•A novel donor-two-acceptor type fluorophore (HHC) for the detection of different guests was designed and synthesized.•The fluorescence of HHC may be modulated by protection/deprotection of its electron donor and response different guests.•A novel selective and sensitive fluorescence probe HHCP for fast detection and intracellular imaging of nitroreductase.By fusion of HBT and hemicyanine, we have designed a novel donor-two-acceptor type fluorophore (HHC) as a platform for the detection of different kinds of guests. HHC displays an emission at 580 nm in aqueous solution and two emission bands at 450 nm and 616 nm as a result of the donor-two-acceptor feature with the existance of CTAB. The fluorescence of HHC may be readily modulated by protection/deprotection of its electron-donating hydroxyl group and response different guests. As an example, we introduced p-nitrobenzyl group, which is sensitive to Nitroreductase (NTR), to the hydroxyl group of HHC and constructed a novel selective and sensitive fluorescence probe HHCP for fast detection and intracellular imaging of nitroreductase.By fusion of HBT and hemicyanine, a novel donor-two-acceptor type fluorophore (HHC) was developed as a platform for the detection of different kinds of guests. As an example, we introduced p-nitrobenzyl group, which is sensitive to Nitroreductase (NTR), to the hydroxyl group of HHC and constructed a novel selective and sensitive fluorescence probe HHCP for fast detection and intracellular imaging of nitroreductase.

Started from salicylic acid (SA) and related commercialized plant activators, based on molecular three-dimensional shape and pharmacophore similarity comparison (SHAFTS), a new lead compound benzotriazole was predicted and a series of benzotriazole derivatives were designed and synthesized. The bioassay showed that benzotriazole had high activity against a broad spectrum of diseases including fungi and oomycetes in vivo, but no activity in vitro. And the introduction of proper groups at the 1'-position and 5'-position was beneficial to the activity. So, they had the potential to be exploited as novel plant activators.Download high-res image (100KB)Download full-size imageA series of novel plant activators possessing benzotriazole scaffold was developed with the help of SHAFTS.

By structure transformation of benzo[k,l]thioxanthene-naphthalimide derivatives (ND-S), a novel series of nonplanar thio-heterocyclic bisnaphthalimide derivatives are designed and synthesized. They display high molar absorptivity and large Stokes shifts. They are also heavy-atom-free photosensitizers with high singlet oxygen quantum yields of 0.75 and 0.82. Thus, these new structures based on the naphthalimide skeleton have great potential for singlet oxygen applications.

A new artificial fluoro-cofactor was developed for the replacement of natural cofactors NAD(P), exhibiting a high hydride transfer ability. More importantly, we established a new and fast screening method for the evaluation of the properties of artificial cofactors based on the fluorescence assay and visible color change.

FLT3 has been validated as a therapeutic target for the treatment of acute myeloid leukemia (AML). In this paper, we describe for the first time, pteridin-7(8H)-one as a scaffold for potent FLT3 inhibitors derived from structural optimizations on irreversible EGFR inhibitors. The representative inhibitor (31) demonstrates single-digit nanomolar inhibition against FLT3 and subnanomolar KD for drug-resistance FLT3 mutants. In profiling of the in vitro tumor cell lines, it shows good selectivity against AML cells harboring FLT3-ITD mutations over other leukemia and solid tumor cell lines. The mechanism of action study illustrates that pteridin-7(8H)-one derivatives suppress the phosphorylation of FLT3 and its downstream pathways, thereby inducing G0/G1 cell cycle arrest and apoptosis in AML cells. In in vivo studies, 31 significantly suppresses the tumor growth in MV4–11 xenograft model. Overall, we provide a structurally distinct chemical scaffold with which to develop FLT3 mutants-selective inhibitors for AML treatment.

EGFR-targeted inhibitors (gefitinib and erlotinib) provided an effective strategy for the treatment of non-small-cell lung cancer. However, the EGFR T790M secondary mutation has become a leading cause of clinically acquired resistance to these agents. Herein, on the basis of the previously reported irreversible EGFR inhibitor (compound 9), we present a structure-based design approach, which is rationalized via analyzing its binding model and comparing the differences of gatekeeper pocket between the T790M mutant and wild-type (WT) EGFR kinases. Guided by these results, a novel 6,7-dioxo-6,7-dihydropteridine scaffold was discovered and hydrophobic modifications at N5-position were conducted to strengthen nonpolar contacts and improve mutant selectivity over EGFRWT. Finally, the most representative compound 17d was identified. This work demonstrates the power of structure-based strategy in discovering lead compounds and provides molecular insights into the selectivity of EGFRL858R/T790M over EGFRWT, which may play an important role in designing new classes of mutant-selective EGFR inhibitors.

