Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd, University of Bath, Claverton Down, Bath BA2 7AY, UK.
J Med Chem. 2010 Mar 11;53(5):2155-70. doi: 10.1021/jm901705h.
Single agents against multiple drug targets are of increasing interest. Hormone-dependent breast cancer (HDBC) may be more effectively treated by dual inhibition of aromatase and steroid sulfatase (STS). The aromatase inhibitory pharmacophore was thus introduced into a known biphenyl STS inhibitor to give a series of novel dual aromatase-sulfatase inhibitors (DASIs). Several compounds are good aromatase or STS inhibitors and DASI 20 (IC(50): aromatase, 2.0 nM; STS, 35 nM) and its chlorinated congener 23 (IC(50): aromatase, 0.5 nM; STS, 5.5 nM) are examples that show exceptional dual potency in JEG-3 cells. Both biphenyls share a para-sulfamate-containing ring B and a ring A, which contains a triazol-1-ylmethyl meta to the biphenyl bridge and para to a nitrile. At 1 mg/kg po, 20 and 23 reduced plasma estradiol levels strongly and inhibited liver STS activity potently in vivo. 23 is nonestrogenic and potently inhibits carbonic anhydrase II (IC(50) 86 nM). A complex was crystallized and its structure was solved by X-ray crystallography. This class of DASI should encourage further development toward multitargeted therapeutic intervention in HDBC.
针对多个药物靶点的单一药物越来越受到关注。双重抑制芳香酶和甾体硫酸酯酶（STS）可能更有效地治疗激素依赖性乳腺癌（HDBC）。因此，将芳香酶抑制剂的药效团引入到已知的联苯 STS 抑制剂中，得到了一系列新型双重芳香酶-硫酸酯酶抑制剂（DASIs）。有几种化合物是良好的芳香酶或 STS 抑制剂，DASI 20（IC50：芳香酶，2.0 nM；STS，35 nM）及其氯化类似物 23（IC50：芳香酶，0.5 nM；STS，5.5 nM）就是在 JEG-3 细胞中表现出异常双重效力的例子。这两个联苯都共享一个含有磺酸盐的 B 环和一个 A 环，A 环中含有一个三唑-1-基甲基，位于联苯桥的间位，对位是一个腈基。在 1 mg/kg po 剂量下，20 和 23 可强烈降低血浆雌二醇水平，并在体内有效抑制肝脏 STS 活性。23 无雌激素活性，可强烈抑制碳酸酐酶 II（IC50 86 nM）。复合物被结晶并通过 X 射线晶体学确定了其结构。此类 DASI 应鼓励进一步开发针对 HDBC 的多靶点治疗干预。
