A novel coumarin-naphthalimide-based ratiometric fluorescent probe for efficiently monitoring of hydrazine in environmental water.

A novel coumarin-naphthalimide-based ratiometric fluorescent probe, called XPT, was synthesized with the aim of achieving high sensitivity and anti-interference for N2H4 detection. The probe XPT consists of coumarin species and naphthalimide species, which act as the energy donor and acceptor, respectively. The phthalimide group functions as the recognition unit for N2H4. Without the presence of hydrazine, the naphthalimide remains in a non-fluorogenic phthalimide mode, disrupting the FRET signal. However, the phthalimide group undergoes the Gabriel reaction to an amine, which induces FRET and consequently causes a shift in the emitted fluorescence from 468 to 528 nm when N2H4 was added. The results of the study demonstrated that XPT exhibits high sensitivity with a limit of detection 2.2 µM, as well as selectivity. Furthermore, it is remarkable that the distribution of N2H4 in real water samples can be monitored by XPT.

A series of DNA targeted Cu (II) complexes containing 1,8-naphthalimide ligands: Synthesis, characterization and in vitro anticancer activity.

Copper(II) complexes are very promising candidates for platinum-based anticancer agents. Herein, three Cu (II) complexes (1-3) containing 1,8-naphthalimide ligands were synthesized and characterized by FT-IR, elemental analysis, ESI-MS and single crystal X-ray diffraction (complex 3). In addition, a control compound (complex 4) without 1,8-naphthalimide ligand was synthesized and characterized. The in vitro anticancer activity of the synthesized complexes against five cancer cell lines and one normal cell line was evaluated by MTS assay. The results displayed the antitumor activity of complexes 1-3 was controlled by the aliphatic chain length of ligands, their cytotoxicity was in the order 3 > 2 > 1, giving the IC50 values ranging from 2.874 ± 0.155 µM to 31.47 ± 0.29 µM against five cancer cell lines. Complex 4 showed less activity in comparison with complex 1-3. Notably, complexes 1-3 displayed much higher selectivity (SI = 2.65 to 10.16) compared to complex 4 (SI = 1.0), indicated that the introduction of 1,8-naphthalimide group not only increased the activity of this series of compounds but also enhanced their specific selectivity to cancer cells. Compound 3 induced apoptosis in cancer cells and blocked the S-phase and G2/M of cancer cells. The interaction with DNA of complexes 3 and 4 was studied by UV/Vis spectroscopic titrations, competitive DNA-binding experiment, viscometry and CD spectra. The results showed that complex 3 interacted with DNA in an intercalating mode, but the interaction mode of compound 4 with DNA was electrostatic interaction.

A multi-stimuli-responsive fluorescence material based on 1,8-naphthalimide.

A pair of 1,8-naphthalimides (NPIs) were designed and successfully synthesized through embellishing amino-containing NPI with 4-diethylaminosalicyladehyde and 4-diethylaminobenzaldehyde, respectively. Their structures were fully confirmed by 1H/13C NMR, HR-MS and FT-IR spectroscopic studies. Their photophysical properties were systematically investigated in different solvents of varied polarity, in THF/water mixtures with varying water fractions (fw), and in THF solvent with varying concentrations of NPIs. It inferred that the distinct differences in emission between two NPIs during self-assembled process could be ascribed that the hydroxyl-containing NPI allowed the excited-state intramolecular proton transfer process between -OH and CH=N units in the aggregation state. Interestingly, the solid of 4-diethylaminosalicyladehyde-functionalized NPI exhibited multi-stimuli-responsive fluorescence changes involving mechanofluorochromism and HCl/NH3 vapor stimulus-induced conversion. However, no remarkable change was observed in the photoluminescence (PL) spectra for the solid of 4-diethylaminobenzaldehyde-functionalized NPI under the stimuli of mechanical force and organic solvent.

A coumarin-naphthalimide-based ratiometric fluorescent probe for nitroxyl (HNO) based on an ICT-FRET mechanism.

Nitroxyl (HNO) is an important reactive nitrogen that is associated with various states in physiology and pathology and plays a unique function in living systems. So, it is important to exploit fluorescent probes with high sensitivity and selectivity for sensing HNO. In this paper, a novel ratiometric fluorescent probe for HNO was developed utilizing intramolecular charge transfer (ICT) and fluorescence resonance energy transfer (FRET) mechanisms. The probe selected coumarin as energy donor, naphthalimide as energy receptor and 2-(diphenylphosphino)benzoate as the sensing site for detecting HNO. When HNO was not present, the 2-(diphenylphosphino)benzoate unit of the probe restricted electron transfer and the ICT process could not occur, leading to the inhibition of FRET process as well. Thus, in the absence of HNO the probe displayed the intrinsic blue fluorescence of coumarin. When HNO was added, the HNO reacted with the 2-(diphenylphosphino)benzoate unit of the probe to yield a hydroxyl group which resulting in the opening of ICT process and the occurring of FRET process. Thus, after providing HNO the probe displayed yellow fluorescence. In addition, the probe showed good linearity in the ratio of fluorescence intensity at 545 nm and 472 nm (I545 nm/I472 nm) with a concentration of HNO (0.1-20 µM). The probe processed a detection limit of 0.014 µM and a response time of 4 min. The probe also specifically identified HNO over a wide pH scope (pH = 4.00-10.00), including physiological conditions. Cellular experiments had shown that this fluorescent probe was virtually non-cytotoxic and could be applied for ratiometric sensing of HNO in A549 cells.

