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The COVID-19, caused by SARS-CoV-2, is threatening public health, and there is no effective treatment. In this study, we have implemented a multi-targeted anti-viral drug design strategy to discover highly potent SARS-CoV-2 inhibitors, which simultaneously act on the host ribosome, viral RNA as well as RNA-dependent RNA polymerases, and nucleocapsid protein of the virus, to impair viral translation, frameshifting, replication, and assembly. Driven by this strategy, three alkaloids, including lycorine, emetine, and cephaeline, were discovered to inhibit SARS-CoV-2 with EC50 values of low nanomolar levels potently. The findings in this work demonstrate the feasibility of this multi-targeting drug design strategy and provide a rationale for designing more potent anti-virus drugs.

Human dihydroorotate dehydrogenase (DHODH) is a viable target for the development of therapeutics to treat cancer and immunological diseases, such as rheumatoid arthritis (RA), psoriasis and multiple sclerosis (MS). Herein, a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents were designed and synthesized. 2-Acrylamidobenzoic acid analog 11 was identified as the lead compound for structure−activity relationship (SAR) studies. The replacement of the phenyl group with naphthyl moieties improved inhibitory activity significantly to double-digit nanomolar range. Further structure optimization revealed that an acrylamide with small hydrophobic groups (Me, Cl or Br) at the 2-position was preferred. Moreover, adding a fluoro atom at the 5-position of the benzoic acid enhanced the potency. The optimization efforts led to potent compounds 42 and 53‒55 with IC50 values of 41, 44, 32, and 42 nmol/L, respectively. The most potent compound 54 also displayed favorable pharmacokinetic (PK) profiles and encouraging in vivo anti-arthritic effects in a dose-dependent manner., Graphical abstract Dihydroorotate dehydrogenase (DHODH) is an attracting target for the treatment of immunological diseases. A series of acrylamide-based novel DHODH inhibitors as potential rheumatoid arthritis (RA) treatment agents were designed and synthesized, among which 54 is the most potent one with good pharmacokinetic profiles and favorable in vivo anti-arthritic effects.Image 1

The experimental liquid phase compositions of the ternary systems (water + n-propanol + n-butyl acetate, ethyl butyrate or n-pentyl acetate) were measured at T = (293.15, 303.15 and 313.15) K under atmospheric pressure. The thermodynamic modified and extended UNIQUAC models were applied to correlate and analyze the experimental values. Ternary phase diagrams at the experimental temperatures were plotted and compared. The linear trend of the measured liquid–liquid equilibrium data was confirmed by using the Bachman equation. Distribution coefficients and separation factors were applied to evaluate extracting capability of n-butyl acetate, ethyl butyrate and n-pentyl acetate to separate n-propanol from (n-propanol + water) solutions.

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC50 of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not. Electronic supplementary material The online version of this article (10.1007/s13238-020-00768-w) contains supplementary material, which is available to authorized users.

An increasing amount of evidence suggests that transmembrane member 16A (TMEM16A)-encoded Ca2+-activated Cl− channels play a crucial role in regulating tumorigenesis. Therefore, specific and potent TMEM16A inhibitors have been proposed to potentially be useful for the treatment of cancer. During drug screening, we found that benzophenanthridine alkaloids (sanguinarine, sanguinarium chloride, sanguinarine nitrate, ethoxysanguinarine, chelerythrine, and dihydrosanguinarine) potently inhibited the recombinant TMEM16A current. The IC50 and Emax values for TMEM16A inhibition of six tested benzophenanthridine alkaloids were 5.6–12.3 μM and 77–91%, respectively. These benzophenanthridine alkaloids also significantly inhibited the endogenous TMEM16A currents and proliferation, migration, and induced apoptosis in LA795 lung adenocarcinoma cells. These data demonstrate that benzophenanthridine alkaloids are novel TMEM16A inhibitors and are potentially useful in specific cancer therapies. These findings also provide new insight for the development of TMEM16A inhibitors.

The farnesoid X receptor (FXR) is a bile acid-sensing transcription factor with indispensable roles in regulating metabolic processes. Nowadays, FXR has become a highly promising drug target for severe liver disorders, especially nonalcoholic steatohepatitis (NASH). A recent study showed that imatinib and its analogues were able to allosterically enhance agonist-induced FXR activation and its target gene expression. However, the allosteric modulation mechanism of FXR by these compounds remains unclear. In this work, the most effective imatinib analogue, P16, was used as a probe to explore this issue by computational approaches. Our results identified one potential allosteric site surrounded by residues Ile335, Phe336, Lys338, Glu339, Leu340, and Leu348, which could efficiently accommodate P16. In addition, the long-time molecular dynamics simulations indicated that the binding of P16 could significantly decrease the fluctuation of the co-activator and enhance the communications between the endogenous ligand chenodeoxycholic acid (CDCA) and FXR. By analyzing the residue interaction network, we observed two unique communication pathways connecting P16 and CDCA through three key residues, Arg331, Ser332, and Phe336. The communications of network organization in the P16-bound complex may allow the synergistic effect of the two compounds via robust signal transmission between the binding sites and global network bridges, which coordinate allosteric transitions and modulate the receptor activity. Our study offers insights into the allosteric modulation occurring in FXR and would be helpful for discovery of new allosteric modulators targeting FXR for further clinical research.

Small regulatory RNAs (sRNAs) act as key regulators in many bacterial signalling cascades. However, in P. aeruginosa, the sRNAs involved in quorum sensing (QS) regulation and their function are still largely unknown. Here, we explored how the prrH locus sRNA influences P. aeruginosa virulence in the context of the QS regulatory network. First, gain- and loss-of-function studies showed that PrrH affects pyocyanin, elastase and rhamnolipid production; biofilm formation; and swimming and swarming motility and impaired the viability of P. aeruginosa in human whole blood. Next, our investigation disclosed that LasI and PhzC/D were directly repressed by PrrH. In addition, RhlI, the key member of the rhl QS system, diminished the expression of PrrH and enhanced the expression of downstream genes. Bioinformatics analysis found two binding sites of RhlR, the transcription factor of the rhl system, on the promoter region of prrH. Further β-galactosidase reporter and qPCR assays confirmed that PrrH was transcriptionally repressed by RhlR. Collectively, our data identified a novel RhlI/R-PrrH-LasI/PhzC/PhzD regulatory circuitry that may contribute to P. aeruginosa pathogenesis. Our findings indicate that PrrH is a quorum regulatory RNA (Qrr) in P. aeruginosa and provide new insight into PrrH’s function.