•A BODIPY-based probe is developed for detection of hypochlorite.•This probe displays excellent reactivity with sodium hypochlorite.•This probe exhibits high sensitivity and selectivity in PBS buffer solution.Developing fluorescent probes for selective and sensitive detection of hypochlorite has received much attention, because hypochlorite is closely related to human health. In this work, a new fluorescent probe based on dipyrromethene boron difluoride (BODIPY) fluorophore using hydrazine as detecting group for hypochlorite was synthesized and fully characterized. The reaction of the probe with sodium hypochlorite is complete within 1 min in phosphate-buffered saline, and the fluorescence of the system significantly enhanced. The probe also exhibits admirable sensitivity and selectivity as well. The results of nuclear magnetic resonance monitoring and high-performance liquid chromatography analysis indicate that the detection process plausibly involves a free radical oxidation mechanism.

A novel single and small molecular theranostic agent (1a) based on a naphthalimide dye has been developed and characterized. The agent (1a) displays excellent fluorescence for cell imaging (fluorescent quantum yields of 0.81) and photodynamic effects for therapeutic effectiveness (micromolar inhibition efficacy in vitro towards a broad spectrum of tumor models and anticancer treatment in vivo on A375 tumor xenograft models). This provides a new approach for simultaneous improvement in two directions using a small molecule as theranostic agent, which usually are in conflict with each other for most traditional theranostic agents.

Probe E3 has been developed as the first ratiometric fluorescent cobalt probe with high sensitivity and selectivity based on internal charge transfer (ICT). Most importantly, the probe achieved the imaging and detection of cobalt in cells with ratiometric measurement.

A fluorescent probe for sensitive detection of hydrazine based on an ESIPT mechanism and a substitution–cyclization–elimination cascade was developed. After the addition of hydrazine, an approximately 50-fold enhancement in fluorescence intensity at 465 nm was observed and the subsequent decrease at 375 nm was observed in 10 min with a detection limit of 0.147 μM. We also detected hydrazine in HeLa cells successfully.

We designed and synthesized a series of 2-thioxo-4-thiazolidinone derivatives and evaluated them on peroxisome proliferator activated receptor γ (PPARγ) binding activities. Through the biological assays, compounds 18 and 38 were highlighted with Ki values of 12.15 nmol/L and 14.46 nmol/L, respectively. Then structure–activity relationship (SAR) was analyzed to screen privileged structural modifications. Moreover, molecular fitting of these compounds onto the approved drug Rosiglitazone in the PPARγ ligand binding domain was performed to elucidate the SAR and explore potential receptor–ligand interactions. These results demonstrate that the 2-thioxo-4-thiazolidinones can be considered as new promising molecular probes with excellent binding activities to PPARγ.A series of 2-thioxo-4-thiazolidinone derivatives was designed, synthesized and biologically evaluated for their PPARγ binding activities. We established a molecular docking based SAR model for PPARγ ligand binding domain.

Protein vicinal dithiols play fundamental roles in intracellular redox homeostasis due to their involvement in protein synthesis and function through the reversible vicinal dithiol oxidation to disulfide. To provide quantitative information about the global distribution and dynamic changes of protein vicinal dithiols in living cells, we have designed and synthesized a ratiometric fluorescent probe (VTAF) for trapping of vicinal dithiol-containing proteins (VDPs) in living cells. VTAF exhibits a ratiometric fluorescence signal upon single excitation, which enables self-calibration of the fluorescence signal and quantification of endogenous vicinal dithiols of VDPs. Its potential for in situ dynamic tracing of changes of protein vicinal dithiols under different cellular redox conditions was exemplified. VTAF facilitated the direct observation of subcellular distribution of endogenous VDPs via ratiometric fluorescence imaging and colocalization assay. And the results suggested that there are abundant VDPs in mitochondria. Moreover, some redox-sensitive VDPs are also present on cell surface which can respond to redox stimulus. This ratiometric fluorescence technique presents an important extension to previous fluorescence intensity-based probes for trapping and quantifying protein vicinal dithiols in living cells, as well as its visible dynamic tracing of VDPs.

A new probe based on the Gabriel mechanism was designed and first used for hydrazine detection with high selectivity against other amines in aqueous solution. Importantly, the probe could be used for gas-state discrimination of hydrazine with different concentrations. Additionally, probe 1 could also be applied for the imaging of hydrazine in living cells.

