.13 μM）和 MCF-7 细胞系的抑制活性最高（IC 1.35 μM）。动力学研究发现化合物 3j 是 STS 的不可逆抑制剂，其 K 和 k 值分别为 86.9 nM 和 158.7 min。
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