ReviewRecent advances in 4-hydroxy-1,8-naphthalimide-based small-molecule fluorescent probes
Introduction
In recent years, more and more scholars pay attention to the exploration of environmental ion and bioactive substance sensing, organic materials, biopharmaceutics, biological imaging, especially in interdisciplinary research [1], [2], [3]. The methods include electrochemical analysis, elemental analysis, mass spectrometry, etc., and great progress has been made [4], [5], [6]. However, there are also some factors that hinder the further development of these methods, mainly in the long analysis time, complicated operations, and expensive instruments. In contrast, fluorescent probe technology has received extensive attention from scholars because of its simple operation, low cost, and rapid detection. With confocal imaging technology, the probe can visualize small molecular substances in organisms, and plays a major role in biochemistry, medical surgery, and other fields [7], [8], [9], [10].
In the past few years, a series of excellent fluorophores (including 1,8-naphthalimide, coumarin, rhodamine, etc.) have been found and synthesized [11], [12], [13], [14], [15], which combine with different recognition receptors to detect small molecular substances in the environment and in vivo. With the rapid development of science and technology, people's requirements for the performance of probes are gradually improved. The design and application of new probes are still an important and interdisciplinary research direction.
1,8-Naphthimide and its derivatives are playing an increasingly important role in the fields of fluorescent materials and dyes due to their excellent photophysical properties, good thermal stability and easy modification [16]. In 2011, our research group used a simple synthesis method to introduce a hydroxy group at the 4-position of 1,8-naphthimide to construct a 4-hydroxy-1,8-naphthimide (HNI) fluorophore. Based on the intramolecular charge transfer (ICT) mechanism, a ratiometric fluorescent probe platform was constructed [17]. As shown in the Fig. 1a, the naphthalimide part has better electron affinity and excellent thermal stability because of its special structure. When hydroxy group is introduced, the water solubility is improved, and the overall structure is easier to modify. The naphthalene ring as a π bridge, the hydroxy group acts as an electron-donating group and forms a D-π-A system with the imine of the electron-accepting group. The important thing is that when different groups are introduced into the hydroxy part, due to the overall ICT and photo-induced electron transfer (PET) effect, the fluorescence emission peak produces red shift or blue shift, as well as fluorescence enhancement and quenching effects [18]. The above conclusion is consistent with the theoretical calculation result [19]. Based on the above advantages of the framework, as we imagined, in the following years, many excellent fluorescent probes emerged based on the HNI platform, detecting species including proteins, amino acids, toxic gases, and molecular events such as pH and water content, which play an important role in biochemistry, material chemistry, etc [20], [21], [22], [23], [24]. Probe combined imaging equipment, visual detection of cells and substances in vivo, is expected to provide important help for the integration of diagnosis and treatment, early disease diagnosis, drug evaluation, and other research directions.
Although excellent reviews of 1,8-naphthalimide (NI) fluorescence sensors have been reported [25], [26], it is a pity that further fluorescent probes based on HNI as the backbone have not been systematically reviewed. Especially, HNI plays an increasingly important role in molecular recognition, biochemistry, biomedicine, and so on. Therefore, it is very valuable to review HNI and its derivatives. In this review, we reviewed various functional fluorescent probes developed by HNI since 2011. The analysis species mainly include reactive oxygen species (ROS), reactive nitrogen species (RNS), reactive sulfur species (RSS), proteins, metal ions, anions, and other important substances (Fig. 1b). The mechanisms used in the recognition process are mainly ICT, PET, and fluorescence resonance energy transfer (FRET). The reaction processes involved mainly include nucleophilic addition reaction, electrophilic addition reaction, hydrolysis reaction, complexation reaction/chelation reaction, protonation process, cyclization process, rearrangement process, and so on. We hope that this review will not only help chemists and biologists, but also lead to the development of more excellent fluorescent probes that can play a role in a wide range of applications in the future.
The main methods for synthesizing 4-hydroxy-1,8-naphthalimide dye are as follows:
(1) In the high-temperature (220 °C) melting system of MnO2, KOH, and KOAc, the direct C–H oxidative of 1,8-naphthalimide to obtain a 4-hydroxyl system (Fig. 2a) [27], the synthesis conditions are relatively harsh.
(2) 4-Bromo-1,8-naphthalimide undergoes Ulmann-type or nucleophilic aromatic substitution reaction in methanol solution to obtain methyl aryl ether, which is treated with strong acid to obtain 4-hydroxy-1,8-naphthalimide (Fig. 2b) [28], [22]. The process generally requires two steps.
