Sensing and Microbiological Activity of a New Blue Fluorescence Polyamidoamine Dendrimer Modified with 1,8-Naphthalimide Units.

A novel second-generation blue fluorescent polyamidoamine dendrimer peripherally modified with sixteen 4-N,N-dimethylaninoethyloxy-1,8-naphthalimide units was synthesized. Its basic photophysical characteristics were investigated in organic solvents of different polarity. It was found that in these solvents, the dendrimer is colorless and emitted blue fluorescence with different intensities depending on their polarity. The effect of the pH of the medium on the fluorescence intensity was investigated and it was found that in the acidic medium, the fluorescence is intense and is quenched in the alkaline medium. The ability of the dendrimer to detect metal ions (Pb2+, Zn2+, Mg2+, Sn2+, Ba2+, Ni2+, Sn2+, Mn2+, Co2+, Fe3+, and Al3+) was also investigated, and it was found that in the presence of Fe3+, the fluorescent intensity was amplified more than 66 times. The antimicrobial activity of the new compound has been tested in vitro against Gram-positive B. cereus and Gram-negative P. aeruginosa. The tests were performed in the dark and after irradiation with visible light. The antimicrobial activity of the compound enhanced after light irradiation and B. cereus was found slightly more sensitive than P. aeruginosa. The increase in antimicrobial activity after light irradiation is due to the generation of singlet oxygen particles, which attack bacterial cell membranes.

Naphthalimide functionalized metal-organic framework for rapid and nanomolar level detection of hydrazine and anti-hypertensive drug nicardipine.

The increasing utilization of hydrazine and its derivatives across diverse sectors highlights the pressing need for efficient detection methods to safeguard human health and the environment. Likewise, nicardipine, a widely used medication for heart diseases, necessitates accurate sensing techniques for clinical research and therapeutic monitoring. Here, we propose a novel approach using a naphthalimide-functionalized Zr-MOF as a fluorometric probe capable of detecting both hydrazine and nicardipine in aqueous medium. Our designed probe exhibited a significant 31-fold increase in fluorescence intensity upon interaction with hydrazine. At the same time, nicardipine induced 86% fluorescence quenching with an exceptionally rapid response time (100 s for hydrazine and 5 s for nicardipine). The designed probe has the ability to detect both analytes at nanomolar concentrations (LOD for hydrazine is 1.11 nM while that for nicardipine is 9.6 nM). Investigation across various wastewater samples and pH conditions further validated its practical utility. The mechanism behind fluorometric sensing of nicardipine was thoroughly investigated using modern instrumentation. Our study presents a versatile and effective approach for detecting hydrazine and nicardipine, addressing crucial needs in both industrial and biomedical contexts.

Synthesis and Biological Properties of Fluorescent Strigolactone Mimics Derived from 1,8-Naphthalimide.

Strigolactones (SLs) have potential to be used in sustainable agriculture to mitigate various stresses that plants have to deal with. The natural SLs, as well as the synthetic analogs, are difficult to obtain in sufficient amounts for practical applications. At the same time, fluorescent SLs would be useful for the mechanistic understanding of their effects based on bio-imaging or spectroscopic techniques. In this study, new fluorescent SL mimics containing a substituted 1,8-naphthalimide ring system connected through an ether link to a bioactive furan-2-one moiety were prepared. The structural, spectroscopic, and biological activity of the new SL mimics on phytopathogens were investigated and compared with previously synthetized fluorescent SL mimics. The chemical group at the C-6 position of the naphthalimide ring influences the fluorescence parameters. All SL mimics showed effects similar to GR24 on phytopathogens, indicating their suitability for practical applications. The pattern of the biological activity depended on the fungal species, SL mimic and concentration, and hyphal order. This dependence is probably related to the specificity of each fungal receptor-SL mimic interaction, which will have to be analyzed in-depth. Based on the biological properties and spectroscopic particularities, one SL mimic could be a good candidate for microscopic and spectroscopic investigations.

Design, synthesis and structure-activity relationship of 1,8-naphthalimide derivatives as highly potent hCYP1B1 inhibitors.