Bruton’s tyrosine kinase (BTK) is a key component of the B cell receptor (BCR) signaling pathway and plays a crucial role in B cell malignancies and autoimmune disorders; thus, it is an attractive target for the treatment of B cell related diseases. Here, we evaluated the BTK inhibitory activity of a series of pyrimido[4,5-d][1,3]oxazin-2-one derivatives. Combining this evaluation with structure-activity relationship (SAR) analysis, we found that compound 2 exhibited potent BTK kinase inhibitory activity, with an IC50 of 7 nM. This derivative markedly inhibited BTK activation in TMD8 B cell lymphoma cells and thus inhibited the in vitro growth of the cells. Further studies revealed that compound 2 dose dependently arrested TMD8 cells at G1 phase, accompanied by decreased levels of Rb, phosphorylated Rb, and cyclin D1. Moreover, following treatment with compound 2, TMD8 cells underwent apoptosis associated with PARP and caspase 3 cleavage. Interestingly, the results of the kinase activity assay on a small panel of 35 kinases showed that the kinase selectivity of compound 2 was superior to that of the first-generation inhibitor ibrutinib, suggesting that compound 2 could be a second-generation inhibitor of BTK. In conclusion, we identified a potent and highly selective BTK inhibitor worthy of further development.

Poor medication adherence is one of the leading causes of suboptimal glycaemic control in approximately half of the patients with type 2 diabetes mellitus (T2DM). Long-acting antidiabetic drugs are clinically needed for improving patients' compliance. Dipeptidyl peptidase-4 (DPP-4) inhibitors play an increasingly important role in the treatment of T2DM because of their favorable properties of weight neutrality and hypoglycemia avoidance. Herein, we report the successful discovery and scale-up synthesis of compound 5, a structurally novel, potent, and long-acting DPP-4 inhibitor for the once-weekly treatment of T2DM. Inhibitor 5 has fast-associating and slow-dissociating binding kinetics profiles as well as slow clearance rate and long terminal half-life pharmacokinetic properties. A single-dose oral administration of 5 (3 mg/kg) inhibited80% of DPP-4 activity for more than 7 days in diabetic mice. The long-term antidiabetic efficacies of 5 (10 mg/kg, qw) were better than those of the once-weekly trelagliptin and omarigliptin, especially in decreasing the hemoglobin A1c level.

Antimicrobial resistance is a public health emergency and warrants coordinated global efforts. Challenge is that no alternative molecular platform has been identified for discovery of abundant antimicrobial hit compounds. Xanthene libraries have been screened for bioactive compounds. However, the potentially accessible chemistry space of xanthene dyes is limited by the existing xanthene synthesis. Herein we report a mild one-step synthesis, which permits late-stage introduction of a xanthene moiety onto i.e. natural products, pharmaceuticals, and bioactive compounds and construction of a focused library of rhodamine dyes exhibiting facile functional, topographical and stereochemical diversity. In vitro screening yields 37 analogs with mid-to-high bactericidal activity against WHO priority drug-resistant pathogens. These findings suggest that synthetic dye libraries exhibiting high structural diversity is a feasible chemical space combating antibacterial resistance, to complement the natural sources.

Arachidonic acid (AA) metabolic network is activated in the most inflammatory related diseases, and small-molecular drugs targeting AA network are increasingly available. However, side effects of above mentioned drugs have always been the biggest obstacle. (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate (HOEC), a natural product acted as an inhibitor of 5-lipoxygenase (5-LOX) and 15-LOX in vitro, exhibited weaker therapeutic effect in high dose than that in low dose to collagen induced arthritis (CIA) rats. In this study, we tried to elucidate the potential regulatory mechanism by using quantitative pharmacology. First, we generated an experimental data set by monitoring the dynamics of AA metabolites’ concentration in A23187 stimulated and different doses of HOEC co-incubated RAW264.7. Then we constructed a dynamic model of A23187-stimulated AA metabolic model to evaluate how a model-based simulation of AA metabolic data assists to find the most suitable treatment dose by predicting the pharmacodynamics of HOEC. Compared to the experimental data, the model could simulate the inhibitory effect of HOEC on 5-LOX and 15-LOX, and reproduced the increase of the metabolic flux in the cyclooxygenase (COX) pathway. However, a concomitant, early-stage of stimulation-related decrease of prostaglandins (PGs) production in HOEC incubated RAW264.7 cells was not simulated in the model. Using the model, we predict that higher dose of HOEC disrupts the flux balance in COX and LOX of the AA network, and increased COX flux can interfere the curative effects of LOX inhibitor on resolution of inflammation which is crucial for the efficient and safe drug design.

Background Multidrug resistance (MDR) in small cell lung cancer (SCLC) is a clinical dilemma in chemotherapy. A natural compound, β-elemene has been found to inhibit MDR cancers. We hypothesized that β-elemene regulated cisplatin-resistant SCLC by targeting autophagy-related miRNA miR-199a-5p. Methods We assessed the IC50 of multiple chemotherapeutic agents toward SCLC cells H446 and MDR SCLC cells H446/EP with or without β-elemene using CCK-8. We overexpressed (OE) and knocked down (KD) miR-199a-5p in H446 and H446/EP and determined the expression of miR-199a-5p, autophagy-related proteins, and the formation of autophagolysosomes using QPCR, western blotting, and MDC staining respectively. We validate the binding of miR-199a-5p to p62 using the Dual-Luciferase assay. Results β-Elemene decreased drug resistance of H446 to cisplatin, etoposide, paclitexal, epirubicin, irinotecan, and vinorelbine. Cisplatin increased LC3II/LC3I, ATG5, p62, and the formation of autophagolysosomes in H446 cells, but not in H446/EP cells, and these effects were blocked by β-elemene. The OE of miR-199a-5p reduced cisplatin-induced increase of LC3II/LC3I, ATG5, p62, and the formation of autophagolysosomes while the KD of miR-199a-5p did the opposite. the OE of miR-199a-5p reduced the luciferase signal of wild-type p62, but not that of p62 with mutations at the predicted binding site. The effect of β-elemene on cisplatin-induced autophagy was validated in OE-H446 and KD-H446/EP. Conclusions β-Elemene prevented MDR in H446 and it prevents cisplatin resistance of H446 by targeting the autophagy regulation of miR-199a-5p.

