Naphthalimides and analogues as antitumor agents:A review on molecular design, bioactivity and mechanism of action

In this review, we retrospect our progress in biological active naphthalimide and analogues as antitumor agents in the past 20 years. On one hand, various derivations in naphthalimide pharmacophores were developed to enhance their DNA binding affinity and antitumor property thereby. Heterocyclic fused naphthalimides, bis-naphthalimides, non-fused substituted naphthalimides and the carboxamide derivatives were synthesized. For example, thio-heterocyclic fused-naphthalimides were designed and evaluated in comparison with their oxo-heterocyclic fused analogues. Extended or created heterocyclebased skeleton were also developed as antitumor agents. On the other hand, we broaden the design strategy of naphthalimide antitumor agents besides DNA intercalation and topo II poison. We have introduced more drug design methods, such as prodrugs, multitarget drugs, computer-aided drug design,photodynamic therapy. For example, we have got naphthalimide derivatives which inhibited topo II and induced LMP by introducing long alkyl chain and polyamines. Several representative compounds were clarified of their antitumor mechanism of action. In all, our research improves the structure diversity of naphthalimide antitumor agents and distinct variances of antitumor targets and mechanism of action.

Synthesis and photochemical properties of two ICT compounds with naphthalimide and diarylamine units

Two new diarylamine-substituted 1, 8-naphthalimide derivatives are synthesized by Cu I/18-crown-6/K2CO3 catalyst system and characterized by Fourier transform infrared （FT- IR）, ^1H-NMR and elemental analyses. The UV-vis absorption and photoluminescent （PL）spectra of the systems in n-hexane, tetrahydrofuran（THF）, and CH2Cl2 are investigated. These naphthalimide molecules have an absorption band centered at about 450 nm, which is assigned to an intramolecular chargetransfer （ICT）transition, and they emit light at 492, 501 nm in a nonpolar solvent such as n-hexane, and at 600, 620 nm in a polar solvent such as CH2Cl2. From the Lippert-Mataga equation, the difference of the dipole moment between the excited state and the ground state is estimated to be 9.2 and 9.8 D for 4- （ diphenylamine ）-N-（ 2-methoxyphenyl ）-1, 8-naphthalimide （ DMN-1 ） and 4-（ 2-naphthylphenylamine ）-N-（ 2- methoxyphenyl）-1, 8-naphthalimide （DMN-2）, respectively. This large change in the dipole moment upon excitation is typical for photoinduced ICT processes.

Synthesis and near-infrared characteristics of novel perylene bisimide dyes bay-functionalized with naphthalimide chromophores

Novel perylene bisimide dyes bay-functionalized with naphthalimide chromophores have been prepared conveniently by coupling of 1,8-naphthalimide and dibromoperylene bisimides. Their optical properties were investigated by UV-vis and fluorescence spectroscopy. The absorption spectra of these compounds showed wide spectral responses from 300 to 700 nm, which would be potentials for application as organic solar cells.

Novel synthesis of N-substituted-calix[4]azacrown derivatives

A novel series of calix[4]azacrown derivatives with the reaction between calix[4]azacrown and the different fluorophore derivatives,which may be useful fluorescent receptors,have been synthesized and structurally characterized by IR,~1H NMR,^（13）C NMR and MS.From their analysis data,it was found those compounds adopted a cone conformation.

Alkynyl-modified Naphthalimide:Synthesis,Crystal Structure and Fluorescence Spectrum

A novel alkynyl substituted N-aryl-1,8-naphthalimide II （C20H11NO2） was synthesized for the discovery and evaluation of new fluorescence probes, and was characterized by X-ray crystal diffraction. It crystallizes in monoclinic, space group P21/n with a = 15.898（3）, b = 5.0102（10）, c = 17.962（4）A, β = 92.97（3）°, V = 1428.7（5） A^3, Z = 4, Mr = 297.30, Dc = 1.382 g/cm^3, F（000） = 616,/J = 0.090 mm^-1, S = 1.011, the final R = 0.0542 and wR = 0.1204 for 1669 observed reflections with I 〉 2σ（I） and 212 variable parameters. Hydrogen-bounding and n-stacking interactions were discussed. The influence of acetylene group on the fluorescence properties was also investigated. In comparison with N-phenyl-1,8-naphthalimide I （C18H11NO2）, few new structure characters and fluorescence properties of the title compound have been found.