An optical probe based on colorimetric and ratiometric as well as chemiluminometric signal outputs is developed for the specific detection of hydrazine. On the basis of a Gabriel-type reaction, hydrazinolysis of a simple probe CF (4-phtalamide-N-(4′-methylcoumarin) naphthalimide) produces both the fluorescence of 7-amino-4-methylcoumarin with the max emission wavelength changed from 480 to 420 nm (along with a color change from yellow to transparent) and the luminol chemiluminescence activated by H2O2 with a max emission wavelength at 450 nm. The experimental detection limit of hydrazine is 3.2 ppb (0.1 μM). Selectivity experiments proved CF has excellent selectivity to hydrazine over other interfering substances. Probe CF was also successfully applied in the vapor hydrazine detection over other interfering volatile analytes. Furthermore, the probe CF loaded thin-layer chromatography (TLC) plate for vapor hydrazine detection limit is 5.4 mg/m3 which is well below the half lethal dose of hydrazine gas for mice (LC50(mice), 330 mg/m3) and National Institute of Occupational Safety and Health’s immediately dangerous to life or health limit (NIOSHIDLH, 66 mg/m3). With H2O2, only hydrazinolysis product luminol can be lighted at 450 nm, other species have no signal. Probe CF can also be used for the detection of hydrazine in HeLa cells.

•Novel metal complexes of naphthalimide–cyclam conjugates were designed, synthesized.•All of the compounds were evaluated of their antitumor activities.•Zn(II) and Cr(III) complexes displayed as multi-target RTK inhibitors.•Representative compound 8a showed antiproliferative and antiangiogenic activities.A novel series of metal complexes of naphthalimide–cyclam conjugates were synthesized and their in vitro antitumor activities were evaluated. The newly-synthesized compounds showed huge diversity of antiproliferative potency due to variety of metal ions and length of alkyl chains, among which the Zn(II) and Cr(III) complexes exhibited comparable antiproliferative activities with amonafide via multiple tyrosine kinase inhibition. Further research revealed that the representative compound 8a displayed broad-spectrum antiproliferative activity against 15 cancer cell lines with average IC50 value 10.18 ± 3.25 μM, and effective antiangiogenic activity on human microvascular endothelial cells (HMEC-1). In brief, metal complexes of naphthalimide–cyclam conjugates were firstly designed and synthesized as multi-target tyrosine kinase inhibitors and proved of their antitumor capacities.A novel series of metal complexes of naphthalimide–cyclam conjugates were designed and synthesized, which displayed as multi-target RTK inhibitors. Representative compound 8a exhibited both broad-spectrum antiproliferative capacity and antiangiogenic activity.

A fluorescent probe (2a-LP) based on an unnatural amino acid (UAA) is developed for the detection of phenylalanine ammonia lyase (PAL). In the presence of PAL, 2a-LP is catalytically deaminated to ortho-amino-transcinnamic acid (o-a-CA), which shows a remarkable “off–on” fluorescence signal. Thus, the probe 2a-LP enables direct visualization of the PAL activity in tomato under UV illumination and has potential in vitro assays.

A ratiometric fluorescent probe for the detection of peroxynitrite (ONOO−) was developed based on a boronate receptor and intramolecular cyclization. It features fast response, good selectivity and high sensitivity with a detection limit of 35 nM. The potential in bio-imaging was exemplified in Hela cells.

Based on a semi-cyanine fluorophore, a selective turn-on fluorescent probe semi-CyHP for the detection of nitroreductase (NTR) and hypoxia was designed and synthesized. It can be activated by NTR and to restore the pull–push electronic systems of semi-CyHF, which strongly fluoresces at 556 nm. Besides, the investigation of the hypoxic tumor cell imaging with semi-CyHP was significant with minimal endogenous interference.

A novel probe containing the azide–coumarin–aldehyde triad (S1) for hydrogen sulfide (H2S) was developed. The fluorophore for signaling is assembled in situ through a H2S triggered intramolecular reduction–cyclization cascade, and has a concomitant 10-fold enhancement of the fluorescent intensity at 520 nm. Fluorescence imaging of H2S in living cells proved its potential for biological application.

A new naphthalimide-based fluorescent turn-on probe (ANAg) was developed for quantitative detection of iodide in aqueous solution. It exhibited a low nanomolar detection limit and high selectivity over other potentially interfering anions and implied the potential for practical applications.

We developed a near-infrared fluorescence probe for the highly selective and sensitive detection of NAT2 activity. An arylamine was designed as the substrate part for NATs, as well as a PET quencher for cyanine dye. CYP1 with a 4-position arylamine displayed efficient PET quenching, and exhibited high selectivity and sensitivity to NAT2 with no response to NAT1. For practical application, we demonstrated CYP1 could exhibit excellent performance for endogenous NAT2 fluorescence imaging in living mice. We further verified the NAT2 distribution in various tissues by detecting the response to the corresponding tissue homogenates. The results were consistent with the fluorescence imaging in vivo and previous research. Above all, the probe CYP1 could selectively and sensitively monitor the NAT2 activity in enzymatic system, living mice and tissue homogenate samples. Therefore, the results indicated that CYP1 has potential use for the detection of NAT2 activity in the clinic and in research.

