新型腺苷衍生抑制剂抑制微小隐孢子虫肌苷 5'-单磷酸脱氢酶。
Novel adenosine-derived inhibitors of Cryptosporidium parvum inosine 5'-monophosphate dehydrogenase.
机构信息
Graduate School of Agriculture, Hokkaido University, Kita-9, Nishi-9, Kita-ku, Sapporo, 060-8589, Japan.
Faculty of Pharmaceutical Science, Hokkaido University, Sapporo, 060-0812, Japan.
出版信息
J Antibiot (Tokyo). 2019 Dec;72(12):934-942. doi: 10.1038/s41429-019-0199-3. Epub 2019 Jul 12.
We have found cyclophane-type adenosine derivatives having p-quinone amide moieties (1 and 2) as weak inhibitors of Cryptosporidium parvum inosine 5'-monophosphate dehydrogenase (CpIMPDH) from the Hokkaido University Chemical Library via the luciferase-based high-throughput screening. To obtain more potent inhibitors, we synthesized four new derivatives free from cyclophane rings (3-6). The N-H derivatives 3 and 5 showed more potent activities (24.4 and 11.1 μM, respectively) in the presence of dithiothreitol (DTT), whereas the N-methyl derivative 4 indicated more potent activity (2.1 μM) without DTT. Conformational analysis of compounds 3 and 4 suggested that N-H amide 3 binds to IMP-binding site in the DTT mediated manner.
我们从北海道大学化学文库中发现了具有对苯醌酰胺部分的环戊二烯型腺苷衍生物（1 和 2），它们是微小隐孢子虫肌苷 5'-单磷酸脱氢酶（CpIMPDH）的弱抑制剂，通过基于荧光素酶的高通量筛选。为了获得更有效的抑制剂，我们合成了四个没有环戊二烯环的新型衍生物（3-6）。在存在二硫苏糖醇（DTT）的情况下，N-H 衍生物 3 和 5 表现出更强的活性（分别为 24.4 和 11.1 μM），而 N-甲基衍生物 4 在没有 DTT 的情况下表现出更强的活性（2.1 μM）。化合物 3 和 4 的构象分析表明，N-H 酰胺 3 以 DTT 介导的方式结合到 IMP 结合位点。
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