Latvian Institute of Organic Synthesis, Riga, Latvia.
Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry, Riga Technical University, Riga, Latvia.
J Enzyme Inhib Med Chem. 2020 Dec;35(1):1011-1020. doi: 10.1080/14756366.2020.1752201.
The clinically used antibiotic Furagin and its derivatives possess inhibitory activity on human (h) carbonic anhydrases (CA, EC 4.2.1.1), some of which are highly expressed in various tissues and malignancies (hCA IX/XII). Furagin exhibited good hCA IX and XII inhibition with s of 260 and 57 nM, respectively. It does not inhibit off-target CA I and poorly inhibited CA II ( = 9.6 μM). Some synthesised Furagin derivatives with aminohydantoin moieties as zinc binding group exhibited weak inhibition of CA I/II, and good inhibition of CA IX/XII with s ranging from 350 to 7400 and 150 to 5600 nM, respectively. Docking and molecular dynamics simulations suggest that selectivity for the cancer-associated CA IX/XII over CA II is due to strong H-bond interactions in CA IX/XII, involving the tail orientated towards hydrophobic area of the active site. These results suggest a possible drug repurposing of Furagin as anti-cancer agent.
临床上使用的抗生素呋喃妥因及其衍生物对人（h）碳酸酐酶（CA，EC 4.2.1.1）具有抑制活性，其中一些在各种组织和恶性肿瘤（hCA IX/XII）中高度表达。呋喃妥因对 hCA IX 和 XII 的抑制作用良好，s 值分别为 260 和 57 nM。它不抑制非靶标 CA I，对 CA II 的抑制作用较差（=9.6 μM）。一些合成的带有氨基乙内酰脲部分作为锌结合基团的呋喃妥因衍生物对 CA I/II 的抑制作用较弱，对 CA IX/XII 的抑制作用良好，s 值分别为 350 至 7400 和 150 至 5600 nM。对接和分子动力学模拟表明，对癌症相关的 CA IX/XII 而非 CA II 的选择性是由于 CA IX/XII 中存在强氢键相互作用，涉及朝向活性位点疏水区域的尾部。这些结果表明呋喃妥因可能被重新用于癌症治疗。