A novel dual-emission fluorescence probe has been developed for specific and sensitive detection of hypochlorite (ClO−). Upon addition of ClO−, significant changes in fluorescence emission intensity at two discrete wavelengths were observed. Meanwhile OONO− led to only a single-channel fluorescence enhancement. This feature makes it a clear advantage in distinguishing ClO−, RNS from other ROS.

A novel long-wavelength fluorescence probe NBP has been developed for the detection of nitroreductase (NTR) and hypoxia. NBP could be activated by NTR at 0.1 μM to release the fluorophore NBF and significant changes in fluorescence emission at 658 nm were observed. This feature makes it advantageous for imaging hypoxic cells with minimal endogenous interference.

The EGFR T790M variant is an important mutation, resulting in approximately 50% of the clinically acquired resistance to approved EGFR inhibitors. Starting with a previously reported pyrimidine-based EGFR inhibitor, a novel pteridin-7(8H)-one scaffold with a high 3D similarity was found and transformed into irreversible inhibitors of the EGFR T790M mutant. The most potent compounds, 3q and 3x, exhibited excellent enzyme inhibitory activities, with subnanomolar IC50 values for both the wild-type and T790M/L858R double mutant EGFRs, as well as potent cellular antiproliferative activities against both gefitinib-sensitive and -resistant cancer cell lines. The in vivo antitumor efficacy study demonstrated that compound 3x significantly inhibited tumor growth and induced tumor stasis in an EGFR-T790M/L858R-driven human nonsmall-cell lung cancer xenograft mouse model. This work demonstrated the utility of this sophisticated computational design strategy for fast 3D scaffold hopping with competitive bioactivities to meet an important clinical need.

Taking the emergence of drug resistance and lack of effective antimalarial vaccines into consideration, it is of significant importance to develop novel antimalarial agents for the treatment of malaria. Herein, we elucidated the discovery and structure–activity relationships of a series of dihydrothiophenone derivatives as novel specific inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH). The most promising compound, 50, selectively inhibited PfDHODH (IC50 = 6 nM, with >14 000-fold species-selectivity over hDHODH) and parasite growth in vitro (IC50 = 15 and 18 nM against 3D7 and Dd2 cells, respectively). Moreover, an oral bioavailability of 40% for compound 50 was determined from in vivo pharmacokinetic studies. These results further indicate that PfDHODH is an effective target for antimalarial chemotherapy, and the novel scaffolds reported in this work might lead to the discovery of new antimalarial agents.

•High sensitivity for palladium species detection, the emission wavelength is 130 nm more than exit wavelength.•Designed a convenient method for trace amounts of palladium detection.•High anti-jamming capability for other metal cations.A highly selective fluorescent probe (OHBT) was designed and synthesized by linking the ESIPT fluorophore N-(3-(benzo[d]thiazol-2-yl)-4-(hydroxyphenyl) benzamide) (HBTBC) to the palladium specificity response group, allyl group, for the detection of palladium species in aqueous solution. The allyl group can be hydrolyzed by Pd0 species through the Pd0-catalyzed Tsuji–Trost reaction and thus release the fluorophore HBTBC, which shows two emission bands. The maximum emission spectra originated from the enol and keto forms at 415 and 555 nm respectively and with no overlap, which implies the high resolution of the palladium detection. The palladium species can also be detected by paper strip because of the solid-state fluorescence of probe HOBT catalyzed by palladium. This method was successfully applied in the palladium related Suzuki–Miyaura coupling reaction and the detection limit is lower than 1 μM.A ESIPT based large wavelength redshift ratiometric fluorescent probe displays high selectivity for palladium species. A convenient method for palladium detection was also developed based on the catalyzed reaction product N-(3-(benzo[d]thiazol-2-yl)-4-(hydroxyphenyl) benzamide) (HBTBC), which has a strong solid state fluorescent in dried filter paper.

Sulfenylation is one of the reversible post-translational modifications, playing significant roles in cellular redox homeostasis and signaling systems. Herein, small fluorescent probe (CPD and CPDDM) based live-cell labelling technology for the visualization of protein sulfenylation responses in living cells has been developed. This approach enables the detection of protein sulfenylation without the need for cell lysis, fixation or purification, and permits the noninvasive study of protein sulfenylation in live cells through the direct fluorescent readout. This technology also can realize dynamic tracking of protein sulfenylation in situ with minimal perturbation to sulfenylated proteins and less interference with cellular function. Information on the global distribution and dynamic changes of endogenous protein sulfenylation has been obtained.