Excellent stability of a catalytic center would facilitate the prolongation of the cycle of a chemical plating bath and the reduction of environmental pollution. In this study, silane (3-aminopropyltriethoxysilane (KH550) and γ-(2,3-epoxypropoxy)propytrimethoxysilane (KH560)) was incorporated in AgNO3 solution to rationally prepare a Ag nanoparticle/polymer brush (Ag/PB) catalytic solution. The effects of the KH560 relative content on the Ag/PB structure and stability were studied. The epoxy group in the KH560 could react with an amino group in the KH550 through direct ring-opening reaction to form a secondary amino group and hydroxyl, which could coadsorb Ag nanoparticles by means of a chelating structure; hence, Ag/PB with superior Ag-adsorbed intensity was established on a polyethylene terephthalate (PET) surface. Ag particles on PB with 75% KH560 revealed the best stability of those measured, and the relative Ag surplus was 56.7% after stability testing. The generated Ag/PB that served as catalytic centers to catalyze the electroless copper plating resulted in a facile technology for preparing Cu/PET composite material. This means that the technology has potential application in a green process for preparing metal/polymer composite materials.

In situ monitoring of products generated by important heterogeneous catalytic reactions is of great significance for chemical industry, particularly when the products or intermediates are not sufficiently stable or occur at trace-level concentrations. It is therefore highly desirable to develop an integrated in situ catalysis and extraction method, which can simultaneously catalyze the reaction and enrich products while maintaining compatibility with analytical instrumentation. Herein, we propose an approach by depositing different types of metal nanocrystals, including gold, platinum, and palladium nanoparticles, onto fibrous silica microspheres coated fibers for integrated in situ catalysis and extraction. As a proof-of-concept, several typical chemical reactions, including the reduction of p-nitrophenol, epoxidation of styrene, oxidation of benzyl alcohol, and dechlorination of p-chlorophenol, were investigated to validate the feasibility of this method. Our results show that these coatings not only function as catalysts to accelerate the selected reactions but also serve as adsorbents to extract the reactants, intermediates, and products for direct gas chromatographic analysis, suggesting the viability of this approach for the in situ evaluation of catalytic processes. By this approach, the yield, selectivity, and kinetics of a reaction can be readily assessed. This approach can also be extended to investigate the catalytic performance of the same metal nanocrystals with different morphology, surface facet, structure, or surface functionalization. This approach will find broad generality for assessing the catalytic efficiency and selectivity of new catalysts or new chemical reactions and dynamic processes in these reactions.

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of coronavirus SARS-CoV-2. Existing direct-acting antiviral (DAA) drugs cannot be applied immediately to new viruses because of virus-specificity, and the development of new DAA drugs from the beginning is not timely for outbreaks. Thus, host-targeting antiviral (HTA) drugs have many advantages to fight against a broad spectrum of viruses, by blocking the viral replication and overcoming the potential viral mutagenesis simultaneously. Herein, we identified two potent inhibitors of DHODH, S312 and S416, with favorable drug-like and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus (H1N1, H3N2, H9N2), Zika virus, Ebola virus, and particularly against the recent novel coronavirus SARS-CoV-2. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knocking-out cells. We also proposed the drug combination of DAA and HTA was a promising strategy for anti-virus treatment and proved that S312 showed more advantageous than Oseltamivir to treat advanced influenza diseases in severely infected animals. Notably, S416 is reported to be the most potent inhibitor with an EC50 of 17nM and SI value >5882 in SARS-CoV-2-infected cells so far. This work demonstrates that both our self-designed candidates and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-repression may have clinical potentials not only to influenza but also to COVID-19 circulating worldwide, no matter such viruses mutate or not.

Textile-based cotton was developed to fabricate the support for triboelectric nanogenerators (TENGs), which would facilitate the improvement of the device wearability and comfort. But, it is difficult to achieve the fabrication of metal textile-based cotton for electrode materials using traditional technology. In this regard, a textile-based TENGs via electroless plating on cotton surface for fabricating electrode material was established, the output performances under different external forces were studied comprehensively to obtain a full understanding of the relationship between the density of electrostatic charge (δ) and strain of polydimethylsiloxane (PDMS) dielectric material. Results showed that active groups on the rough cotton surface would facilitate the adsorption of Pd2+, and then reduce of Ni2+ to Ni atom in electroless nickel solution. As a result, core-sheath micronfiber yarn with weave structure was fabricated. It is flexible, lightweight, flexible with typical performance of TENGs electrode. The device had stable and excellent performances, and a maximum open-circuit voltage of about 8.3 V was observed from stress of 3.8 kPa or strain of 1.7 × 10−6 on PDMS layer. More importantly, a new calculation method for the PDMS strain of formation δ was proposed by equation of state. It was also revealed that the δ and PDMS strain represented a linear regression relation when the device under weigh mass of 0.22–0.52 kg, stress of 0.69–1.63 kPa and strain of 0.3–0.72 × 10−6. Nevertheless, further increasing stress, actual δ value is firstly higher and then lower than the theoretical value due to fabric fiber deformation.

Natural flavonoids are ubiquitous in dietary plants and vegetables and have been proposed to have antiviral, antioxidant, cardiovascular protective, and anticancer effects. Volume-regulated anion channels (VRACs), which are essential for cell volume regulation, have been proposed to play a key role in cell proliferation and migration, apoptosis, transepithelial transport, and cancer development. In this study, we screened a group of 53 structurally related natural flavonoids and three synthetic flavonoids for their inhibitory activities on VRAC currents. A whole-cell patch technique was used to record VRAC currents in the human embryonic kidney (HEK) 293 and human umbilical vein endothelial (HUVEC) cells. The 5'-bromo-2-deoxyuridine (BrdU) assay technique was used to investigate cell proliferation. At 100 μM, 34 of 53 compounds significantly inhibited hypotonic extrasolution-induced VRAC currents by > 50% in HEK293 cells. Among these compounds, luteolin, baicalein, eupatorin, galangin, quercetin, fisetin, karanjin, Dh-morin, genistein, irisolidone, and prunetin exhibited the highest efficacy for VRAC blockade (the mean inhibition > 80%) with IC50s of 5-13 μM and Emaxs of about 87-99%. We also studied the effects of three synthetic flavonoids on VRAC currents in HEK293 cells. Flavoxate showed high inhibition efficacy toward VRAC currents (IC50 = 2.3 ± 0.3 μM; Emax = 91.8% ± 2.7%). Finally, these flavonoids inhibited endogenous VRAC currents and cell proliferation in endothelial cells. This study demonstrates that natural and synthetic flavonoids are potent VRAC current inhibitors, and VRAC inhibition by flavonoids might be responsible for their anti-angiogenic effects.