Human cytochrome P450 1B1 enzyme (hCYP1B1), a member of hCYP1 subfamily, plays a crucial role in multiple diseases by participating in many metabolic pathways. Although a suite of potent hCYP1B1 inhibitors have been previously reported, most of them also act as aryl hydrocarbon receptor (AhR) agonists that can up-regulate the expression of hCYP1B1 and then counteract their inhibitory potential in living systems. This study aimed to develop novel efficacious hCYP1B1 inhibitors that worked well in living cells but without AhR agonist effects. For these purposes, a series of 1,8-naphthalimide derivatives were designed and synthesized, and their structure-activity relationships (SAR) as hCYP1B1 inhibitors were analyzed. Following three rounds SAR studies, several potent hCYP1B1 inhibitors were discovered, among which compound 3n was selected for further investigations owing to its extremely potent anti-hCYP1B1 activity (IC50 = 0.040 nM) and its blocking AhR transcription activity in living cells. Inhibition kinetic analyses showed that 3n potently inhibited hCYP1B1 via a mix inhibition manner, showing a Ki value of 21.71 pM. Docking simulations suggested that introducing a pyrimidine moiety to the hit compound (1d) facilitated 3n to form two strong interactions with hCYP1B1/heme, viz., the C-Br⋯π halogen bond and the N-Fe coordination bond. Further investigations demonstrated that 3n (5 µM) could significantly reverse the paclitaxel (PTX) resistance in H460/PTX cells, evidenced by the dramatically reduced IC50 values, from 632.6 nM (PTX alone) to 100.8 nM (PTX plus 3n). Collectively, this study devised a highly potent hCYP1B1 inhibitor (3n) without AhR agonist effect, which offered a promising drug candidate for overcoming hCYP1B1-associated drug resistance.

Identification of naphthalimide-derivatives as novel PBD-targeted polo-like kinase 1 inhibitors with efficacy in drug-resistant lung cancer cells.

Targeting polo-box domain (PBD) small molecule for polo-like kinase 1 (PLK1) inhibition is a viable alternative to target kinase domain (KD), which could avoid pan-selectivity and dose-limiting toxicity of ATP-competitive inhibitors. However, their efficacy in these settings is still low and inaccessible to clinical requirement. Herein, we utilized a structure-based high-throughput virtual screen to find novel chemical scaffold capable of inhibiting PLK1 via targeting PBD and identified an initial hit molecule compound 1a. Based on the lead compound 1a, a structural optimization approach was carried out and several series of derivatives with naphthalimide structural motif were synthesized. Compound 4Bb was identified as a new potent PLK1 inhibitor with a KD value of 0.29 µM. 4Bb could target PLK1 PBD to inhibit PLK1 activity and subsequently suppress the interaction of PLK1 with protein regulator of cytokinesis 1 (PRC1), finally leading to mitotic catastrophe in drug-resistant lung cancer cells. Furthermore, 4Bb could undergo nucleophilic substitution with the thiol group of glutathione (GSH) to disturb the redox homeostasis through exhausting GSH. By regulating cell cycle machinery and increasing cellular oxidative stress, 4Bb exhibited potent cytotoxicity to multiple cancer cells and drug-resistant cancer cells. Subcutaneous and oral administration of 4Bb could effectively inhibit the growth of drug-resistant tumors in vivo, doubling the survival time of tumor bearing mice without side effects in normal tissues. Thus, our study offers an orally-available, structurally-novel PLK1 inhibitor for drug-resistant lung cancer therapy.

Biotin-tagged fluorescent probe for in situ visualization of γ-glutamyl transpeptidase in cancerous cells and tissues.

γ-Glutamyl transpeptidase (GGT), a cell-surface enzyme, is strongly implicated in mammalian malignancy growth and migration processes including human hepatocarcinogens. However, simply and conveniently detect of GGT on the cell membrane remains highly challenging. In this study, a biotin-tagged fluorescent probe Nap-biotin-glu was developed using glutamic acid, naphthalimide, and biotin as the reaction site, fluorescent reporter, and membrane-targeting group, which required only three steps. Colocalization fluorescence imaging and immunofluorescence analysis indicated that probe Nap-biotin-glu was successfully realized in situ visualizing of GGT on the cell membrane.Owing to the significant over-expressed GGT level in tumor, the probe was successfully applied to distinguish cancer tissues from adjacent normal tissues.