A highly sensitive colorimetric and ratiometric sensor for fluoride ion

A new benzoimidazole-naphthalimide derivative 4 was synthesized and its photophysical properties were studied. This compound showed highly selectively and sensitive colorimetric and ratiometric sensing ability for fluoride anion.

White light generation by regulating hydrogen bond-sensitive ESPT of naphthalimide dyes

White light emitting systems of pure organic materials have attracted extensive research interest due to their better compatibility and functional scalability.The reported organic white light materials are mainly based on the multi-channel emission regulation of the compound itself or the mixing of multicolor luminescence materials,but studies on the dependence between multicolor luminescence and the external environment are lacking,which limits the application of these materials in areas such as identification and sensing.This paper reports that the 4-or 3?hydroxyl-substituted naphthalimides NapH1 and NapH2 form intermolecular hydrogen bonds with adjacent molecules in the environment,and undergo excited-state intermolecular proton transfer under irradiation,resulting in blue-yellow or blue-red dual fluorescence emission,respectively.Since the two compounds have different two-color luminescence channels and the two-color intensity ratio is affected by the environment,and the intermolecular hydrogen bond is determined by the hydrogen bond receptor,polarity,and temperature in the environment,the full spectrum from blue to red light and white light emission can be obtained by adjusting the mixing ratio of the two dyes and the solvent polarity and the ambient temperature.This environmentally sensitive white emission is used to detect the alkalinity of different papers,and the dyed paper can be used as a test strip for acid-base vapor detection.

Tuning hot carrier transfer dynamics by perovskite surface modification

Understanding the role of perovskite surface passivators in hot carriers transfer dynamics is important to develop highly efficient perovskite solar cells(PSCs).In this work,we have designed and synthesized a naphthalimide-based organic small molecule(NCN)for perovskite surface defect passivator.We reveal that the introduction of NCN not only reduces the density of perovskite defect-state,but also promotes hot carriers(HCs)cooling in perovskite through the transient absorption spectroscopy measurements.Fast HCs cooling permits HCs transfer from perovskite layer into NCN layer,thus resulting in the decreased charge-carrier recombination in NCN-treated device.As expected,the power conversion efficiency(PCE)of PSCs with NCN is enhanced to 22.02%from 19.95%for the control device.The findings are relevant for developing highly efficient PSCs.

Propeller-shaped NI isomers of cathode interfacial material for efficient organic solar cells

Cathode interfacial materials(CIMs)stand as critical elemental in organic solar cells(OSCs),which can align energy levels,and foster ohmic contacts between the cathode and active layer of the OSCs.Nevertheless,the lagging advancement in CIMs has concurrently engendered the oversight of theoretical inquiries pertaining to the impact of molecular structure on their performance.Delving into this realm,we present two propeller-shaped isomers,4,4',4''-(benzo[1,2-b:3,4-b':5,6-b'']trithiophene-2,5,8-triyl)tris(2-(3-(dimethylamino)propyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione)(3ONIN)and 6,6',6''-(benzo[1,2-b:3,4-b':5,6-b'']trithiophene-2,5,8-triyl)tris(2-(3-(dimethylamino)propyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione)(3PNIN),distinguished by their molecular planarity,as a promising foundation for crafting highly efficient OSCs.This study illuminates the superiority of 3PNIN with more plane structure,exemplified by its enhanced molar extinction coefficient,deeper lowest unoccupied molecular orbital(LUMO)and highest occupied molecular orbital(HOMO)energy levels,intensified self-doping effect,heightened electron mobility,and elevated conductivity,in comparison to its counterpart,3ONIN.As a result,3PNIN and 3ONIN-treated OSC devices yield efficiencies of 17.73%and 16.82%,respectively.This finding serves as a compelling validation of the critical role played by molecular planarity in influencing CIM performance.

A series of naphthalimide azoles: Design, synthesis and bioactive evaluation as potential antimicrobial agents

A series of naphthalimide azoles as potential antibacterial and antifungal agents were conveniently and efficiently synthesized starting from commercially available 6-bromobenzo[de]isochromene-l,3-dione. All the new compounds were characterized by NMR, IR, MS and HRMS spectra. Their antimicrobial activities were evaluated against four Gram-positive bacteria, four Gram-negative bacteria and two fungi using two-fold serial dilution technique. The biological assay indicated that most of the prepared compounds exhibited inhibition to the tested strains. In particular, the triazolium derivatives not only gave higher ef- ficacy than their corresponding precursory azoles, but also demonstrated comparable or even better potency than the reference drugs Chloromycin, Orbifloxacin and Fluconazole. Some factors including structural fragments, pH and ClogP values of the target molecules were also preliminarily discussed.