Because the transcription factor activator protein-1 (AP-1) regulates a variety of protein-encoding genes, it is a participant in many cellular functions, including proliferation, transformation, epithelial mesenchymal transition (EMT), and apoptosis. Inhibitors targeting AP-1 have potential use in the treatment of cancer and other inflammatory diseases. Here, we identify veratramine as a potent natural modulator of AP-1, which selectively binds to a specific site (TRE 5′-TGACTCA-3′) of the AP-1 target DNA sequence and regulates AP-1-dependent gene transcription without interfering with cystosolic signaling cascades that might lead to AP-1 activation. Moreover, RNA-seq experiments demonstrate that veratramine does not act on the Hedgehog signaling pathway in contrast to its analogue, cyclopamine, and likely does not harbor the same teratogenicity and toxicity. Additionally, veratramine effectively suppresses EGF-induced AP-1 transactivation and transformation of JB6 P+ cells. Finally, we demonstrate that veratramine inhibits solar-ultraviolet-induced AP-1 activation in mice. The identification of veratramine and new findings in its specific regulation of AP-1 down stream genes pave ways to discovering and designing regulators to regulate transcription factor.

Fluorinations play the momentous impact in tuning the optical absorption, energy levels, aggregation and microstructurally morphology. Two acceptor-donor-acceptor (A-D-A) non-fullerene small molecular acceptors (SMAs), namely, 2T-(PDI-HD)2 and F2T-(PDI-HD)2, by incorporating two fluorine atoms into the central 2,2′-bithiophene linked core, were synthesized. The resultant PDI-based SMAs had excellent thermo- and photo-stability, wide absorption ranging from 300 to 700 nm, and ELUMOs of −3.71 to −3.84 eV. It was demonstrated that the enhanced molar absorption coefficient, elevated ELUMO, slightly strengthened film aggregation and lowered miscibility with donor PTB7-Th were observed after incorporating fluorine atom onto the SMAs. Further surface electrostatic potential (ESP) calculation elucidated that the fluorination could increase molecular polarity and maximize the ESP difference between PTB7-Th and SMAs, facilitating exciton dissociation and the charge transport. Accordingly, an 39.01% improved PCE from 1.82% to 2.53% was yielded in PTB7-Th:F2T-(PDI-HD)2 based device, mainly benefitting from 26.17% enhanced JSC and 22.82% elevated FF even if the adverse condition of decreased VOC. This improvement was profited from the increased absorption coefficient, enhanced electron mobility as well as favorable microstructurally morphology. The results demonstrated that inserting fluorine atoms into the central linked core was an effective strategy to improve the device performance.

The transmembrane member 16A (TMEM16A)-encoded Ca2+-activated Cl− channel (CaCC) is expressed in interstitial cells of Cajal (ICCs) and involved in the generation of the slow-wave currents of gastrointestinal (GI) smooth muscles. TMEM16A modulators have been shown to positively or negatively regulate the contraction of gastrointestinal smooth muscle. Therefore, targeting the pharmacological modulation of TMEM16A may represent a novel treatment approach for gastrointestinal dysfunctions such as constipation and diarrhoea. In this study, evodiamine and rutecarpine were extracted from the traditional Chinese medicine Evodia rutaecarpa and identified as novel TMEM16A inhibitors with comparable inhibitory effects. Their effects on intestinal peristalsis were examined. Whole-cell patch clamp results show that evodiamine and rutecarpine inhibited TMEM16A Cl− currents in CHO cells. The half-maximal inhibition values (IC50) of evodiamine and rutecarpine on TMEM16A Cl− currents were 11.8 ± 1.3 μΜ and 9.2 ± 0.4 μM, and the maximal effect values (Emax) were 95.8 ± 5.1% and 99.1 ± 1.6%, respectively. The Lys384, Thr385, and Met524 in TMEM16A are critical for evodiamine and rutecarpine's inhibitory effects. Further functional studies show that both evodiamine and rutecarpine can significantly suppress the peristalsis in isolated guinea-pig ileum. These findings demonstrate that evodiamine and rutecarpine are new TMEM16A inhibitors and support the regulation effect of TMEM16A modulators on gastrointestinal motility.

Spinal cord injury (SCI) is generally divided into primary and secondary injuries, and apoptosis is an important event of the secondary injury. As an endogenous bile acid and recognized endoplasmic reticulum (ER) stress inhibitor, tauroursodeoxycholic acid (TUDCA) administration has been reported to have a potentially therapeutic effect on neurodegenerative diseases, but its real mechanism is still unclear. In this study, we evaluated whether TUDCA could alleviate traumatic damage of the spinal cord and improve locomotion function in a mouse model of SCI. Traumatic SCI mice were intraperitoneally injected with TUDCA, and the effects were evaluated based on motor function assessment, histopathology, apoptosis detection, qRT-PCR, and western blot at different time periods. TUDCA administration can improve motor function and reduce secondary injury and lesion area after SCI. Furthermore, the apoptotic ratios were significantly reduced; Grp78, Erdj4, and CHOP were attenuated by the treatment. Unexpectedly, the levels of CIBZ, a novel therapeutic target for SCI, were specifically up-regulated. Taken together, it is suggested that TUDCA effectively suppressed ER stress through targeted up-regulation of CIBZ. This study also provides a new strategy for relieving secondary damage by inhibiting apoptosis in the early treatment of spinal cord injury.