Self-Internal Standard Fluorescence for Ultrasensitive Detecting of mtDNA to Evaluate Matrilineal Genetic Defect Levels.

Mitochondrial DNA (mtDNA) is a unique genetic material characterized by maternal inheritance. It possesses a circular structure devoid of histone protection and exhibits low cellular abundance, which poses great challenges for its sensitive and selective detection at the living cell level. Herein, we have designed three bis-naphthylimide probes with varying linker lengths (NANn-OH, n = 0, 2, 6), facilitating the formation of distinct twisted or folded molecular conformations in the free state. These probes emit the red fluorescence around 627 nm with different fluorescence quantum yields (ΦNAN0-OH = 0.0016, ΦNAN2-OH = 0.0136, and ΦNAN6-OH = 0.0125). When encountering mtDNA (0.4-3.4 µg/mL), these probes undergo conformational changes depending on the length of the attached C-strand and exhibit a gradually increasing fluorescence signal around 453 nm. The fluorescence intensity increased to 13.5-fold, 1.9-fold, and 8.2-fold, respectively. Notably, the red fluorescence intensities around 627 nm remain constant throughout this process, thus serving as an inherent correction mechanism for proportional fluorescence signal enhancement to improve selectivity and sensitivity. NAN0-OH, NAN2-OH, and NAN6-OH showed good linearity for mtDNA in the range of 0.4-3.4 µg/mL with detection limits of LODNAN0-OH = 1.04 µg/mL, LODNAN2-OH = 1.10 µg/mL, and LODNAN6-OH = 1.15 µg/mL. Cellular experiments reveal that NAN6-OH effectively monitors curcumin-induced mtDNA damage in HepG-2 cells while enabling monitoring of genetic mtDNA damage. We anticipate that this tool holds significant potential for the precise evaluation of maternal genetic defects, thereby enhancing hypersensitive assessment in clinical medicine.

A naphthalimide-based fluorescent platform for endoplasmic reticulum targeted imaging.

A series of naphthalimide dyes (TRNATR, MOTNAMOT, MPNAMP, TYNATY, PNAP and IZNAIZ) were designed and synthesized by altering the side chains of the naphthalimide. Without the need for ER-targeting groups, the first five dyes were found to specifically target the ER, likely due to their well-suited lipophilic properties. Furthermore, TRNATR and TYNATY were proven effective for studying ER stress, showing promise in tracking ER autophagy in living cells triggered by tunicamycin and nutritional starvation.

Instant in situ highlighting of latent fingerprints by a green fluorescent probe based on aggregation-induced emission.

Fluorescence sensing of latent fingerprints (LFPs) has gained extensive attention due to its high sensitivity, non-destructive testing, low biotoxicity, ease of operation, and the potential for in situ visualization. However, the realization of in situ visualization of LFPs especially with green emission and rapid speed is still a challenge. Herein, we synthesized an amphibious green-emission AIE-gen TPE-NI-AOH (PLQY = 62%) for instant in situ LFP detecting, which integrates the excellent fluorescence properties of naphthalimide (NI) with a hydrophilic head and the AIE character as well as the donating property of tetraphenylethene (TPE). TPE-NI-AOH in ethanol/water binary solvent was used as an environmentally friendly LFP developer and achieved in situ green-fluorescence visualization of LFPs. The fluorescence signal achieves its 60% saturated intensity in 0.37 s and nearly 100% in 2.50 s, which is an instant process for the naked eye. Moreover, level 3 details and super-resolution images of LFPs could be observed clearly. Besides, the TPE-NI-AOH developer could be stored for at least 6 months, suitable for long-term storage. This instant in situ highlighting method does not require post-processing operations, providing a more convenient, rapid, and efficient detection method of LFPs. This work would inspire the further advancement of fluorescent sensors for fingerprint imaging.

Synthesis and Characterization of Sulfonamide-Containing Naphthalimides as Fluorescent Probes.