Naphthalimide-based fluorescent probe for Hg2+ detection and imaging in living cells and zebrafish.

A simple naphthalimide-based fluorescent probe was designed and synthesized for the determination of mercury ion (Hg2+ ). The probe showed a noticeable fluorescence quenching response for Hg2+ . When added with Hg2+ , the fluorescence intensity of the probe at 560 nm was remarkably decreased with the color changed from yellow to colorless under ultraviolet (UV) light. The probe had a notable selectivity and sensitivity for Hg2+ and displayed an excellent sensing performance when detecting Hg2+ at low concentration (19.5 nM). The binding phenomenon between the probe and Hg2+ was identified by Job's method and high-resolution mass spectrometry (HRMS). Moreover, the probe was not only utilized to identify Hg2+ in real samples with satisfactory results (92.00%-110.00%) but also was successfully used for bioimaging in cells and zebrafish. The recognition mechanism has been verified by transmission electron microscopy (TEM) for the first time. All the results showed that the probe could be used as a potent useful tool for detection of Hg2+ .

Naphthalimide-based new architecture for fluorescence turn-on sensing of Cu2+ and colorimetric detection of F-/CN.

A new molecular structure 1 has been developed on naphthalimide motif. The amine and triazole binding groups have been employed at the 4-position of naphthalimide to explore the sensing behavior of molecule 1. Single crystal x-ray diffraction and other spectroscopic techniques confirm the identity of 1. Compound 1 exhibits high selectivity and sensitivity for Cu2+ ions in CH3CN. The binding of Cu2+ shows âˆ¼ 70-fold enhancement in emission at 520 nm. The binding follows 1:1 interaction and the detection limit is determined to be 6.49 × 10-7 M. The amine-triazole binding site in 1 also corroborates the detection of F- through a colour change in CH3CN. Initially H-bonding and then deprotonation of amine -NH- in the presence of F- are the sequential steps involved in F- recognition with a detection limit of 4.13 × 10-7 M. Compound 1 is also sensible to CN- like F- ion and they are distinguished by Fe3+ ion. Cu2+-ensemble of 1 fluorimetrically recognizes F- among the tested anions and vice-versa. The collaborative effect of amine and triazole motifs in the binding of both Cu2+ and F-/CN- has been explained by DFT calculation.

A mitochondria-targeted ratiometric fluorescent sensor based on naphthalimide derivative-functionalized silica-based nanodots for imaging formaldehyde in living cells and zebrafish.

A mitochondria-targeted ratiometric fluorescent sensor (Mito-Si-NA) for formaldehyde (FA) has been constructed by functionalizing silica-based nanodots (silica-based ND). As the fluorescence reference and carrier, the silica-based ND conjugate with small molecule probe for FA via covalent. Further modifying with mitochondria targeting moiety enables the sensor to specifically target mitochondria. In the presence of FA, the emission of silica-based ND remain constant to act as an internal reference (445 nm) while the response signal of small molecule probe was gradually enhanced (545 nm). This sensor exhibits excellent selectivity towards FA with great changes of fluorescence intensity ratio values (I545/I445). The FA ratiometric fluorescence imaging in mitochondria was achieved successfully. In addition, the sensor was also successfully used for imaging FA in zebrafish. The good performance of Mito-Si-NA for FA bioimaging confirms that Mito-Si-NA is an appealing imaging tool to monitor FA in mitochondria and shows great potential to study the functions of FA on mitochondria.

Engineered Artesunate-Naphthalimide Hybrid Dual Drug for Synergistic Multimodal Therapy against Experimental Murine Lymphoma.