In this study, starting from a lead compound discovered by virtual screening, a series of novel heterocyclic substituted benzenesulfonamides were designed and synthesized as new carbonic anhydrase IX (CA IX) inhibitors. Some compounds exhibited potent inhibitory effects against CA IX (in the low nanomolar range) as well as high selectivity against other carbonic anhydrase isozymes (CA I and CA II). The most potent and selective compound 27 could inhibit CA IX in the subnanomolar level with IC50 of 0.48 nM, which increased the potency by about 40-fold against CA IX compared with the lead compound 26, and presented more than 103 fold selectivity over CA I and CA II. The structure–activity relationship (SAR) based on the docking experiments further elucidated the effects of the compounds on the bioactivity and selectivity.Graphical abstractThrough structural optimization, a more potent and high selectivity CA IX inhibitor 27 was obtained.Highlights► Novel benzenesulfonamides CA IX inhibitors were designed and synthesized. ► Structure optimization was carried out on the basis of the lead compound. ► High activity and selectivity of compound 27 was studied and explained.

•Novel naphthalimide derivatives were synthesized.•The compounds were topo II inhibitors and showed good antiproliferative activity.•For the first time, naphthalimides were proved to be tyrosine kinase inhibitors.•8d displayed effective antiangiogentic activity by inhibiting tyrosine kinases.Novel naphthalimide derivatives were designed and synthesized to modulate both topoisomerase II (topo II) and receptor tyrosine kinases (RTKs). Most target compounds exhibited effective and selective antiproliferative activities against three cancer cell lines by inhibiting topo II. The IC50 values ranged from 1.5 to 19.1 μM. Moreover, compounds 8d and 12d moderately inhibited various angiogenesis-related RTKs, including FGFR1, VEGFR2 and PDGFRα. The representative compound 8d was then proved to possess antiangiogenic activity, which was evidenced by the inhibition of migration and tube formation activities of HMEC-1 cells. To our knowledge, it is the first time naphthalimides were identified as tyrosine kinases inhibitors (TKIs) besides their conventional cytotoxicity.A novel series of naphthalimides were synthesized. Several of them could inhibit both topo II and angiogenesis-related receptor tyrosine kinases. The representative compound 8d not only was potent antiproliferative agent, but also exhibited effective antiangiogenic activity at 10 μM

Three series of novel oxo-heterocyclic fused naphthalimide derivatives (8a–8f, 13a–13d, 17a–17d) were prepared. The newly-synthesized compounds, and their thio-heterocyclic fused analogs (1a–1c, 2a–2d, 3a–3c) exhibited potent antiproliferative activity correlated well with their structure. Further research demonstrated that all the representative compounds 13a, 2a and 17a, 3a showed strong inhibition activity to topo II similarly with amonafide, and also potent topo I inhibition activity, which was seldom reported before for naphthalimide derivatives. Preliminary exploration proved their DNA sequence preference. In all, dual topo I/topo II inhibition and DNA sequence preference might contribute to enhancing tumor selectivity and overcoming drug resistance.Three series of oxo-heterocyclic fused naphthalimides were prepared. The relatively weak DNA intercalators were potent dual topo I/topo II inhibitors.Highlights► Novel oxo-heterocyclic fused naphthalimides were synthesized. ► Potent antiproliferative activities and preliminary SAR were observed. ► Naphthalimides are proved to be dual topo I/II inhibitors.

The 1,2,3-thiadiazole-carboxylate moiety was reported to be an important pharmacophore of plant activators. In this study, a series of novel plant activators based on thieno[2,3-d]-1,2,3-thiadiazole-6-carboxylate were designed and synthesized and their biological activity as plant activators was studied. The structures of the novel compounds were identified by 1H NMR, 19F NMR and HRMS. The in vivo bioassay showed that these novel compounds had good efficacy against seven plant diseases. Especially, compounds 1a and 1c were more potent than the commercialized plant activator BTH. Almost no fungicidal activity was observed for the active compounds in the in vitro assay, which matched the requirements as plant activators.A series of novel plant activators were reported and their efficacies were evaluated both in vivo and in vitro. Result showed that the fluoro-containing plant activators were more potent than commercial BTH.

A polymeric fluorescent sensor PNME, consisting of A4 and N-isopropylacrylamide (NIPAM) units, was synthesized. PNME exhibited dual responses to pH and temperature, and could be used as an intracellular pH sensor for lysosomes imaging. Moreover, it also could sense different temperature change in living cells at 25 and 37 °C, respectively.

A highly selective colorimetric and fluorescence enhanced probe S1 (M2@Cu) for histidine and histidine-rich proteins has been developed. In neutral aqueous ethanol solution, probe S1 can selectively detect histidine out of twenty DNA encoded amino acids by showing a color change from brownish red to light green, and with a fluorescence enhancement up to 99-fold at 537 nm, simultaneously.

