Identification and synthesis of substituted pyrrolo[2,3-d]pyrimidines as novel firefly luciferase inhibitors

被引：19

作者：

Liu, Yang ^{[1
]}

Fang, Jianping ^{[2
]}

Cai, Haiyan ^{[3
]}

Xiao, Fei ^{[2
]}

Ding, Kan ^{[2
]}

Hu, Youhong ^{[1
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med, Glycochem & Glycobiol Lab, Shanghai 201203, Peoples R China

[3] Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2012年 / 20卷 / 18期

关键词：

Luciferase; Inhibitor; Pyrrolo[2,3-d]pyrimidine; High-throughput screening; Molecular docking; BINDING; ASSAYS;

D O I：

10.1016/j.bmc.2012.07.035

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A novel firefly luciferase inhibitor (3a) with a pyrrolo[2,3-d] pyrimidine core was identified in a cell-based NF-kappa B luciferase reporter gene assay. It potently inhibited the firefly luciferase derived from Photinus pyralis with an IC50 value of 0.36 +/- 0.05 mu M. 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 IC50 value of 0.06 +/- 0.01 mu M. 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. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：5473 / 5482

页数：10

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