Nanosized MnZn ferrite particles, with narrow size distribution, regular morphology and high saturation magnetization have been synthesized via a modified hydrothermal method. This modified hydrothermal method involves a chemical co-precipitation of hydroxides under a vacuum condition using potassium hydroxide as precipitating agent, followed by a separate hydrothermal process. The microstructure and magnetic properties of the synthesized nanoparticles were investigated by X-ray diffraction (XRD), Raman spectroscopy, field emission scanning electron microscopy (FESEM), high resolution transmission electron microscopy (HRTEM) and vibrating sample magnetometer (VSM). The effects of different synthesis conditions (excess ratio of precipitating agent and hydrothermal reaction time) on the microstructure and magnetic properties of the as-synthesized nanoparticles were discussed. The magnetic measurements indicated that the obtained samples were superparamagnetic in nature at room temperature. Moreover, the MnZn ferrite nanoparticles with excellent magnetic performance could be synthesized at 180 °C for a short reaction time (3 h).

Experimental approaches for determining the metabolic properties of the drug candidates are usually expensive, time-consuming and labor intensive. There is a great deal of interest in developing computational methods to accurately and efficiently predict the metabolic decomposition of drug-like molecules, which can provide decisive support and guidance for experimentalists. Here, we developed an integrated, low false positive and reaction types extensive metabolism prediction approach called RD-Metabolizer (Reaction Database-based Metabolizer). RD-Metabolizer firstly employed the detailed reaction SMARTS patterns to encode different metabolism reaction types with the aim of covering larger chemical reaction space. 2D fingerprint similarity calculation model was built to calculate the metabolic probability of each site in a molecule. RDKit was utilized to act on pre-written reaction SMARTS patterns to correct the metabolic ranking of each site in a molecule generated by the 2D fingerprint similarity calculation model as well as generate corresponding structures of metabolites, thus helping to reduce the false positive metabolites. Two test sets were adopted to evaluate the performance of RD-Metabolizer in predicting SOMs and structures of metabolites. The results indicated that RD-Metabolizer was better than or at least as good as several widely used SOMs prediction methods. Besides, the number of false positive metabolites was obviously reduced compared with MetaPrint2D-React. The accuracy and efficiency of RD-Metabolizer was further illustrated by a metabolism prediction case of AZD9291, which is a mutant-selective EGFR inhibitor. RD-Metabolizer will serve as a useful toolkit for the early metabolic properties assessment of drug-like molecules at the preclinical stage of drug discovery. Graphical abstract A visual example of the metabolic site and the corresponding metabolite of Chloroquine predicted by RD-Metabolizer

SummaryBackground and purpose Natural flavonoids are ubiquitous in dietary plants and vegetables and have been proposed to have antiviral, antioxidant, cardiovascular protective, and anticancer effects. Transmembrane member 16A (TMEM16A) encoded Ca2+-activated Cl- channels play a variety of physiological roles in many organs and tissues. Overexpression of TMEM16A is also believed to be associated with cancer progression. Therefore, inhibition of TMEM16A may be a potential target for cancer therapy. In this study, we screened a broad spectrum of flavonoids for their inhibitory activities on TMEM16A currents. Experimental approach A whole-cell patch technique was used to record the currents. The BrdU assay and transwell technique were used to investigate cell proliferation and migration. Key results Using a concentration of 100 μM, 10 of 20 compounds caused significant inhibition of TMEM16A currents (rate of inhibition >50%). The IC50 (and Emaxs) values (in μM) for TMEM16A inhibition by luteolin, galangin, quercetin, and fisetin were 9.5 ± 1.1 (83.7 ± 3.7%), 4.5 ± 0.6 (92.4 ± 4.0%), 13.7 ± 1.7 (87.7 ± 4.8%), and 12.0 ± 1.5 (83.9 ± 4.5%), respectively. To examine the physiological relevance of these findings, we also studied the effects of these flavonoids on endogenous TMEM16A currents in addition to cell proliferation and migration in LA795 cancer cells. Among the flavonoids tested, we detected a highly significant correlation between TMEM16A current inhibition and cell proliferation/migration reduction. Conclusions and Implications This study demonstrates that flavonoids are TMEM16A current inhibitors and suggests flavonoids have anti-cancer effects via this mechanism.

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.

Objectives Flavonoids are present in varying concentrations in plant foods and have been reported to have numerous pharmacological activities, such as anti-cancer, antioxidant, anti-inflammatory, hepatoprotective, and vasodilator effects. We found that quercetin, fisetin, and some related flavonoid derivatives could inhibit human ether-a-go-go-related gene (hERG) K+ channels. Key findings In this study, we tested the effects of a series of flavonoids on the hERG K+ channel expressed in HEK293 cells. For the first time, we demonstrate that quercetin and fisetin (Fise) are potent hERG current blockers. The 50% inhibiting concentration (IC50) and maximum efficacy (Emax) of quercetin were 11.8 ± 0.9 μM and 82 ± 2%, while those of fisetin were 38.4 ± 6 μM and 100 ± 6%, respectively. Luteolin (Lute) was a less potent inhibitor of hERG current (48 ± 1% at 100 μM). Galangin, kaempferol, and isorhamnetin (100 μM) showed weaker activity on the hERG currents. Conclusion These results suggest that quercetin, fisetin, and luteolin are potent hERG K+ channel inhibitors and reveal the structure-activity relationship of natural flavonoids.

Mn0.8Zn0.2Fe2O4 nanoparticles with improved saturation magnetization were prepared by a modified hydrothermal method. This method involves a chemical co-precipitation of hydroxides under a vacuum condition using potassium hydroxide as a precipitating agent, followed by a separate hydrothermal process. To understand the advantages of the modified hydrothermal method proposed above, a sample having identical stoichiometry was prepared by conventional hydrothermal method, during which the preparation of precursor was conducted in an open system. The samples were characterized by XRD, X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, and TEM. The magnetic property was tested by vibrating sample magnetometer (VSM). XPS results show that the Mn cations of the nanoparticles prepared by modified hydrothermal method have lower average valence. The MnZn ferrite nanoparticles prepared by modified hydrothermal method have smaller diameter (16.1 nm, calculated by XRD) and higher room temperature saturation magnetization, 80 emu/g, which is even better than the reported value. The saturation magnetization of the particles prepared by modified hydrothermal method is 1.6 times of the particles prepared by conventional hydrothermal method.