Aggregation-induced emission or aggregation-caused quenching?Impact of covale nt bridge between tetraphenylethene and naphthalimide

Understanding the physical mechanisms governing aggregation-induced-emission(AIE)and aggrega-tion-caused-quenching plays a vital role in developing functional AIE materials.In this work,tetraphenylethene(TPE,a classical AiEgen)and naphthalimide(NI,a popular fluorophore with ACQ characteristics)were connected through non-conjugated linkages and conjugated linkages.We showed that the nonconjugated-linkage of TPE to NI fragments leads to substantial PET in molecular aggregates and ACQ.In con trast,the conjugated conn ection between TPE and NI moieties results in the AIE phenomenon by suppressing twisted intramolecular charge transfer.This work provides an important guideline for the rational design of AIE materials.

Highly sensitive and selective ratiometric fluorescent copper sensors: Different binding affinities modulated by three separate side chains of naphthalimide

A series of compounds 1-11 with different side chains of naphthalimide as fluorescent copper sensors were designed and synthesized. Compounds 1, 9, 10 and 11 presented a high selectivity to Cu2+ in a neutral aqueous environment. Here 1, 9 and 10 showed selectivity and affinity to Cu2+ with an association constant of about ～106. It gave somewhat response to Ag+, Co2+, Ni2+ and Fe2+ while 1 detected copper. 9 and 10 displayed better selectivity by changing their hydrophobic side chains to the hydrophilic ones on imide moieties. 11, with one flexible side chain, showed high selectivity and an association constant (Ka = 2.2 × 108), which were much higher than those of 1, 9 and 10. These results indicated that the selectivity and affinity could be improved by changing side chains of naphthalimide. That might provide a novel strategy or method for the development of fluorescent sensors.

Naphthalimide-modified near-infrared cyanine dye with a large stokes shift and its application in bioimaging

Developing the novel fluorescent dyes with a larger Stokes shift is still a challenge in the research of fluorescence probes. In this work, a naphthalimide-modified near-infrared cyanine dye with an emission at 785 nm has been synthesized for lysosome-targeting imaging. This fluorescent dye showed a large Stokes shift（up to 165 nm） and favorable lysosome-targeting property, which facilitated it to be a potential candidate for studying of lysosomal functions. The result also indicated that the probe is a promising contrast agent for in vivo imaging in mouse models.

Novel benzimidazole derived naphthalimide triazoles: synthesis, antimicrobial activity and interactions with calf thymus DNA

A novel series of benzimidazole derived naphthalimide triazoles and some corresponding triazoliums have been successfully synthesized and characterized by 1H NMR, 13 C NMR, 1H-1H COSY, IR and HRMS spectra. All the new compounds were screened for their antimicrobial activities in vitro by two-fold serial dilution. 2-Chlorobenzyl triazolium 8g and compound 9b with octyl group exhibited the best antibacterial activities among all the tested compounds, especially against S. aureus with inhibitory concentration of 2 μg/mL which was equipotent potency to Norfloxacin(MIC=2 μg/mL) and more active than Chloromycin(MIC=7 μg/mL). Triazoliums 8g and 8f bearing 3-fluorobenzyl moiety displayed the best antifungal activities(MIC=2-19 μg/mL) against all the tested fungal strains without being toxic to PC12 cell line within concentration of 128 μg/m L. Further investigations by fluorescence and UV-Vis spectroscopic methods revealed that the compound 8g could effectively intercalate into calf thymus DNA to form the 8g-DNA complex which could block DNA replication, exerting powerful antimicrobial activities.

