Binding-induced, turn-on fluorescence of the EGFR/ERBB kinase inhibitor, lapatinib.
Binding-induced, turn-on fluorescence of the EGFR/ERBB kinase inhibitor, lapatinib.
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DOI：
10.1039/c5ob00239g
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发表时间：
2015-05-07
影响因子：
3.2
通讯作者：
Landgraf R
中科院分区：
文献类型：
--
作者：
Wilson JN;Liu W;Brown AS;Landgraf R
我们报告了EGFR/ERBB抑制剂拉帕替尼的生物物理性质、结合诱导的开启发射和细胞摄取和分布的荧光成像。拉帕替尼，一种II型（即非活性状态）抑制剂，靶向EGFR受体酪氨酸激酶家族的ATP结合口袋。DFT计算预测拉帕替尼的6-呋喃基喹唑啉核应该表现出具有电荷转移特征的激发态和3.4 eV的S 0到S1跃迁能量。吸收证实了在近紫外到紫色的光跃迁，而荧光光谱表明，光电子对溶剂极性高度敏感。拉帕替尼的疏水性导致溶液中的荧光聚集体，然而，与脂质载体蛋白BSA或ERBB 2的激酶结构域结合，产生光谱学上不同的光发射。ERBB 2过表达MCF 7和BT 474细胞中拉帕替尼摄入的共聚焦荧光显微镜成像显示细胞内抑制剂池，其发射谱与聚集的拉帕替尼一致。
We report the photophysical properties, binding-induced turn-on emission, and fluorescence imaging of the cellular uptake and distribution of lapatinib, an EGFR/ERBB inhibitor. Lapatinib, a type II, i.e. inactive state, inhibitor that targets the ATP binding pocket of the EGFR family of receptor tyrosine kinases. DFT calculations predict that the 6-furanylquinazoline core of lapatinib should exhibit an excited state with charge transfer character and an S0 to S1 transition energy of 3.4 eV. Absorption confirms an optical transition in the near UV to violet, while fluorescence spectroscopy shows that photoemission is highly sensitive to solvent polarity. The hydrophobicity of lapatinib leads to fluorescent aggregates in solution, however, binding to the lipid-carrier protein, BSA or to the kinase domain of ERBB2, produces spectroscopically distinct photoemission. Confocal fluorescence microscopy imaging of lapatinib uptake in ERBB2-overexpressing MCF7 and BT474 cells reveals pools of intracellular inhibitor with emission profiles consistent with aggregated lapatinib.