Aberrant activation of B cell receptor (BCR) signal transduction cascade contributes to the propagation and maintenance of B cell malignancies. The discovery of mall molecules with high potency and selectivity against Bruton’s tyrosine kinase (BTK), a key signaling molecule in this cascade, is particularly urgent in modern treatment regimens. Herein, a series of pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione derivatives were reported as potent BTK inhibitors. Compounds 17 and 18 displayed strong BTK inhibitory activities in the enzymatic inhibition assay, with the IC50 values of 1.2 and 0.8 nM, respectively, which were comparable to that of ibrutinib (IC50 = 0.6 nM). Additionally, compound 17 had a more selective profile over EGFR than ibrutinib. According to the putative binding poses, the molecular basis of this series of compounds with respect to potency against BTK and selectivity over EGFR was elucidated. In further experiments at cellular level, compounds 17 and 18 significantly inhibited the proliferation of Ramos and TMD8 cells. And they arrested 75.4% and 75.2% of TMD8 cells in G1 phase, respectively, at the concentration of 1 µM.

Transmembrane protein 16A (TMEM16A) regulates a wide variety of cellular activities, including epithelial fluid secretion and maintenance of ion homeostasis. Lipopolysaccharide (LPS), an outer membrane component of Gram-negative bacteria, is one of the major causes of acute lung injury (ALI). In this study, we investigated the effects of LPS on the expression of TMEM16A in LA795 cells and mouse lung tissue and the potential mechanism. Result: We detected the expression of TMEM16A in LA795 cells and mouse lung tissue by RT-PCR, Western blot, and RNA interference techniques. TMEM16A expression was significantly increased by LPS stimulation in LA795 cells and in mouse lung tissue. Moreover, the LPS-induced TMEM16A expression enhancement in lung tissue was much more prominent in the alveolar epithelial region than in bigger airway epithelial cells. The typical TMEM16A current was recorded, and LPS treatment significantly enhances the current amplitude in LA795 cells. TMEM16A shRNA or TMEM16A inhibitor (T16Ainh-A01) did not affect alveolar fluid clearance (AFC), while co-application of T16Ainh-A01 induced a stronger AFC inhibition than LPS alone. LPS notably and synchronously enhanced Akt phosphorylation (p-Akt) and TMEM16A expression in a time-dependent manner in LA795 cells. Taken together, our results suggest that TMEM16A maybe plays an important role in pathological conditions of LPS-induced ALI as a protective protein.

Molybdenum disulfide (MoS2) has attracted extensive attention as a non-noble metal electrocatalyst for hydrogen evolution reaction (HER). Controlling the skeleton structure at the nanoscale is paramount to increase the number of active sites at the surface. However, hydrothermal synthesis favors the presence of the basal plane, limiting the efficiency of catalytic reaction. In this work, perfect hollow MoS2 microspheres capped by hollow MoS2 nanospheres (hH-MoS2) were obtained for the first time, which creates an opportunity for improving the HER electrocatalytic performance. Benefiting from the controllable hollow skeleton structure and large exposed edge sites, high-efficiency HER activity was obtained for stacked MoS2 thin shells with a mild degree of disorder, proving the presence of rich active sites and the validity of the combined structure. In general, the obtained hollow micro/nano MoS2 nanomaterial exhibits optimized electrocatalytic activity for HER with onset overpotential as low as 112 mV, lo...

Human dihydroorotate dehydrogenase (hDHODH) is an enzyme that catalyzes the fourth step in de novo pyrimidine biosynthesis, and its inhibitors restrict the growth of rapidly proliferating cells. Therefore, hDHODH has been reported as an attractive target for the treatment of cancer and autoimmune diseases. In this study, several quinoline derivatives were identified as potent inhibitors against hDHODH, among which compound A9 was the most potent one with an IC50 value of 9.7 nM. We further verified by thermal shift assay (TSA), surface plasmon resonance (SPR) and X-ray crystallography that A9 could directly bind to the target hDHODH. The crystal structure of hDHODH in complex with compound A9 was refined to 1.90 A and the binding mode of compound A9 was summarized. Moreover, structure–activity relationship (SAR) analysis of quinoline derivatives with hDHODH indicated that quinoline derivatives with a carboxyl group in R1, a bromine atom in R2 and a para-alkyl-substituted phenyl group in R5, were beneficial for potency against hDHODH, which plays an important role in inhibitor design and optimization.

RSK2 (p90 ribosomal S6 kinase 2) is a serine/threonine kinase expressed in a variety of cancers. Molecular-targeted inhibition of RSK2 as a potential therapeutic strategy for human cancers has been documented. In this work, a series of isoindole-1,3-dione derivatives as novel RSK2 inhibitors were designed and synthesized from a hit discovered in our previous study. Some compounds were confirmed to be moderately potent RSK2 inhibitors with IC50 values of about 0.5 μM. Structure–activity relationship analysis and binding mode studies by molecular docking were performed.

Plants can develop multifaceted system resistance as a result of infection with pathogens, insects, and some specific microbes or after treatment with specific chemicals.1 Among them, systemic acquired resistance (SAR) and induced systemic resistance (ISR)2 are the two most important types. To activate them, a large number of chemical inducers have been exploited based on the SA pathway. However, the JA pathway was rarely investigated for new plant activators. In this study, starting from JA and its analogs, based on the molecular three-dimensional shape and pharmacophore similarity comparison (SHAFTS), a new lead compound, pyrrolidone, as a new scaffold of plant activators was predicted and a series of 1-phenyl-5-pyrrolidone-3-carboxylic acid derivatives were designed and synthesized. The bioactivity was evaluated, and most of the compounds showed satisfactory activity; especially, compounds 7–11 showed almost no in vitro activity but excellent efficacy against tested diseases, and the prediction of the virtual screening results was also confirmed, which promoted the application of SHAFTS in the development of pesticides.

The efficacy of EGFR inhibitors is frequently affected by acquired resistance. EGFR19D/T790M/C797S mutation is one of the primary reasons for the emergence of resistance after treatment with the third-generation EGFR inhibitors such as AZD9291, CO1686 and Olmutinib. To overcome the resistance mutation 19D/T790M/C797S, we designed and prepared a series of indole derivatives with the terminal hydroxyl of alkyl chain to increase extra interaction with the Asp855 in the conservative DFG site. Activity evaluation, structure-activity relationship and docking analysis were also carried out. Among them, compound 12e displayed significant inhibitory activity against EGFR19D/T790M/C797S (IC50 = 15.3 nM) and good selectivity over EGFR WT (IC50 > 1000 nM), L858R/T790M (IC50, 156.6 nM) and L858R/T790M/C797S (IC50, 218.3 nM) respectively. Furthermore, 12e exhibited good growth inhibition activity, induced G1 phase cell cycle arrest and apoptosis in BaF3/EGFR19D/T790M/C797S cells by suppressing EGFR phosphorylation signaling pathway. In all, our study might provide a novel structural design method and lay the solid foundation for the development of the 4th generation EGFR19D/T790M/C797S inhibitors.