Lymphoma can effectively be treated with a chemotherapy regimen that is associated with adverse side effects due to increasing drug resistance, so there is an emergent need for alternative small-molecule inhibitors to overcome the resistance that occurs in lymphoma management and overall increase the prognosis rate. A new series of substituted naphthalimide moieties conjugated via ester and amide linkages with artesunate were designed, synthesized, and characterized. In addition to the conjugates, to further achieve a theranostic molecule, FITC was incorporated via a multistep synthesis process. DNA binding studies of these selected derivatives by ultraviolet-visible (UV-vis), fluorescence spectroscopy, intercalating dye (EtBr, acridine orange)-DNA competitive assay, and minor groove binding dye Hoechst 33342-DNA competitive assay suggested that the synthesized novel molecules intercalated between the two strands of DNA due to its naphthalimide moiety and its counterpart artesunate binds with the minor groove of DNA. Napthalimide-artesunate conjugates inhibit the growth of lymphoma and induce apoptosis, including ready incorporation and reduction in cell viability. The remodeled drug has a significant tumoricidal effect against solid DL tumors developed in BALB/c mice in a dose-dependent manner. The novel drug appears to inhibit metastasis and increase the survival of the treated animals compared with untreated littermates.

Synthesis, Characterization, Cytotoxicity, Cellular Imaging, Molecular Docking, and ADMET Studies of Piperazine-Linked 1,8-Naphthalimide-Arylsulfonyl Derivatives.

To reduce the mortality and morbidity associated with cancer, new cancer theranostics are in high demand and are an emerging area of research. To achieve this goal, we report the synthesis and characterization of piperazine-linked 1,8-naphthalimide-arylsulfonyl derivatives (SA1-SA7). These compounds were synthesized in good yields following a two-step protocol and characterized using multiple analytical techniques. In vitro cytotoxicity and fluorescent cellular imaging of the compounds were assessed against non-cancerous fibroblast (3T3) and breast cancer (4T1) cell lines. Although the former study indicated the safe nature of the compounds (viability = 82-95% at 1 µg/mL), imaging studies revealed that the designed probes had good membrane permeability and could disperse in the whole cell cytoplasm. In silico studies, including molecular docking, molecular dynamics (MD) simulation, and ADME/Tox results, indicated that the compounds had the ability to target CAIX-expressing cancers. These findings suggest that piperazine-linked 1,8-naphthalimide-arylsulfonyl derivatives are potential candidates for cancer theranostics and a valuable backbone for future research.

Research Progress on Structure-Activity Relationship of 1,8-Naphthalimide DNA Chimeras Against Tumor.

The development of 1,8-naphthalimide derivatives as cell probes, DNA targeting agents, and anti-tumor drugs is one of the research hotspots in the field of medicine. Naphthalimide compounds are a kind of DNA embedder, which can change the topological structure of DNA by embedding in the middle of DNA base pairs, and then affect the recognition and action of topoisomerase on DNA. Aminofide and mitonafide are the first 2 drugs to undergo clinical trials. They have good DNA insertion ability, can embed DNA double-stranded structure, and induce topoisomerase II to cut part of pBR322DNA, but not yet entered the market due to their toxicity. In this paper, the design and structure-activity relationship of mononaphthalimide and bisaphthalimide compounds were studied, and the relationship between the structure of naphthalimide and anti-tumor activity was analyzed and discussed. It was found that a variety of structural modifications were significant in improving anti-tumor activity and reducing toxicity.

Synthesis of organic-solvent-soluble cellulose and preparation of fluorescent polyurethanes for the detection and removal of Hg+ ions.

Modifying cellulose to obtain materials with favorable processing properties and functions is highly significant, especially, for the detection and removal of heavy metal ions. In this study, fluorescent cellulose-based polyurethane (PU) films containing naphthalimide fluorophore were synthesized and could use for the convenient detection and removal of Hg+ ions. Firstly, the microcrystalline cellulose was treated with SOCl2 to convert some -OH groups into -Cl. Simultaneously, a naphthalimide derivative (NAN) with -NH- groups was synthesized. Subsequently, a fluorescent cellulose-based probe (Cel-NAN) was prepared by utilizing the substitution reaction between -Cl on cellulose and -NH- on NAN. Finally, two cellulose-based fluorescent PU films (Cel-NAN-PU1 and Cel-NAN-PU2) were successfully synthesized by reacting the unreacted -OH groups on Cel-NAN with PEG-1000 and HDI/IPDI. These as-prepared PU films could serve as portable fluorescence test papers to Hg+ ions in aqueous solutions. Upon contact with Hg+ ions, the fluorescence was quenched, acting as a "turn-off" probe. Simultaneously, these films could serve as adsorbents for the removal of Hg+ ions from aqueous systems. Cel-NAN-PU1 film exhibited a removal efficiency over 80 % and an adsorption capacity of 8.4 mg·cm-2 for Hg+. These cellulose-based fluorescent PU films possess promising potential in the field of mercury pollution control.