Anaphthalimide-based fluorescent probe for mercapto-containing compounds

A polarity-sensitive fluorescent probe MNP was rationally designed and synthesized with naphthalimide as the fluorophore and maleimide as the receptor for thiols. MNP is weakly fluorescent due to the photoinduced electron-transfer （PET） from the fluorophore to the receptor, and it displays evidently solvatochromic UV-vis and fluorescence spectra： the emission shifted from 495 nm in n-hexane to 545 nm in phosphate buffer solution. Michael addition reaction between thiols and the maleimide in MNP inhibited the PET process, which led to about eight-fold fluorescence enhancement. In addition, MNP showed highly sensitivity to rnercapto-containing proteins and it could detect as low as 20.4 μg/mL of BSA in PBS. MNP has potential in fluorescent imaging of thiols in living cells.

A hydrophilic fluorescent polymer containing naphthalimide moiety as chemosensor for microbioreactors

A novel hydrophilic copolymer P(NI-HEMA) containing the pendant group of naphthalimide moiety has been prepared. In the aqueous buffer solution, its film on the glass substrate shows an obvious fluorescence change and excellent linear relevance in the pH range of 5.8-8.0. Specifically, using the isobestic point at 406 nm as excitation wavelength can avoid the UV irradiation and the tedious calibration process. The film stability and hydrophilicity of copolymer P(NI-HEMA) were studied. Because of the easy synthesis, low price and high linear relevance to pH, the hydrophilic chemosensor film of P(NI- HEMA) could be potentially applied as a low-cost pH indicator for high-throughput bioprocessing in microreactors.

A ratiometric near-infrared naphthalimide-based fluorescent probe with high sensitivity for detecting Fe^(2+)in vivo

Iron is one of the essential trace elements in the human body.It plays an important role in human biology and pathology.Deregulation of iron levels in cells is associated with disease development.In this work,we synthesized a novel near-infrared intramolecular charge transfer(ICT)based ratiometric fluorescent probe to detect Fe^(2+),by using naphthalimide and indole moieties as building blocks.Our work showed that the radiometric probe has excellent selectivity,sensitivity and rapid response.Moreover,we could successfully perform real-time monitoring of Fe^(2+) in He La cells and C.elegans.

Synthesis of 1,8-naphthalimide-based fluorescent nano-probes and their application in pH detection

Two kinds of fluorescent nano-probes（pH-A and pH-B） with different diameters for the determination of H＋concentration, based on photo-induced electron transfer mechanism, were synthesized through click reaction. In which 1,8-naphthalimide was employed as the fluorophore and N,N-dimethylethylenediamine as the receptor. The effects of particle size and linker length on the photophysical properties of the probe were studied. The results revealed that the nano-probes were more sensitive toward pH with increasing particle size. The fluorescence intensity at 529 nm（I529） of the nano-probe p H-A of 120 nm exhibited good linear relationship with solution＇s pH in the range of 6–8. The probe p H-A displayed excellent selectivity and competition toward proton over other possible coexisted ions, and it could be applied to detect pH in realistic samples（river water, urine）.

NAPHTHALIMIDE BASED DISPERSE DYES FOR NYLON 6 AND POLYESTER(PET) FIBERS:SYNTHESIS AND EVALUATION OF TECHNICAL PROPERTIES IN THE PRESENCE OF UREA

Technical properties of two naphthalimide based disperse dyes on nylon 6 and polyester fibers were investigated in the presence of urea. The two naphthalimide based disperse dyes were synthesized. The dyes were purified and then fully characterized using 1H-NMR, FTIR and melting point analysis. Dispersion of the dyes was prepared in water and applied on nylon 6 and PET fibers. The dyes offered good build-up properties on the substrates. In order to increase dye adsorption of the substrates, urea was added into the dyebath. By adding urea, the dye adsorption of polyester was increased significantly, while the increase of that of nylon 6 was not marked. The dyes showed good fastness properties on the substrates.

A Bioorthogonal-Activated Fluorescence Turn-On Probe Based on Nitrone-Modified 1,8-Naphthalimide for Live-Cell Imaging

A nitrone-modified 1,8-naphthalimide was desig ned as a novel bioorthog on alactivated turn-on probe based on strain-promoted alkyne-nitrone cycloadditio n(SPANC).The bioorthog onal cycloadducts were subseque ntly tran sformed into fluoresce nt rearra nge-ment products by photo-accelerati on,which exhibited sign ificant fluoresce nee enhan ceme nt,large stokes shift,and high fluores-cence qua ntum yield.DFT calculati ons were performed to elucidate the fluoresce nee OFF-ON mecha nism.This fluoroge nic strategy was successfully applied to labeling of proteins and visualizing mitochondria in live cells in real time.