Ufmylation was proved to play a crucial role in hematopoietic stem cell (HSC) survival and erythroid differentiation, ufmylation deficiency induces acute anemia and lethality of embryos and adults in mouse models. To screen some compounds to rescue phenotypes induced by gene deletion, in this study, we used DDRGK1F/F ; CreERT2 conditional knockout mice, DDRGK1F/F ; CreERT2 bone marrow (BM) and fetal liver cells (FL), Uba5, and DDRGK1 knockdown human CD34 cell in vivo and in vitro, we found salubrinal, a novel inhibitor of eIF-2α dephosphorylation, promoted erythropoiesis at early stage, and partly rescued the acute anemia induce by DDRGK1 deficiency through upregulation of ufmylation and erythroid transcription factors. In phenylhydrazine (PHZ)-induced hemolytic anemia mice, interestingly, salubrinal could significantly improve hemocrit and red blood cell (RBC) indices of the mice treated with PHZ via upregulation of ufmylation. Its novel function was verified to attenuate unfolded protein response (UPR) and cell death programs, and to keep endoplasmic reticulum (ER) homeostasis in HSCs. Taken together results, it suggested that salubrinal may be a promising antianemic agent targeted by ufmylation.

CA IX has attracted much attention as a promising target for the development of new anticancer agents. In this study, a series of sulfonamide derivatives were designed and synthesized as potential CA IX inhibitors from a lead compound (benzoyl thioureido benzene sulfonamide) discovered by virtual screening. The bioassay demonstrated that some of the synthesized compounds exhibited potent inhibitory activity against CA IX in the subnanomolar range and high selectivity over isozymes CA I and CA II. Among them, compound 6a displayed inhibitory activity against CA IX with an IC(50) value of 0.48 nM and about 1500-fold selectivity over CA II. The structure–activity relationship and CA IX selectivity of the new sulfonamide derivatives were also analyzed by molecular docking.

The inhibition of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) potentially represents a new treatment option for malaria, as P. falciparum relies entirely on a de novo pyrimidine biosynthetic pathway for survival. Herein, we report a series of pyrimidone derivatives as novel inhibitors of PfDHODH. The most potent compound, 26, showed high inhibition activity against PfDHODH (IC50 = 23 nM), with >400-fold species selectivity over human dihydroorotate dehydrogenase (hDHODH). The brand-new inhibitor scaffold targeting PfDHODH reported in this work may lead to the discovery of new antimalarial agents.

Farnesoid X receptor (FXR) is a member of nuclear receptor family involved in multiple physiological processes through regulating specific target genes. The critical role of FXR as a transcriptional regulator makes it a promising target for diverse diseases, especially those related to metabolic disorders such as diabetes and cholestasis. However, the underlying activation mechanism of FXR is still a blur owing to the absence of proper FXR modulators. To identify potential FXR modulators, an in-house natural product database (NPD) containing over 4,000 compounds was screened by structure-based virtual screening strategy and subsequent hit-based similarity searching method. After the yeast two-hybrid (Y2H) assay, six natural products were identified as FXR antagonists which blocked the CDCA-induced SRC-1 association. The IC50 values of compounds 2a, a diterpene bearing polycyclic skeleton, and 3a, named daphneone with chain scaffold, are as low as 1.29 and 1.79 μM, respectively. Compared to the control compound guggulsterone (IC50 = 6.47 μM), compounds 2a and 3a displayed 5- and 3-fold higher antagonistic activities against FXR, respectively. Remarkably, the two representative compounds shared low topological similarities with other reported FXR antagonists. According to the putative binding poses, the molecular basis of these antagonists against FXR was also elucidated in this report.

Four new dolabellane-type diterpene alkaloids, glandulamines A – D (1 – 4), together with twelve known compounds (5 – 16), were isolated from the seeds of Nigella glandulifera using repeated column chromatography and semipreparative HPLC. The structures of 1 – 16 were elucidated based on NMR data analysis, HRMS experiments and other spectroscopic interpretations. The absolute configuration of 5 was determined by single-crystal X-ray diffraction data for the first time. Compounds 10 and 12 showed human dihydroorotate dehydrogenase inhibitory activity with IC50 values of 61.1 ± 5.3 and 45.9 ± 3.0 µM, respectively. Molecular docking of the active compound 12 and positive control teriflunomide on the inhibitor-binding site of human dihydroorotate dehydrogenase was subsequently performed to visualize the interaction pattern. In addition, compounds 8 and 10 exhibited inhibitory effects against lipopolysaccharide-induced nitric oxide production with inhibition rates of 61 and 41%, respectively, at the concentration of 10 µM. Compounds 9 and 12 showed cytotoxic activities with cell viability varying from 29 ~ 57% at 100 µM against T98G, U87, U251, and GL261 glioma cancer cell lines. These data provide new insights on the pharmacologically active compounds of this plant widely used in folk medicine.

Oxidative stress and neuroinflammation are highly relevant to the pathological processes of various neurodegenerative diseases including Alzheimer's disease (AD). (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate (HOEC), a novel 5-lipoxygenase inhibitor, was isolated from the whole plant of Incarvillea mairei var granditlora (Wehrhahn) Grierson. In this study, we investigated the protective effect of HOEC on hydrogen peroxide (H2O2) and lipopolysaccharide (LPS) -induced cytotoxicity and neuroinflammation in vitro and in vivo. MTT assay, LDH release assay, morphological observation and Hoechst 33342/PI dual staining followed by EIA, immunofluorescence staining and Western Blotting analysis were performed to elucidate the neuroprotective effect of HOEC. Treatment with HOEC at various concentrations prior to H2O2 exposure significantly enhanced cell viability, decreased LDH release, prevented cell morphologic changes and apoptosis. Instead of PGE2 reduction, HOEC markedly inhibited the production of LTB4 and suppressed the macrophage-mediated neurotoxicity. Western blotting and immunofluorescence staining showed that HOEC inhibited H2O2-induced p38 phosphorylation and NF-κB activation. Neuroprotective effect of HOEC was abolished by a p38 inhibitor. Further in vivo studies of LPS-induced neuroinflammation confirmed the anti-inflammatory effects of HOEC. These findings that HOEC protects SH-SY5Y cells from H2O2 and LPS-induced injury via arachidonic acid network modulation followed by p38 MAPK and NF-κB signaling, might make HOEC be considered as a therapeutic candidate for prevention and treatment of neurodegenerative diseases involving oxidative stress or/and inflammation.