Plant activators are a novel kind of agrochemicals that could induce resistance in many plants against a broad spectrum of diseases. To date, only few plant activators have been commercialized. In order to develop novel plant activators, a series of benzo-1,2,3-thiadiazole-7-carboxylate derivatives were synthesized, and the structures were characterized by 1H NMR, IR, elemental analyses, and HRMS or MS. Their potential systemic acquired resistance as plant activators was evaluated as well. Most of them showed good activity, especially, fluoro-containing compounds 3d and 3e, which displayed excellent SAR-inducing activity against cucumber Erysiphe cichoracearum and Colletotrichum lagenarium in assay screening. Field test results illustrated that compounds 3d and 3e were more potent than the commercial plant activator, S-methyl benzo[1,2,3]thiadiazole-7-carbothioate (BTH) toward these pathogens. Further, the preparation of compound 3d is more facile than BTH with lower cost, which will be helpful for further applications in agricultural plant protection.

The first highly selective and sensitive fluorescent probe Z1 for detection of carbonic anhydrase IX (CA IX) over isoforms CA I and CA II was developed. As demonstrated, Z1 worked effectively in both enzymatic systems and living hypoxia cells.

The near-infrared fluorescent probes S1 and S2 based on the BODIPY skeleton were designed and synthesized. They showed different selectivity in various aqueous buffer solutions. Judicious choice of buffer solutions can modulate the selectivity of fluorescent sensors toward a specific metal ion.

A fluorescent sensor for cadmium (CS) based on the BODIPY fluorophore exploiting the PET (Photoinduced Electron Transfer) mechanism was prepared. CS exhibited high selectivity and sensitivity for detecting cadmium in aqueous buffer solution. In addition, the complex of CS with cadmium could detect pyrophosphate (PPi) selectively and sensitively.

A novel series of acenaphtho[1,2-b]pyrrole derivatives as potent and selective inhibitors of fibroblast growth factor receptor 1 (FGFR1) were designed and synthesized. In silico target prediction revealed that tyrosine kinases might be the potential targets of the representative compound 2, which was subsequently validated by enzyme-linked immunosorbent assay (ELISA) for its selective and active FGFR1 inhibition of various tyrosine kinases. The structure–activity relationship (SAR) analysis aided by molecular docking simulation in the ATP-binding site demonstrated that acenaphtho[1,2-b]pyrrole carboxylic acid esters (2–5) are potent inhibitors of FGFR1 with IC50 values ranging from 19 to 77 nM. Furthermore, these compounds exhibited favorable growth inhibition property against FGFR-expressing cancer cell lines with IC50 values ranging from micromolar to submicromolar. Western blotting analysis showed that compounds 2, 3, and 2b inhibited activation of FGFR1 and extracellular-signal regulated kinase 1/2 (Erk1/2).

A series of novel aliphatic N-oxide of naphthalimides (A1–A5) were designed and prepared. The N–O group was firstly introduced into the amine side chain tailed to planar naphthalimide chromophore as hypoxic bioreductive marker. Fluorescence image analysis showed that the compounds could be used as potential markers for hypoxic cells (V79) in vitro especially for A1 with 17 times hypoxic-oxic fluorescence differential, which was probably due to the bis-bioreduction mechanism.The N–O group was introduced into the amine side chain of chromophore as a hypoxic marker for the first time to identify hypoxic cells in solid tumor.Highlights► Novel aliphatic N-oxide of naphthalimides were designed and prepared. ► The N–O group was introduced into the amine side chain as bioreductive marker. ► Compounds A1–A5 could be used as potential markers for hypoxic cells (V79) in vitro. ► Compound A1 showed 17 folds hypoxic-oxic fluorescence differential.

A novel NAT2 specific probe has been developed for sensitive detection of the activity of NAT2. Upon NAT2 catalyzed acetylation of the molecule to N-acetyl-amonafide, the ratiometric response of fluorescence with significant changes in wavelength and intensity is observed. Its significant application potential has been successfully demonstrated in cellular systems.

Based on the advantages of multitarget drugs for cancer treatment, a new class of naphthalimides was designed, synthesized, and proved to inhibit topoisomerase II (topo II), induced lysosomal membrane permeabilization (LMP), and ultimately caused apoptosis and cell death. The majority of compounds 7a−d and 8a−d potently inhibited the growth of the five tested cancer cell lines with IC50 values ranging from 2 to 10 μM and are more active than amonafide, a naphthalimide that was in phase III clinical trials. These compounds were tested for their interactions with DNA and their cell-free topo II inhibition activities, which demonstrated these compounds were weak DNA binders but modest topo II inhibitors. Furthermore, compounds 7b−d were found to notably induce LMP and exhibited better antiproliferative activity compared with their single-target analogues. All of the newly synthesized compounds were demonstrated to efficiently induce apoptosis via a mitochondrial pathway. Accordingly, a new paradigm was suggested for the design of novel multitarget anticancer drugs.