Visualization of an Endogenous Mitochondrial Azoreductase Activity under Normoxic Conditions Using a Naphthalimide Azo-Based Fluorogenic Probe.

In this paper, we demonstrate the existence of an endogenous mitochondrial azoreductase (AzoR) activity that can induce the cleavage of N═N double bonds of azobenzene compounds under normoxic conditions. To this end, 100% OFF-ON azo-based fluorogenic probes derived from 4-amino-1,8-naphthalimide fluorophores were synthesized and evaluated. The in vitro study conducted with other endogenous reducing agents of the cell, including reductases, demonstrated both the efficacy and the selectivity of the probe for AzoR. Confocal experiments with the probe revealed an AzoR activity in the mitochondria of living cells under normal oxygenation conditions, and we were able to demonstrate that this endogenous AzoR activity appears to be expressed at different levels across different cell lines. This discovery provides crucial information for our understanding of the biochemical processes occurring within the mitochondria. It thus contributes to a better understanding of its function, which is implicated in numerous pathologies.

Naphthalimide-based Functional Glycopolymeric Nanoparticles as Fluorescent Probes for Selective Imaging of Tumor Cells.

A series of functional glycopolymer nanoparticles with 1,8-naphthalimide motif was designed, synthesized and applied for tumor cell imaging. With the pH-sensitive and aggregation-induced emission (AIE) effect of the 1,8-naphthalimide fluorescent probe, the presence of glucose-based glycopolymers enhanced its water-solubility and biocompatibility. Owing to the dual tumor-targeting effects of the dense glucose part and the boronic ester modification, the obtained glycopolymers showed high affinity to tumor cells, with a much faster staining rate than normal cells, indicating a great potential for diagnosis and treatments of cancers.

An Outlook of the Structure Activity Relationship (SAR) of Naphthalimide Derivatives as Anticancer Agents.

The efficacy of drugs against cancer in clinical settings may be limited due to pharmacokinetic issues, side effects and the emergence of drug resistance. However, a class of anticancer drugs known as naphthalimides have proven to be very effective. These derivatives have demonstrated to be effective in treating different types of cancers and exhibit strong DNA binding affinity. The anticancer properties of the naphthalimide derivatives allow them to target a number of cancer cell lines. Researchers have investigated the anticancer activity of numerous naphthalimide derivatives, such as heterocyclic fused, non-fused substituted, metal-substituted and carboxamide derivatives. Surprisingly, some derivatives demonstrate greater activity than the reference norms, such as cisplatin, amonafide, mitonafide and others and are selective against many cell lines. The primary objective of this research is to comprehend the effects of various substitution patterns on the structure-activity relationship (SAR) of these derivatives and the instances in which they enhance or reduce this biological activity.

Nucleolus imaging based on naphthalimide derivatives.

Nucleolus was an important cellular organelle. The abnormal morphology and number of the nucleolus have been considered as diagnostic biomarkers for some human diseases. However, the imaging agent based on nucleolus was limited. In this manuscript, a series of nucleolar fluorescent probes based on naphthalimide derivatives (NI-1 âˆ¼ NI-5) had been designed and synthesized. NI-1 âˆ¼ NI-5 could penetrate cell membranes and nuclear membranes, achieve clear nucleolar staining in living cells. These results suggested that the presence of amino groups on the side chains of naphthalimide backbone could enhance the targeting to the cell nucleolus. In addition, the molecular docking results showed that NI-1 âˆ¼ NI-5 formed hydrogen bonds and hydrophobic interactions with RNA, and exhibited enhanced fluorescence upon binding with RNA. These results will provide favorable support for the diagnosis and treatment of nucleolus-related diseases in the future.

