State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Bioorg Med Chem. 2012 Sep 15;20(18):5473-82. doi: 10.1016/j.bmc.2012.07.035. Epub 2012 Jul 28.
A novel firefly luciferase inhibitor (3a) with a pyrrolo[2,3-d]pyrimidine core was identified in a cell-based NF-κB luciferase reporter gene assay. It potently inhibited the firefly luciferase derived from Photinus pyralis with an IC(50) value of 0.36 ± 0.05 μM. Kinetic analysis of 3a inhibition showed that it is predominantly competitive with respect to D-luciferin and uncompetitive with respect to ATP. Therefore, several pyrrolo[2,3-d]pyrimidine analogues were prepared to further investigate the structure-activity relationship (SAR) for luciferase inhibition. The most potent inhibitor of this series was 4c, which showed an IC(50) value of 0.06 ± 0.01 μM. In addition, molecular docking studies suggested that both 3a and 4c could be accommodated in the D-luciferin binding pocket, which is expected for a predominantly competitive inhibitor with respect to D-luciferin.
在基于细胞的 NF-κB 荧光素酶报告基因检测中，发现了一种具有吡咯并[2,3-d]嘧啶核心的新型荧光素酶抑制剂（3a）。它能够强烈抑制来自 Photinus pyralis 的荧光素酶，IC50 值为 0.36±0.05 μM。3a 抑制的动力学分析表明，它主要对 D-荧光素呈竞争性抑制，对 ATP 呈非竞争性抑制。因此，制备了几种吡咯并[2,3-d]嘧啶类似物，以进一步研究荧光素酶抑制的构效关系（SAR）。该系列中最有效的抑制剂是 4c，其 IC50 值为 0.06±0.01 μM。此外，分子对接研究表明，3a 和 4c 都可以容纳在 D-荧光素结合口袋中，这对于主要对 D-荧光素呈竞争性抑制的抑制剂是预期的。