A tumor-targeting fluorescent probe has attracted increasing interest in fluorescent imaging for the noninvasive detection of cancers in recent years. Sulfonamide-containing naphthalimide derivatives (SN-2NI, SD-NI) were synthesized by the incorporation of N-butyl-4-ethyldiamino-1,8-naphthalene imide (NI) into sulfonamide (SN) and sulfadiazine (SD) as the tumor-targeting groups, respectively. These derivatives were further characterized by mass spectrometry (MS), nuclear magnetic resonance spectroscopy (1H NMR), Fourier transform infrared spectroscopy (FT-IR), ultraviolet-visible spectroscopy (UV), and a fluorescence assay. In vitro properties, including cell cytotoxicity and the cell uptake of tumor cells, were also evaluated. Sulfonamide-containing naphthalimide derivatives possessed low cell cytotoxicity to B16F10 melanoma cells. Moreover, SN-2NI and SD-NI can be taken up highly by B16F10 cells and then achieve good green fluorescent images in B16F10 cells. Therefore, sulfonamide-containing naphthalimide derivatives can be considered to be the potential probes used to target fluorescent imaging in tumors.

Discovery of novel 1,8-naphthalimide piperazinamide based benzenesulfonamides derivatives as potent carbonic anhydrase IX inhibitors and ferroptosis inducers for the treatment of triple-negative breast cancer.

A novel series of 1,8-naphthalimide piperazinamide based benzenesulfonamides derivatives were designed and synthesized as carbonic anhydrase IX (CA IX) inhibitors and ferroptosis inducers for the treatment of triple-negative breast cancer (TNBC). The representative compound 9o exhibited more potent inhibitory activity and selective against CA IX over off-target CA II, compared with positive control SLC-0111. Molecular docking study was also performed to gain insights into the binding interactions of 9o in the binding pocket of CAIX. Moreover, compound 9o exhibited superior antitumor activities against breast cancer cells under hypoxia than that of normoxia conditions. Mechanism studies revealed that compound 9o could act as DNA intercalator and effectively suppressed cell migration, arrested the cell cycle at G1/S phase and induced apoptosis in MDA-MB-231 cells, while inducing ferroptosis accompanied by the dissipation of MMP and the elevation intracellular levels of ROS. Notably, in vivo studies demonstrated that 9o effectively inhibited tumor growth and metastasis in a highly metastatic murine breast cancer 4 T1 xenograft model. Taken together, this study suggests that compound 9o represents a potent and selective CA IX inhibitor and ferroptosis inducer for the treatment of TNBC.

Dual fluorescence response of calix[4]arene-1,8-naphthalimide derivatives towards Hg(II) /Cr(VI) and their antimicrobial studies of transparent biofilms with hyaluronic acid.

In this study, 4-sulfo-1,8-naphthalimide calixarene of derivatives were prepared (3 and 4) then transparent biofilms of the Ag salts of these compounds were formed in the presence of hyaluronic acid (HA), and antimicrobial properties were investigated. In chemosensor studies, the sensing ability behavior of 3 and 4 towards some cations and anions was investigated by fluorescence spectroscopy. It was observed that the prepared chemosensors show selectivity towards Hg(II) and Cr(VI). Ligand-ion interaction occurs according to the photo-induced electron transfer (PET) mechanism. The stoichiometric ratio was calculated by using Stern-Volmer plot method and binding constant Ksv values were found as 5.2 × 107 M-1 and 5.5 × 107 M-1 for 3-Hg(II) and 4-Hg(II) complexes, respectively and 4.0 × 107 M-1 and 4.3 × 107 M-1 for 3-Cr(VI) and 4-Cr(VI) complexes. The detection limits of the complexes of 3-Hg(II) and 4-Hg(II) are 6.35 × 10-12and 6.81 × 10-12, while those of 3-Cr(VI) and 4-Cr(VI) are 1.41 × 10- 11and 8.37 × 10-12, respectively. As a result of the antimicrobial test performed with these compounds, it was observed that the most effective material was HA-3Ag, which showed a significant antibacterial effect against Sarcina lutea (S. lutea) at a minimum inhibitory concentration (MIC) value of 0.097 mg/mL.

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.

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.

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.

A naphthalimide-based portable fluorescent sensor integrated with a photoelectric converter for rapid and on-site detection of type II pyrethroids in celery.

