Search

Herein, an activable fluorescent probe for peroxynitrite (ONOO−), named NOP, was constructed for the accurate imaging in the processes of formation and inhibition of drug-induced liver injury induced by Acetaminophen (APAP). During the in-solution tests on the general optical properties, the probe showed advantages including good stability, wide pH adaption, high specificity and sensitivity in the monitoring of ONOO−. Subsequently, the probe was further applied in the model mice which used APAP to induce the injury and used inhibiting agents (GSH, Glu, NAC) to treat the induced injury. The construction of the liver injury model was confirmed by the pathological staining and the serum indexes including ALT, AST, ALP, TBIL as well as LDH. During the formation of the drug-induced liver injury, the fluorescence in the red channel enhanced in both time-dependent and dose-dependent manners. In inhibition tests, the inhibition of the liver injury exhibited the reduction of the fluorescence intensity. Therefore, NOP could achieve the accurate imaging in the processes of formation and inhibition of drug-induced liver injury. The information here might be helpful for the early diagnosis and the screening of potent treating candidates in liver injury cases.

Hypothermal photothermal therapy, as a non-invasive therapy method, is becoming ever more prevalent. However, due to cellular heat resistance from the generation of heat shock proteins (HSPs) and the monotonicity of therapeutic modality, the antitumor efficacy is severely restricted. Herein, a self-supplied O2 multifunctional nanoplatform mediated by glucose oxidase (GOx) is developed, which may combine starvation therapy (ST) and hypothermal photothermal therapy (HPTT) for tumor therapy. The obtained nanoplatform, UM@ICG@GOX@HA (UMIGH), was assembled by the UIO-66 core, MnO2, indocyanine green (ICG) and hyaluronic acid (HA). GOx was introduced to decrease the ATP level thus alleviating the HSPs-mediated heat tolerance, while the loaded MnO2 could decompose intratumoral H2O2 into O2, which enhanced the effect of HPTT and ST. Due to the coated HA, UMIGH could target the high expressed CD44 in CT26 tumor cells. The active targeting and NPs-associated passive targeting promoted the uptake of nanoparticles. Furthermore, ICG encapsulated in UMIGH NPs could also accurately image tumors. This synergistic treatment strategy of HPTT and ST exhibited an excellent anti-proliferation effect on colon cancer cells in vitro and mouse xenograft model in vivo, which might bring an informatic strategy for future investigations.

The study aimed to achieve enhanced targeted cytotoxicity and cell-internalization of cisplatin-loaded deoxyribonucleic acid-nanothread (CPT-DNA-NT), mediated by scavenger receptors into HeLa cells. DNA-NT was developed with stiff-topology utilizing circular-scaffold to encapsulate CPT. Atomic force microscopy (AFM) characterization of the DNA-NT showed uniformity in the structure with a diameter of 50–150 nm and length of 300–600 nm. The successful fabrication of the DNA-NT was confirmed through native-polyacrylamide gel electrophoresis analysis, as large the molecular-weight (polymeric) DNA-NT did not split into constituting strands under applied current and voltage. The results of cell viability confirmed that blank DNA-NT had the least cytotoxicity at the highest concentration (512 nM) with a viability of 92% as evidence of its biocompatibility for drug delivery. MTT assay showed superior cytotoxicity of CPT-DNA-NT than that of the free CPT due to the depot release of CPT after DNA-NT internalization. The DNA-NT exhibited targeted cell internalizations with the controlled intracellular release of CPT (from DNA-NT), as illustrated in confocal images. Therefore, in vitro cytotoxicity assessment through flow cytometry showed enhanced apoptosis (72.7%) with CPT-DNA-NT (compared to free CPT; 64.4%). CPT-DNA-NT, being poly-anionic, showed enhanced endocytosis via scavenger receptors.