Salicylic acid (SA) and methyl jasmonate (MJ) are important plant signal molecules to cause systemic acquired resistance (SAR), while it’s reported that they also have wide spectrum antitumor activities. Benzothiadiazole-7-carboxylates are plant activators which can cause SAR just like SA and MJ. To investigate whether the benzothiadiazole-7-carboxylate family is endowed with anticancer activities, several benzothiadiazole-7-carboxylate derivatives are synthesized and their inhibition to P388 murine leukemia cell and A549 human lung cancer cell compared with MJ are evaluated. The data indicated that benzo-1,2,3-thiadiazole-7-carboxylic acid 2-benzoyloxyethyl ester has a higher inhibition ability to the cancer cell P388 and A549, compared with MJ.

Novel naphthalimides with two heterocyclic side chains of 2-nitroimidazole for bioreductive binding were designed, synthesized, and used as fluorescent markers for hypoxic cells. Their evaluation for imaging tumor hypoxia was carried out in V79 cells, CHO cells, and 95D cells in vitro by using fluorescence scan ascent. A2 and A4 showed a very large differential fluorescence between hypoxic and oxic cells (V79 cells) in vitro and are promising candidate markers for hypoxic cells.

Novel bioreductive and long-wavelength fluorescent markers for hypoxic cells in solid tumor, 9-isocyano-8H-acenaphtho[l,2-b]pyrrol-8-one with the side chain of 2-nitroimidazole, were designed, synthesized, and evaluated in V79 379A Chinese hamster cells in vitro. Compounds A2 and A4 showed good hypoxic–oxic fluorescence differential in vitro (V79 cells) by using fluorescence scan ascent.Novel bioreductive and long-wavelength fluorescent markers for hypoxic cells in solid tumor, 8-oxo-8H-cyclopenta[a]acenaphthylene-7-carbonitriles with 2-nitroimidazole were designed, synthesized, and evaluated in V79 379 A Chinese hamster cells in vitro.

•We assessed the anti-inflammatory effect of 7b in LPS-induced RAW 264.7 cells and primary macrophages.•7b inhibited production of PGE2, NO by suppressing COX-2 and iNOS expression.•7b inhibited COX-2 and iNOS expression by inhibiting NF-kB activation.•NF-kB activation inhibition by 7b was mediated by ERK1/2 and p38 MAPK.•7b directly inhibited TAK1, leading to down-regulation of ERK1/2 and p38 MAPK pathways.Inflammatory response plays an important role not only in the normal physiology but also in the pathology such as cancers. 7b, a novel naphthalimide-based DNA intercalator, has exhibited anti-inflammatory effects in phorbol12-myristate 13-acetate/phytohemagglutinin (PMA/PHA)-induced inflammatory responses of Jurkat T cells in our previous study. Here, we tried to further investigate its anti-inflammatory potential and the possible underlying mechanisms in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and primary mouse macrophages. In our current study, ELISA and Real-time PCR revealed that non-toxic doses of 7b reduced the production and expression of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in LPS-induced RAW264.7 cells and primary mouse macrophages. Moreover, 7b dose-dependently suppressed the production of prostaglandin E2 (PGE2), nitric oxide (NO). Except for COX-1, non-toxic doses of 7b exhibited parallel inhibition of LPS-induced expression of COX-2 and iNOS at both mRNA and protein levels. The molecular mechanism was associated with inhibition of the phosphorylation/degradation of IκB-α and nuclear translocation of the NF-κB p65. Further analysis of upstream mechanisms showed that blocking of NF-κB activation by 7b was mediated by inhibiting TAK1-downstream extracellular signal-regulated kinase (ERK1/2) and p38 kinase signal pathway. Taken together, these results indicated that 7b exhibited anti-inflammatory effects by targeting inhibiting TAK1, leading to ERK1/2- and p38 MAPK-mediated inactivation of NF-κB in LPS-stimulated RAW264.7 cells, and this would make 7b a strong candidate for further study as anti-inflammatory agent.

The first highly selective and sensitive fluorescent probe Z1 for detection of carbonic anhydrase IX (CA IX) over isoforms CA I and CA II was developed. As demonstrated, Z1 worked effectively in both enzymatic systems and living hypoxia cells.

The near-infrared fluorescent probes S1 and S2 based on the BODIPY skeleton were designed and synthesized. They showed different selectivity in various aqueous buffer solutions. Judicious choice of buffer solutions can modulate the selectivity of fluorescent sensors toward a specific metal ion.

A fluorescent probe for sensitive detection of hydrazine based on an ESIPT mechanism and a substitution–cyclization–elimination cascade was developed. After the addition of hydrazine, an approximately 50-fold enhancement in fluorescence intensity at 465 nm was observed and the subsequent decrease at 375 nm was observed in 10 min with a detection limit of 0.147 μM. We also detected hydrazine in HeLa cells successfully.