The on-site detection of pyrethroids, particularly type II pyrethroids, remains a challenging task in complex vegetable samples. Herein, a novel method based on naphthalimide was developed to realize the specific detection of type II pyrethroids by hydrolyzing and utilizing the compound m-phenoxybenzaldehyde (3-PBD). Hydrazine group, used as the appropriate moiety, was introduced into the fluorescent dye 1,8-naphthalimide to construct the fluoroprobe NAP. In the presence of 3-PBD, NAP displayed the prominently enhanced fluorescence and also exhibited high selectivity. This proposed method exhibited high anti-inference effects in complex media, realizing sensitive detection of 3-PBD with linear range of 2.15-800 µM and a low detection limit (LOD) of 0.64 µM. The underlying fluorescence-responsive mechanisms were in-depth elucidated by combining spectral analyses with TD-DFT theoretical calculations. Additionally, a direct and rapid hydrolysis method for deltamethrin in celery was established, achieving a high hydrolysis efficiency of >90% within 15 min. Furthermore, a portable fluorescence sensor (PFS) was developed based on high-power LEDs and photodetectors. PFS supplied a LOD of 2.23 µM for 3-PBD and exhibited comparable stability by a fluorescence spectrometer when detecting celery hydrolysate. Moreover, external power source is not required for PFS operations, thereby enabling rapid and on-site detection by transmitting data to a smartphone via bluetooth. These findings extend the academic knowledge in the field of specific pyrethroids detection and contribute to the development of on-site methods for pesticide residual analyses in food matrices.

Bacterial cell death to overcome drug resistance with multitargeting bis-naphthalimides as potent antibacterial agents against Enterococcus faecalis.

The increasing frequency of drug-resistant pathogens poses serious health issues to humans around the globe, leading to the development of new antibacterial agents to conquer drug resistance and bacterial infections. In view of this, we have synthesized a series of bis-naphthalimides to respond to awful drug resistance. Bioactivity assay and structure-activity relationship disclosed that compounds 5d and 5o exhibit potent antibacterial activity against E. faecalis, outperforming the marketed antibiotics. These drug candidates not only inhibit the biofilm formation of E. faecalis but also display rapid bactericidal properties, thus delaying the development of drug resistance within 20 passages. To explore the mechanism of antibacterial activity against E. faecalis, biofunctional examination was carried out which unveiled that 5d and 5o effectively disrupt bacterial cell membranes, causing the leakage of cytoplasmic contents and metabolic activity loss. Concurrently, 5d and 5o effectively intercalate with DNA to block DNA replication, causing the build-up of excessive reactive oxygen species and inhibiting the glutathione activity, ultimately leading to oxidative damage of E. faecalis and cell death. In addition, these compounds readily bind with HSA with a high binding constant, indicating that these drug candidates could be easily delivered to the target site. The above finding manifested that these newly synthesized bis-naphthalimides with multitargeting antibacterial properties offer a new prospect to overcome drug resistance.

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.

Polymorphism Dependent Cytotoxicity, Cellular Uptake, and Live Cell Imaging Studies on Napthalimide-Vinyl-Phenothiazine Conjugate.

Polymorphism-dependent cytotoxicity and cellular uptake of drug molecules have been studied for the past two decades. However, the visualization of polymorph-dependent cellular uptake and cytotoxicity using microscopy imaging techniques has not yet been reported. The luminescent polymorph is an ideal candidate to validate the above hypothesis. Herein, we report the polymorph-dependent cellular uptake, cytotoxicity, and bio-imaging functions of polymorphs 1Y and 1R of a naphthalimide-phenothiazine dyad. These polymorphs show different luminescence colors in the solid state and exhibit aggregation-induced enhanced emission (AIEE) in the DMSO-Water mixture. Bioimaging, cytotoxicity assay, and fluorescence-activated cell sorting (FACS) studies revealed that these polymorphs show different levels of cytotoxicity, cellular uptake, localization, and imaging potential. Detailed photophysical, morphological, and biological studies revealed that the difference in molecular conformation in these polymorphs enables them to form aggregates of different sizes and morphology, which leads to the differential uptake of these into the cells and consequently shows different cytotoxicity and imaging potentials.

Investigating the Serum Albumin Binding Behavior of Naphthalimide Based Fluorophore Conjugates: Spectroscopic and Molecular Docking Approach.

In the present study, naphthalimide-pyrazole-benzothiazole based fluorescent analogs were synthesized by substituting different primary and secondary amines on the naphthalimide nucleus and were evaluated for their sensitivity and selectivity towards serum albumin. Among various synthesized analogues compound 25 showed the most significant change with serum albumin and was further studied for selective detection and mode of interaction with serum albumin. Here, we compared the binding interaction of fluorescent probe 25 for variation/detection of two 76 % structurally resembling proteins HSA and BSA, by spectroscopic experiments. The compound shows more selectivity for HSA and BSA with a higher binding constant and evident visible change in the emission spectra of two serum albumins among different bioanalytes. The mode of interaction of 25 with human serum albumin and bovine serum albumin was investigated by FT-IR, circular dichroism, and DLS techniques to find out the change in the microenvironment and variation in the structure of serum albumin proteins. Higher binding affinity and specific selectivity of 25 with a limit of detection of 0.69 µM and 1.4 µM towards HSA and BSA compared to other bioanalytes make it a significant fluorescent probe for quantitatively detecting serum albumins at the very early stage of many fatal diseases.

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.