A urease inhibitor with good in vivo profile is considered as an alternative agent for treating infections caused by urease-producing bacteria such as Helicobacter pylori. Here, we report a series of N-monosubstituted thioureas, which act as effective urease inhibitors with very low cytotoxicity. One compound (b19) was evaluated in detail and shows promising features for further development as an agent to treat H. pylori caused diseases. Excellent values for the inhibition of b19 against both extracted urease and urease in intact cell were observed, which shows IC50 values of 0.16 ± 0.05 and 3.86 ± 0.10 µM, being 170- and 44-fold more potent than the clinically used drug AHA, respectively. Docking simulations suggested that the monosubstituted thiourea moiety penetrates urea binding site. In addition, b19 is a rapid and reversible urease inhibitor, and displays nM affinity to urease with very slow dissociation (koff=1.60 × 10−3 s−1) from the catalytic domain.

Aim: This study aims to analyze the prognostic value of seven tumor makers and also investigate the response of palliative chemotherapy in advanced NSCLC patients with advanced disease.Methods: Medical records of 278 advanced NSCLC Chinese patients who received six cycles of palliative chemotherapy were retrospectively reviewed under ethical approval (JSCH2019K-011). Univariate and multivariate Cox regression analyses were performed using SPSS 24 to find the clinical value of these tumor markers and to identify the factors that were associated with progression-free survival (PFS), as well as the response to palliative chemotherapy.Results: In baseline characteristic, the high levels of CEA, CA-125, CA-199, AFP, NSE, CYFRA21-1, and CA15-3 were detected in 209 (75.18%), 139 (50.0%), 62 (22.30%), 18 (6.47%), 155 (55.75%), 176 (63.30%), and 180 (64.74%) patients, respectively. Univariate analysis revealed that patients with high vs. normal levels of all tumor markers had an increased risk of poor prognosis. In the multivariable Cox regression model, the patient with (high vs. normal) CYFRA21-1 levels (HR = 1.454, P = 0.009) demonstrated an increased poor PFS. However, patients with (high vs. normal) CA19-9 levels (HR = 0.524, P < 0.0001) and NSE levels (HR = 0.584, P < 0.0001) presented a decreased risk of PFS. Also, patients receiving 3-drugs regimen had better PFS compared to those on 2-drugs regimen (P = 0.043).Conclusions: The high levels of CYFRA21-1 was correlated with a poor prognostic factor of PFS for Advanced NSCLC patients. However, the high levels of CA19-9 and NSE were associated with a better prognostic factor of PFS. Additionally, smoking habits and tumor status had a poor prognostic factor of PFS. Moreover, we found that antiangiogenic therapy has high efficacy with first-line chemotherapy and longer PFS of NSCLC patients.

Abstract Epilepsy is a chronic neurodegenerative disease, and accumulating evidence suggests its pathological progression is closely associated with peroxynitrite (ONOO−). However, understanding the function remains challenging due to a lack of in vivo imaging probes for ONOO− determination in epileptic brains. Here, the first near‐infrared imaging probe (named ONP) is presented for tracking endogenous ONOO− in brains of kainate‐induced epileptic seizures with high sensitivity and selectivity. Using this probe, the dynamic changes of endogenous ONOO− fluxes in epileptic brains are effectively monitored with excellent temporal and spatial resolution. In vivo visualization and in situ imaging of hippocampal regions clearly reveal that a higher concentration of ONOO− in the epileptic brains associates with severe neuronal damage and epileptogenesis; curcumin administration can eliminate excessively increased ONOO−, further effectively protecting neuronal cells. Moreover, by combining high‐content analysis and ONP, a high‐throughput screening method for antiepileptic inhibitors is constructed, which provides a rapid imaging/screening approach for understanding epilepsy pathology and accelerating antiseizure therapeutic discovery.

A novel 4,4'-bipyridine linked dinuclear copper(II) complex, [Cu2L2(bipy)](NO3)2·bipy (L = 2-{[2-(2-hydroxyethylamino)ethylimino]methyl}-6-methylphenol; bipy = 4,4'-bipyridine), was prepared and characterized by elemental analyses, IR spectroscopy, and single-crystal X-ray diffraction. The Cu∙∙∙Cu distance is 11.129(2) Å. The CuII atom is coordinated by one phenolate O, one imine N, and one amine N atoms of a Schiff base ligand, and one N atom of the bridging 4,4'-bipyridine ligand, forming a square planar geometry. In the crystal structure of the complex, the dinuclear copper complex cations are linked by 4,4'-bipyridine molecules through intermolecular O–H···N hydrogen bonds, to form 1D chains running in the [2 0 –1] direction.