The flower-like MoS2/BiVO4 composite with heterojunction has been successfully fabricated by a two-step approach. A possible formation mechanism of this heterostructure was investigated. The calculated valence band offset (VBO) and conduction band offset (CBO) of MoS2/BiVO4 heterojunction showed that the VBO and CBO of MoS2/BiVO4 are 1.4 and 0.3 eV, respectively, implying the formation of well-defined staggered type II band alignment. The photodegradation of methylene blue (MB) was adopted to assess the photocatalytic ability of the pristine MoS2 and BiVO4 as well as MoS2/BiVO4 composites. It exhibited that the MoS2/BiVO4 composite structures performed much better than that of the pristine MoS2 and BiVO4, which was due to the staggered band alignment formed between the two structures. Besides, the corresponding mechanism of enhanced photocatalysis regarding the separation of the photogenerated electron–hole pairs for the heterojunction has also been investigated by the first-principles calculation.

The amine-catalyzed inverse electron demand Diels-Alder reaction of unsymmetrical tetrazines with aldehydes and ketones was investigated. We found that only one regioisomer could be observed when pyrrolidine was applied as the catalyst. Using this reaction, fluorogenic dyes could be developed with a tetrazine unit as the “triggering group”.

Two types of molybdenum disulfide (MoS2) titania nanoheterojunctions with different morphologies were synthesized via two different approaches. They were facile and additive-free hydrothermal processes, which resulted in a high material productivity and controllable morphologies. Both the synthesis and their growth mechanisms are discussed in this paper. The field emission properties of MoS2 titania nanoheterojunctions were investigated in this research. The experimental data indicated that the MoS2@TiO2 heterojunctions had an excellent field emission performance with a turn-on field of 2.2 V μm(-1) and threshold field of 3.6 V μm(-1) on Si substrate because of the large quantities of sharp edges. Furthermore, because the p-n heterojunctions were formed, the photocatalytic activities of both composites were evaluated by monitoring the photodegradation of methylene blue. The results showed that the TiO2@MoS2 heterojunctions had better photocatalytic properties with 90% degradation within 100 minutes. The morphological differences generated from different synthetic approaches made a huge impact on the composites' properties.

A novel β-D-2′-deoxy-2′-α-fluoro-2′-β- C -(fluoromethyl)uridine phosphoramidate prodrug ( 1 ) has been synthesized. This compound exhibits submicromolar-level antiviral activity in vitro against HCV genotypes 1b, 1a, 2a, and S282T replicons (EC 50 = 0.18–1.13 μM) with low cytotoxicity (CC 50 > 1000 μM). Administered orally, prodrug 1 is well tolerated at doses of up to 4 g/kg in mice, and produces a high level of the corresponding triphosphate in rat liver.

For decades, skin cancer incidence has increased, mainly because of oncogenic signaling pathways activated by solar ultraviolet (UV) irradiation (i.e., sun exposure). Solar UV induces multiple signaling pathways that are critical in the development of skin cancer, and therefore the development of compounds capable of targeting multiple molecules for chemoprevention of skin carcinogenesis is urgently needed. Herein, we examined the chemopreventive effects and the molecular mechanism of (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate (HOEC), isolated from Incarvillea mairei var. grandiflora (Wehrhahn) Grierson. HOEC strongly inhibited neoplastic transformation of JB6 Cl41 cells without toxicity. PI3K, ERK1/2, and p38 kinase activities were suppressed by direct binding with HOEC in vitro. Our in silico docking data showed that HOEC binds at the ATP-binding site of each kinase. The inhibition of solar UV-induced PI3K, ERK1/2, and p38 kinase activities resulted in suppression of their downstream signaling pathways and AP1 and NF-κB transactivation in JB6 cells. Furthermore, topical application of HOEC reduced skin cancer incidence and tumor volume in SKH-1 hairless mice chronically exposed to solar UV. In summary, our results show that HOEC exerts inhibitory effects on multiple kinase targets and their downstream pathways activated by solar UV in vitro and in vivo. These findings suggest that HOEC is a potent chemopreventive compound against skin carcinogenesis caused by solar UV exposure. Cancer Prev Res; 7(8); 856–65. ©2014 AACR.

Human dihydroorotate dehydrogenase (hDHODH), one of the attractive targets for the development of immunosuppressive drugs, is also a potential target of anticancer drugs and anti-leukemic drugs. The development of promising hDHODH inhibitors is in high demand. Based on the unique binding mode of our previous reported 4-thiazolidinone derivatives, via molecular docking method, three new series 4-thiazolidinone derivatives were designed and synthesized as hDHODH inhibitors. The preliminary structure&ndash, activity relationship was investigated. Compound 9 of biphenyl series and compound 37 of amide series displayed IC50 values of 1.32 &mu, M and 1.45 &mu, M, respectively. This research will provide valuable reference for the research of new structures of hDHODH inhibitors.

In this work, we presented a naphthalimide–rhodamine based fluorescence resonance energy transfer system (FRET) NR1 as a ratiometric and intracellular pH probe, in which 1,2,3-triazole was identified as an ideal bridge and biocompatibility. It could selectively monitor pH variations in methanol/HEPES solution at room temperature. When the pH changed from 6.20 to 2.00, both the fluorescence intensities at 580 nm and the intensity ratios, R ( I 580 nm / I 538 nm ) increased, which allowed the detection of pH changes by both normal fluorescence and ratiometric fluorescence methods. The observation is consistent with the increased FRET from the 1,8-naphthalimide (donor) to the ring-opened, colored form of rhodamine (acceptor). Moreover, as NR1 is lysosomal with low cytotoxicity, it will be helpful for investigating the pivotal role of H + in a biological context, especially in lysosomes through direct intracellular imaging.