A novel long-wavelength fluorescence probe NBP has been developed for the detection of nitroreductase (NTR) and hypoxia. NBP could be activated by NTR at 0.1 μM to release the fluorophore NBF and significant changes in fluorescence emission at 658 nm were observed. This feature makes it advantageous for imaging hypoxic cells with minimal endogenous interference.

A new probe based on the Gabriel mechanism was designed and first used for hydrazine detection with high selectivity against other amines in aqueous solution. Importantly, the probe could be used for gas-state discrimination of hydrazine with different concentrations. Additionally, probe 1 could also be applied for the imaging of hydrazine in living cells.

Probe E3 has been developed as the first ratiometric fluorescent cobalt probe with high sensitivity and selectivity based on internal charge transfer (ICT). Most importantly, the probe achieved the imaging and detection of cobalt in cells with ratiometric measurement.

A highly selective colorimetric and fluorescence enhanced probe S1 (M2@Cu) for histidine and histidine-rich proteins has been developed. In neutral aqueous ethanol solution, probe S1 can selectively detect histidine out of twenty DNA encoded amino acids by showing a color change from brownish red to light green, and with a fluorescence enhancement up to 99-fold at 537 nm, simultaneously.

A fluorescent probe (2a-LP) based on an unnatural amino acid (UAA) is developed for the detection of phenylalanine ammonia lyase (PAL). In the presence of PAL, 2a-LP is catalytically deaminated to ortho-amino-transcinnamic acid (o-a-CA), which shows a remarkable “off–on” fluorescence signal. Thus, the probe 2a-LP enables direct visualization of the PAL activity in tomato under UV illumination and has potential in vitro assays.

A novel NAT2 specific probe has been developed for sensitive detection of the activity of NAT2. Upon NAT2 catalyzed acetylation of the molecule to N-acetyl-amonafide, the ratiometric response of fluorescence with significant changes in wavelength and intensity is observed. Its significant application potential has been successfully demonstrated in cellular systems.

We developed a near-infrared fluorescence probe for the highly selective and sensitive detection of NAT2 activity. An arylamine was designed as the substrate part for NATs, as well as a PET quencher for cyanine dye. CYP1 with a 4-position arylamine displayed efficient PET quenching, and exhibited high selectivity and sensitivity to NAT2 with no response to NAT1. For practical application, we demonstrated CYP1 could exhibit excellent performance for endogenous NAT2 fluorescence imaging in living mice. We further verified the NAT2 distribution in various tissues by detecting the response to the corresponding tissue homogenates. The results were consistent with the fluorescence imaging in vivo and previous research. Above all, the probe CYP1 could selectively and sensitively monitor the NAT2 activity in enzymatic system, living mice and tissue homogenate samples. Therefore, the results indicated that CYP1 has potential use for the detection of NAT2 activity in the clinic and in research.

Sulfenylation is one of the reversible post-translational modifications, playing significant roles in cellular redox homeostasis and signaling systems. Herein, small fluorescent probe (CPD and CPDDM) based live-cell labelling technology for the visualization of protein sulfenylation responses in living cells has been developed. This approach enables the detection of protein sulfenylation without the need for cell lysis, fixation or purification, and permits the noninvasive study of protein sulfenylation in live cells through the direct fluorescent readout. This technology also can realize dynamic tracking of protein sulfenylation in situ with minimal perturbation to sulfenylated proteins and less interference with cellular function. Information on the global distribution and dynamic changes of endogenous protein sulfenylation has been obtained.

A novel dual-emission fluorescence probe has been developed for specific and sensitive detection of hypochlorite (ClO−). Upon addition of ClO−, significant changes in fluorescence emission intensity at two discrete wavelengths were observed. Meanwhile OONO− led to only a single-channel fluorescence enhancement. This feature makes it a clear advantage in distinguishing ClO−, RNS from other ROS.

A polymeric fluorescent sensor PNME, consisting of A4 and N-isopropylacrylamide (NIPAM) units, was synthesized. PNME exhibited dual responses to pH and temperature, and could be used as an intracellular pH sensor for lysosomes imaging. Moreover, it also could sense different temperature change in living cells at 25 and 37 °C, respectively.

A new artificial fluoro-cofactor was developed for the replacement of natural cofactors NAD(P), exhibiting a high hydride transfer ability. More importantly, we established a new and fast screening method for the evaluation of the properties of artificial cofactors based on the fluorescence assay and visible color change.

A new naphthalimide-based fluorescent turn-on probe (ANAg) was developed for quantitative detection of iodide in aqueous solution. It exhibited a low nanomolar detection limit and high selectivity over other potentially interfering anions and implied the potential for practical applications.