Two new hydrazone compounds, N'-(2-bromobenzylidene)-2-(4-nitrophenoxy)acetohydrazide (1) and N'-(4-nitrobenzylidene)-2-(4-nitrophenoxy)acetohydrazide (2), were prepared and structurally characterized by elemental analysis, IR, UV-Vis and 1H NMR spectroscopy, and single-crystal X-ray diffraction. Compound 1 crystallizes in the monoclinic space group P21/n with unit cell dimensions of a = 5.3064(5) Å, b = 18.202(2) Å, c = 15.970(2) Å, β = 95.866(3)º, V = 1534.4(2) Å3, Z = 4, R1 = 0.0457, and wR2 = 0.0975. Compound 2 crystallizes in the monoclinic space group P21/c with unit cell dimensions of a = 4.6008(7) Å, b = 14.451(2) Å, c = 23.296(3) Å, β = 93.620(2)º, V = 1545.8(4) Å3, Z = 4, R1 = 0.0441, and wR2 = 0.0985. Structures of the compounds are stabilized by hydrogen bonds and π···π interactions. The urease inhibitory activities of the compounds were studied. Both compounds show strong urease inhibitory activities, with IC50 values of 8.4 and 20.2 μM, respectively.

A series of caffeic acid amides D1-D17 bearing 2,3,4,5-tetrahydrobenzo-[b][1,4]dioxocine units has been synthesized and their biological activities evaluated for potential antiproliferative and EGFR inhibitory activity. Of all the compounds studied, compound D9 showed the most potent inhibitory activity (IC50 = 0.79 μM for HepG2 and IC50 = 0.36 μM for EGFR). The structures of compounds were confirmed by 1H-NMR, ESI-MS and elemental analysis. Among all, the structure of compound D9 ((E)-N-(4-ethoxyphenyl)-3-(2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)acrylamide) was also determined by single-crystal X-ray diffraction analysis. Compound D9 was found to be a potential antitumor agent according to biological activity, molecular docking, apoptosis assay and inhibition of HepG2.

Glycyrrhizin (GA) analogs in the form of 3-glucuronides and 18-epimers were synthesized and their anticancer activities were evaluated. Alkaline isomerization of monoglucuronides is reported. In vitro and in vivo studies showed that glycyrrhetinic acid monoglucuronides (GAMGs) displayed higher anticancer activities than those of bisglucuronide GA analogs, while anticancer activity of the 18α-epimer was superior to that of the 18β-epimer. 18α-GAMG was firstly nicely bound to epidermal growth factor receptor (EGFR) via six hydrogen bonds and one charge interaction, and the docking calculation proved the correlation between anticancer activities and EGFR inhibitory activities. Highly active 18α-GAMG is thus of interest for the further studies as a potential anticancer agent.

Cyclooxygenase-2 (COX-2) as a rate-limiting metabolism enzyme of arachidonic acid has been found to be implicated in tumor occurrence, angiogenesis, metastasis as well as apoptosis inhibition, regarded as an attractive therapeutic target for cancer therapy. In our research, a series of dihydropyrazole derivatives containing benzo oxygen heterocycle and sulfonamide moieties were designed as highly potent and selective COX-2 inhibitors by computer-aided drug analysis of known COX-2 inhibitors. A total of 26 compounds were synthesized and evaluated COX-2 inhibition and pharmacological efficiency both in vitro and in vivo with multi-angle of view. Among them, compound 4b exhibited most excellent anti-proliferation activities against SW620 cells with IC50 of 0.86 ± 0.02 µM than Celecoxib (IC50 = 1.29 ± 0.04 µM). The results favored our rational design intention and provides compound 4b as an effective COX-2 inhibitor available for the development of colon tumor therapeutics.

