Recent advances in 4-hydroxy-1,8-naphthalimide-based small-molecule fluorescent probes

Highlights

• This review fully discusses the excellent photophysical properties of HNI dyes.

• The synthesis of HNI and its applications in the detection of analytes are introduced.

• This review gives a detailed outlook on the research of probes based on HNI dyes.

Abstract

In recent years, more and more chemists and biologists pay attention to the research of fluorescent probes, and great progress has been made in the design and application. In this review, we first discuss the excellent photophysical properties of 4-hydroxy-1,8-naphthalimide (HNI) structure, including excellent photostability, high fluorescence quantum yield, and easy modification of the structure. Then, by discussing the fluorescence behavior of the probe in the corresponding recognition process, the contributions of fluorescent probes built on the platform of HNI in the fields of chemical sensing, biological imaging, pharmaceutical chemistry, environment and food safety in the past ten years are systematically introduced (173 references). At the same time, we hope to develop more powerful fluorescent chemical sensors, which can play a more extensive and exciting role in the future.

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.