Michael addition–elimination–cyclization based turn-on fluorescence (MADELCY TOF) probes for cellular cysteine imaging and estimation of blood serum cysteine and aminoacylase-1,Analyst

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Michael addition–elimination–cyclization based turn-on fluorescence (MADELCY TOF) probes for cellular cysteine imaging and estimation of blood serum cysteine and aminoacylase-1
Analyst ( IF 3.6 ) Pub Date : 2022-07-12 , DOI: 10.1039/d2an00713d
Dastgir Shakil Shaikh ₁ , Sangeeta Parmar ₁ , Dimpy Kalia ₁

Affiliation

Oxidative stress is a hallmark of a range of diseases including cancer, HIV-AIDS and cardiovascular disorders. Blood plasma cysteine (Cys) is an established biomarker for oxidative stress, rendering the development of sensitive and technically straightforward approaches for its estimation extremely desirable. Herein, we achieve this goal by developing a series of Michael addition–elimination–cyclization based turn-on fluorescence (MADELCY TOF) probes that selectively detect Cys over other amino acids and biothiols such as homocysteine (Hcy) and glutathione (GSH). Cysteine detection by these compounds involves cascaded fluorophore release via the Michael addition of the cysteinyl thiol followed by the elimination of a leaving group and lactamization via the cysteinyl amine. Conveniently, the Cys-reactivity of these probes can be tuned via both inductive and mesomeric effects imparted by their β′ position-substituents. One of our probes that contains the p-nitrophenyl group at its β′ position demonstrated rapid kinetics (t_1/2 = 2.9 min) with excellent sensitivity (detection limit = 8.2 nM) towards Cys. This probe also enabled the sensitive (detection limit = 9.5 pM) estimation of the blood plasma levels of the cancer and liver cirrhosis biomarker, the aminoacylase-1 (ACY-1) enzyme. Furthermore, another probe of our library enabled live cell imaging of cellular Cys allowing us to develop an imaging-based assay to monitor hydrogen peroxide-induced oxidative stress in mammalian cells.

中文翻译：

基于迈克尔加法-消除-环化的开启荧光 (MADELCY TOF) 探针用于细胞半胱氨酸成像和血清半胱氨酸和氨酰化酶-1 的估计

氧化应激是一系列疾病的标志，包括癌症、艾滋病毒-艾滋病和心血管疾病。血浆半胱氨酸 (Cys) 是一种既定的氧化应激生物标志物，因此开发灵敏且技术上简单的方法来估计其非常可取。在这里，我们通过开发一系列基于迈克尔加成-消除-环化的开启荧光 (MADELCY TOF) 探针来实现这一目标，这些探针可以选择性地检测 Cys 而不是其他氨基酸和生物硫醇，例如同型半胱氨酸 (Hcy) 和谷胱甘肽 (GSH)。这些化合物对半胱氨酸的检测涉及通过半胱氨酰硫醇的迈克尔加成，然后通过消除离去基团和内酰胺化来级联荧光团释放。半胱胺。方便地，这些探针的半胱氨酸反应性可以通过它们的 β' 位置取代基赋予的感应和介观效应来调节。我们的一种探针在其 β' 位置包含对硝基苯基基团，表现出对 Cys 的快速动力学（t _1/2 = 2.9 min）和出色的灵敏度（检测限 = 8.2 nM）。该探针还能够对癌症和肝硬化生物标志物氨酰化酶-1 (ACY-1) 的血浆水平进行灵敏的（检测限 = 9.5 pM）估计。此外，我们图书馆的另一个探针能够对细胞 Cys 进行活细胞成像，从而使我们能够开发一种基于成像的分析方法来监测哺乳动物细胞中过氧化氢诱导的氧化应激。

更新日期：2022-07-12

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