Two mononuclear complexes, [Ni(acac)2]·0.5CH3OH (1) and[Co(acac)2NO3]·2H2O (2) (acac = pentane-2,4-dione), have been synthesized andcharacterized by single crystal X-ray analysis. Complex 1 crystallizes in the monoclinicspace group P21/c with a = 9.295(4), b = 11.450(5), c = 12.974(6) å, V = 1379.1(11) å3,β = 92.854(7), and Z = 4. Complex 2 crystallizes in the triclinic space group P(-1) with a= 8.153(9), b = 9.925(11), c = 10.355(12), V = 746.3(15) å3, α = 70.530(16), β =71.154(15), γ = 80.698(16) and Z = 2. Complex 1 has a one-dimensional chain-likestructure, which is extended by weak hydrogen contacts, while complex 2 shows a three–dimensional network structure.

A series of novel 2-(1,3-diaryl- 4,5-dihydro-1H-pyrazol-5-yl)phenol derivatives (C1-C24) have been synthesized. The B-Raf inhibitory activity and anti-proliferation activity of these compounds have been tested. Compound C6 displayed the most potent biological activity against B-RafV600E (IC50 = 0.15 µM) and WM266.4 human melanoma cell line (GI50 = 1.75 µM), being comparable with the positive control (Vemurafenib and Erlotinib) and more potent than our previous best compounds. The docking simulation was performed to analyze the probable binding models and poses while the QSAR model was built to check the previous work as well as to introduce new directions. This work aimed at seeking more potent inhibitors as well as discussing some previous findings. As a result, the introduction of ortho-hydroxyl group on 4,5-dihydro-1H-pyrazole skeleton did reinforce the anti-tumor activity while enlarging the group on N-1 of pyrazoline was also helpful.

A total of 19 novel (3a-3s) N'-benzoyl-3-(4-bromophenyl)-1H-pyrazole-5-carbohydrazide analogs were designed, synthesized, and evaluated for biological activities as potential DNA gyrase inhibitors. The results showed that compound 3k can strongly inhibit Staphylococcus aureus DNA gyrase and Bacillus subtilis DNA gyrase (with IC50 of 0.15 µg/mL and 0.25 µg/mL, respectively). Structure-activity relationships were also discussed base on the biological and docking simulation results.

4-Anilinoquinazolines as an important class of protein kinase inhibitor are widely investigated for epidermal growth factor receptor (EGFR) tyrosine kinase or epidermal growth factor receptor 2 (HER2) inhibition. A series of novel 6-salicyl-4-anilinoquinazoline derivatives 9-27 were prepared and evaluated for their EGFR/HER2 tyrosine kinase inhibitory activity as well as their antiproliferative properties on three variant cancer cell lines (A431, MCF-7, and A549). The bioassay results showed most of the designed compounds exhibited moderate to potent in vitro inhibitory activity in the enzymatic and cellular assays, of which compound 21 revealed the most potent dual EGFR/HER2 inhibitory activity, with IC50 values of 0.12 µM and 0.096 µM, respectively, comparable to the control compounds Erlotinib and Lapatinib. Furthermore, the kinase selectivity profile of 21 was accessed and demonstrated its good selectivity over the majority of the close kinase targets. Docking simulation was performed to position compound 21 into the EGFR/HER2 active site to determine the probable binding pose. These new findings along with molecular docking observations could provide an important basis for further development of compound 21 as a potent EGFR/HER2 dual kinase inhibitor.

A series of novel benzohydrazide derivatives containing dihydropyrazoles have been synthesized as potential epidermal growth factor receptor (EGFR) kinase inhibitors and their biological activities as potential antiproliferative agents have been evaluated. Among these compounds, compound H20 exhibited the most potent antiproliferative activity against four cancer cell line variants (A549, MCF-7, HeLa, HepG2) with IC50 values of 0.46, 0.29, 0.15 and 0.21 μM respectively, which showed the most potent EGFR inhibition activities (IC50 = 0.08 μM for EGFR). Molecular modeling simulation studies were performed in order to predict the biological activity and activity relationship (SAR) of these benzohydrazide derivatives. These results suggested that compound H20 may be a promising anticancer agent.