Spectroscopic and Biological Properties of the 3-Imino-1,8-naphthalimide Derivatives as Fluorophores for Cellular Imaging.

This paper presents the photophysical and biological properties of eight 3-imino-1,8-naphthalimides. The optical properties of the compounds were investigated in the solvents that differed in their polarity (dichloromethane, acetonitrile, and methanol), including three methods of sample preparation using different pre-dissolving solvents such as dimethyl sulfoxide or chloroform. In the course of the research, it was found that there are strong interactions between the tested compounds and DMSO, which was visible as a change in the maximum emission band (λem) of the neat 3-imino-1,8-naphthalimides (λem = 470-480 nm) and between the compounds and DMSO (λem = 504-514 nm). The shift of the emission maximum that was associated with the presence of a small amount of DMSO in the sample was as much as 41 nm. In addition, the susceptibility of imines to hydrolysis in the methanol/water mixture with increasing water content and in the methanol/water mixture (v/v; 1:1) in the pH range from 1 to 12 was discussed. The studies showed that the compounds are hydrolysed in the CH3OH/H2O system in an acidic environment (pH in the range of 1 to 4). In addition, it was found that partial hydrolysis occurs in systems with an increased amount of water, and its degree may depend on the type of substituent on the imine bond. The compounds tended to quench the emission (ACQ) in the aggregated state and increase the emission related to the protonation of the imine bond. Moreover, it was found that the substituent in the imine bonds influenced a compound's individual photophysical properties. Biological tests, including cytotoxicity studies and cellular localisation, were also performed for all of the molecules. All of the tested compounds exhibited green fluorescence in the MCF-7 cells and showed co-localisation in the mitochondria, endoplasmic reticulum, and lysosome. The obtained photophysical and biological results indicate the promising potential use of the tested compounds as cellular dyes.

Sensitive Detection of Various Forms of Hydrogen Sulfide via Highly Selective Naphthalimide-Based Fluorescent Probe.

Hydrogen sulfide (H2S) is an important gasotransmitter, but only a few methods are available for real-time detection. Fluorescent probes are attractive tools for biological applications because of their high sensitivity, convenience, rapid implementation, noninvasive monitoring capability, and simplicity in fluorescent imaging of living cells and tissues. Herein, we report on a pro-fluorescent probe, NAP-Py-N3 based on naphthalimide derivative, which was found to show high selectivity toward H2S over various other analytes, including biothiols, making it feasible to detect H2S. After reaction with H2S, this probe showed rapid and significant turn-on green fluorescent enhancement at 553 nm (about 54-fold, k2 = 9.62 M-1s-1), high sensitivity (LOD: 15.5 nM), significant Stokes shift (118 nm), and it was found that the fluorescence quantum yield of fluorescence product can reach 0.36. Moreover, the probe has also been successfully applied to detect the gaseous H2S and to confirm the presence of H2S released from modern organic donors, which in recent years have been commonly used to investigate the role of H2S in biological systems. All the results indicate that this probe is excellent and highly valuable.

Fabrication of 1,8-naphthalimide modified cellulose derivative composite fluorescent hydrogel probes and their application in the detection of Cr(VI).

The design and development of a rapid and quantitative method for the detection of heavy metal ions is of great importance for environmental protection. We have prepared a 1,8-Naphthalimide modified cellulose composite fluorescent hydrogel (CENAEA/PAA) with a stereo double network structure. Characterized by excellent hydrogel functional structure and fluorescence detection performance, it can efficiently and selectively identify and detect Cr(VI) with linear quenching in the range of 0-400 µmol/L and detection limit of 0.58 µmol/L for Cr(VI). The results show that the CENAEA/PAA can effectively adsorb Cr(VI) with a maximum adsorption capacity of 189.04 mg/g. Finally, the morphological characteristics, chemical structure, fluorescence properties and adsorption behavior of CENAEA/PAA were analyzed and fitted well with the pseudo-second-order model and Freundlich model. Thus, the present work provides a green and sustainable approach for the synthesis of a functional material that can be used for the detection and adsorption of heavy metal ions.