(3) Using DMSO as a solvent, K2CO3 as a base, and N-hydroxyphthalimide as a reagent, the 4-chloro-1,8-naphthalimides can be prepared into 4-hydroxy-1,8-naphthalimide in one step (Fig. 2c) [29], the reaction process is relatively simple.
(4) The target product was obtained by heating and stirring 4-chloro-1,8-naphthalimides with Pd(OAc)2, t-BuXPhos and K2CO3 in DMF/H2O solution (Fig. 2d) [30], the yield of this process is high.
Section snippets
Fluorescent probes for reactive oxygen species (ROS)
ROS have high chemical activity, which include hydrogen peroxide (H2O2), hydroxy radicals (OH), peroxyl radicals (ROO), singlet oxygen (1O2), superoxide anion radicals (O2−), and hypochlorous acid/hypochlorite (HOCl/OCl−). In the life system, the production of ROS mainly depends on the respiration of mitochondria, and can also be produced by external stimulation, such as the use of some anti-inflammatory drugs and traumatic injury [31]. There is no doubt that ROS have essential impacts on cell
Fluorescent probes for reactive nitrogen species (RNS)
Reactive nitrogen species (RNS) include NO, NO2, ONOO−, and HNO, etc. Reactive nitrogen species are important chemical reactive species in human body, which can damage cells via nitrosative stress [55]. Due to their important roles in physiological processes, more and more fluorescent probes have been developed in recent years to detect reactive nitrogen species in the environment and in organisms.
Fluorescent probes for reactive sulfur species (RSS)
There are various types of endogenous active species in organisms, mainly in the form of reducing proteins, various small molecules and ions. Reactive sulfur species (RSS) refer to the general term of sulfur-containing active substances in organisms, including cysteine (Cys), hydrogen sulfide (H2S), homocysteine (Hcy), glutathione (GSH), etc. They have their own functions in cells, and they are closely related to each other. Not only the concentration of RSS in different tissues is different,
Fluorescent probes for metal ions
Metal ions are necessary for organisms because they play a big part in chemical, biological and environmental processes [91], [92], [93]. Metal ions can be broadly divided into two categories: the first category of metal ions is essential nutrient elements such as K+, Na+, Mg2+, Zn2+, etc. These metal ions regulate intramolecular communication, normal cell function, oxygen transport, photosynthesis, and charge transfer [94], [95]. They are very important in maintaining the homeostasis and
Fluorescent probes for enzyme
Enzyme is a protein or RNA produced by a living cell that is highly specific and highly catalytic to its substrate. Enzymes are a kind of very important biocatalyst. Enzymes are responsible for the efficient and specific chemical reactions in organisms under extremely mild conditions. Enzymes are involved in many life activities in organisms, such as metabolism, nutrient transfer and energy conversion [128], [129]. Therefore, enzymes are closely related to the life and health of human body.
Fluorescent probes for important anions
Anion plays an important role in many aspects of people's life and medical treatment. It also plays an important role in chemistry and life processes. Some anions are also irreplaceable in important biological processes such as signal transduction, information storage and expression [157]. In conclusion, the selective identification of anions is beneficial to the analysis of their roles in organisms. In recent years, a number of fluorescent probes have been designed to detect anion, mainly
Fluorescent probes for hydrazine
In 2014, Duan et al. developed a ratiometric fluorescent probe (108) based on 4-hydroxynaphthalimide fluorophore to detect hydrazine (Fig. 101) [21]. The probe contains an acetyl group as recognition receptor based on the selective deprotection mechanism of hydrazine to acetyl group. Due to the selective deprotection of the acetate group of the probe by hydrazine, the ratiometric fluorescence spectra changed significantly and color of the probe also changed, which could be distinguished by the
Conclusions and prospects
1,8-Naphthalimide is an important member of fluorescent dyes. In 2011, our research group introduced hydroxy groups on its 4-position, which improved the quantum efficiency of fluorescence, made it easier to modify, and greatly improved its application range. After the efforts of researchers in the past decade, fluorophores based on 4-hydroxy-1,8-naphthalimide have been widely used in chemical sensing, biological imaging, pharmaceutical chemistry, environmental, and food safety and other
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgment
We gratefully acknowledge financial support from the National Natural Science Foundation of China (21777053 and 21607053) and A Project of Shandong Province Higher Educational Youth Innovation Science and Technology Program (2019KJD005).
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