In the title compound, C15H12BrClN2O4, the configuration of the C=N double bond can be described as trans. The two aromatic rings in this Schiff base are nearly coplanar with a dihedral angle between their mean planes of 15.4 (2)°. In the crystal, molecules are linked via O—H...N and C—H...O interactions.

The title compound, C10H11I2NO, was prepared by the reaction of 3,5-diiodosalicylaldehyde with propylamine in ethanol. The molecule adopts an E conformation with respect to the C=N bond and the aromatic ring. The aromatic ring and the imino unit are close to being coplanar, with a dihedral angle of 2.6 (3)° between their planes. This planarity is assisted by the formation of an intramolecular O—H...O hydrogen bond.

The asymmetric unit of the title compound, C13H8ClI2NO, contains half of the molecule situated on a mirror plane. The hydroxy group is involved in the formation of an intramolecular O—H...N hydrogen bond. π–π interactions between the benzene rings of neighbouring molecules [centroid–centroid distance = 3.629 (3) Å] form stacks along the b axis. In the crystal, weak C—H...O and C—H...Cl interactions are observed.

The title compound, C13H8BrI2NO, was prepared by the reaction of 3,5-diiodosalicylaldehyde with 4-bromophenylamine in ethanol. There is an intramolecular O—H...N hydrogen bond in the molecule, which generates an S(6) ring. The dihedral angle between the benzene rings is 2.6 (3)°.

The asymmetric unit of the title compound, C20H16ClN3S, contains two independent molecules, A and B. In molecule A, the dihedral angles between the central benzene ring and the pendant chlorobenzene and phenyl rings are 6.37 (15) and 64.79 (15)°, respectively. The corresponding values in molecule B are 28.21 (14) and 82.11 (16)°, respectively. Each molecule features an intramolecular N—H...N hydrogen bond, which generates an S(5) ring. In the crystal, molecules A and B form dimers, being linked by two N—H...S hydrogen bonds with graph-set notation R22(8).

The molecule of the title compound, C16H16N2O4, exists in the E configuration with respect to the central C=N double bond. The dihedral angle between the two benzene rings is 2.17 (9) Å. In the crystal, molecules are linked via O—H...N hydrogen bonds into chains that propagate along the b-axis direction. There is also π–π stacking of inversion-related molecules, with interplanar spacings of 3.479 (5) Å and ring centroid–centroid distances of 3.876 (4) Å.

In the title compound, C14H16O3 [systematic name: (3R*,3aR*)-3-(3-furanyl)-3a,7-dimethyl-3a,4,5,6-tetrahydro-2-benzofuran-1(3H)-one], the pendant methyl and furan groups attached to the stereogenic centres lie to the same side of the fused ring system. The dihedral angle between the five-membered rings is 74.8 (2)°; the fused five-membered ring adopts a twisted conformation. In the crystal, molecules are linked by weak C—H...O interactions, which generate [100] chains.

The author list in the paper by Ding [Acta Cryst. (2010), E66, o2633] is corrected.

In the title compound, C15H13N3O2S2, the dihedral angle between the aromatic rings is 87.8 (2)°. In the crystal, inversion dimers occur linked by pairs of N—H...S hydrogen bonds.

In the title compound, C15H12ClN3O2S2, the dihedral angle between the aromatic rings is 89.71 (10)°. In the crystal, inversion dimers linked by pairs of N—H...S hydrogen bonds occur.

In the title molecule, C21H16O8, the dihedral angle between the ring systems is 58.5 (1)°. In the crystal, C—H...O interactions help to establish the packing.

The title compound, C18H18FNO3, consists of three individually planar subunits, namely two substituted benzene rings and one aminoacrylate group. The dihedral angle between the two benzene rings is 47.48 (8)°. The aminoacrylate group forms dihedral angles of 57.95 (7) and 11.27 (6)° with the methoxyphenyl and fluorophenyl rings, respectively.