Evaluation of Imidazole-Based Compounds as Heme Oxygenase-1 Inhibitors
Evaluation of Imidazole-Based Compounds as Heme Oxygenase-1 Inhibitors
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DOI：
10.1111/cbdd.12015
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发表时间：
2012-12-01
影响因子：
3
通讯作者：
Salerno, Loredana
中科院分区：
文献类型：
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作者：
Sorrenti, Valeria;Guccione, Salvatore;Salerno, Loredana
咪唑为基础的化合物先前在我们的实验室合成的选择和重新考虑作为血红素加氧酶-1从大鼠脾脏微粒体组分的抑制剂。大多数测试化合物是良好的抑制剂，IC 50值在低微摩尔范围内。还在无膜全长重组人血红素加氧酶-1上测定化合物;除了化合物11和13分别抑制54%和20%的酶外，所有测试的化合物在100 μ m浓度下都不能与人血红素加氧酶-1相互作用。还通过光谱分析检查了最具活性的化合物11与血红素或血红素缀合的人血红素加氧酶-1的结合。当血红素不与人血红素加氧酶-1结合时，化合物11仅在比抑制大鼠血红素加氧酶-1所需浓度高50倍（100 μ m）的浓度下引起血红素谱的变化;当血红素与人血红素加氧酶-1结合时，化合物11也能够在低微摩尔浓度下形成血红素-化合物11复合物。为了获得关于测试化合物与酶的结合模式的信息，进行对接研究和药效团分析。模板对接结果与实验抑制数据和基于结构的药效模型一致。这些数据可用于设计新的OH-1抑制剂。
Imidazole-based compounds previously synthesized in our laboratory were selected and reconsidered as inhibitors of heme oxygenase-1 obtained from the microsomal fractions of rat spleens. Most of tested compounds were good inhibitors with IC50 values in the low micromolar range. Compounds were also assayed on membrane-free full-length recombinant human heme oxygenase-1; all tested compounds were unable to interact with human heme oxygenase-1 at 100 mu m concentrations with the exception of compounds 11 and 13 that inhibited the enzyme of 54% and 20%, respectively. The binding of the most active compound 11 with heme or heme-conjugated human heme oxygenase-1 was also examined by spectral analyses. When heme was not conjugated to human heme oxygenase-1, compound 11 caused changes in the heme spectrum only at concentration 50-fold (100 mu m) higher than that required to inhibit rat heme oxygenase-1; when heme was conjugated to human heme oxygenase-1, compound 11 was able to form a heme-compound 11 complex also at low micromolar concentrations. To obtain information on the binding mode of the tested compounds with enzyme, docking studies and pharmacophore analysis were performed. Template docking results were in agreement with experimental inhibition data and with a structure-based pharmacophoric model. These data may be exploitable to design new OH-1 inhibitors.