Molecular Design Strategy to Construct the Near-Infrared Fluorescent Probe for Selectively Sensing Human Cytochrome P450 2J2

Jing Ning, Tao Liu, Peipei Dong, Wei Wang, Guangbo Ge, Bo Wang, Zhenlong Yu, Lei Shi, Xiangge Tian, Xiaokui Huo, Lei Feng, Chao Wang, Chengpeng Sun, Jing-Nan Cui, Tony D James, Xiaochi Ma

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1126-1134
Number of pages9
JournalJournal of the American Chemical Society
Volume141
Issue number2
Early online date10 Dec 2018
DOIs
Publication statusPublished - 16 Jan 2019

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Molecular Design Strategy to Construct the Near-Infrared Fluorescent Probe for Selectively Sensing Human Cytochrome P450 2J2. / Ning, Jing; Liu, Tao; Dong, Peipei; Wang, Wei; Ge, Guangbo; Wang, Bo; Yu, Zhenlong; Shi, Lei; Tian, Xiangge; Huo, Xiaokui; Feng, Lei; Wang, Chao; Sun, Chengpeng; Cui, Jing-Nan; James, Tony D; Ma, Xiaochi.

In: Journal of the American Chemical Society, Vol. 141, No. 2, 16.01.2019, p. 1126-1134.

Research output: Contribution to journalArticle

Ning, J, Liu, T, Dong, P, Wang, W, Ge, G, Wang, B, Yu, Z, Shi, L, Tian, X, Huo, X, Feng, L, Wang, C, Sun, C, Cui, J-N, James, TD & Ma, X 2019, 'Molecular Design Strategy to Construct the Near-Infrared Fluorescent Probe for Selectively Sensing Human Cytochrome P450 2J2', Journal of the American Chemical Society, vol. 141, no. 2, pp. 1126-1134. https://doi.org/10.1021/jacs.8b12136
Ning, Jing ; Liu, Tao ; Dong, Peipei ; Wang, Wei ; Ge, Guangbo ; Wang, Bo ; Yu, Zhenlong ; Shi, Lei ; Tian, Xiangge ; Huo, Xiaokui ; Feng, Lei ; Wang, Chao ; Sun, Chengpeng ; Cui, Jing-Nan ; James, Tony D ; Ma, Xiaochi. / Molecular Design Strategy to Construct the Near-Infrared Fluorescent Probe for Selectively Sensing Human Cytochrome P450 2J2. In: Journal of the American Chemical Society. 2019 ; Vol. 141, No. 2. pp. 1126-1134.
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AU - Ning, Jing

AU - Liu, Tao

AU - Dong, Peipei

AU - Wang, Wei

AU - Ge, Guangbo

AU - Wang, Bo

AU - Yu, Zhenlong

AU - Shi, Lei

AU - Tian, Xiangge

AU - Huo, Xiaokui

AU - Feng, Lei

AU - Wang, Chao

AU - Sun, Chengpeng

AU - Cui, Jing-Nan

AU - James, Tony D

AU - Ma, Xiaochi

PY - 2019/1/16

Y1 - 2019/1/16

N2 - 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.

AB - 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.

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