个人信息Personal Information
教授
博士生导师
硕士生导师
主要任职:化工学院院长、党委副书记
性别:男
毕业院校:北京大学
学位:博士
所在单位:化工学院
学科:无机化学. 应用化学. 精细化工
办公地点:大连理工大学西部校区F208
联系方式:0411-84986296 liutao@dlut.edu.cn https://liutao.dlut.edu.cn/
电子邮箱:liutao@dlut.edu.cn
Molecular Design Strategy to Construct the Near-Infrared Fluorescent Probe for Selectively Sensing Human Cytochrome P450 2J2
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论文类型:期刊论文
发表时间:2019-01-16
发表刊物:JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
收录刊物:SCIE、PubMed、EI、ESI高被引论文
卷号:141
期号:2
页面范围:1126-1134
ISSN号:0002-7863
关键字:Biochemistry; Biological systems; Fluorescence; Infrared devices; Metabolism; Probes; Real time systems; Tumors, Biological functions; Complex biological systems; Endogenous compound; Near-infrared fluorescent; Near-infrared fluorophores; Oxidative metabolism; Pathological process; Real time monitoring, Diagnosis
摘要:Cytochrome P450 2J2 (CYP2J2), a key enzyme responsible for oxidative metabolism of various xenobiotics and endogenous compounds, participates in a diverse array of physiological and pathological processes in humans. Its biological role in tumorigenesis and cancer diagnosis remains poorly understood, owing to the lack of molecular tools suitable for real-time monitoring CYP2J2 in complex biological systems. Using molecular design principles, we were able to modify the distance between the catalytic unit and metabolic recognition moiety, allowing us to develop a CYP2J2 selective fluorescent probe using a near-infrared fluorophore (E)-2-(2-(6-hydroxy-2,3-dihydro-1H-xanthen-4-yl)vinyl)-3,3-dimethyl-1-propyl-3H-indol-1-ium iodide (HXPI). To improve the reactivity and isoform specificity, a self-immolative linker was introduced to the HXPI derivatives in order to better fit the narrow substrate channel of CYP2J2, the modification effectively shortened the spatial distance between the metabolic moiety (O-alkyl group) and catalytic center of CYP2J2. After screening a panel of O-alkylated HXPI derivatives, BnXPI displayed the best combination of specificity, sensitivity and applicability for detecting CYP2J2 in vitro and in vivo. Upon O-demethylation by CYP2J2, a self-immolative reaction occurred spontaneously via 1,6-elimination of p-hydroxybenzyl resulting in the release of HXPI. Allowing BnXPI to be successfully used to monitor CYP2J2 activity in real-time for various living systems including cells, tumor tissues, and tumor-bearing animals. In summary, our practical strategy could help the development of a highly specific and broadly applicable tool for monitoring CYP2J2, which offers great promise for exploring the biological functions of CYP2J2 in tumorigenesis.