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In nature, cyclopropylcarbinyl cation is often involved in cationic cascade reactions catalyzed by natural enzymes to produce a great number of structurally diverse natural substances. However, mimicking this natural process with artificial organic catalysts remains a daunting challenge in synthetic chemistry. We report a small molecule–catalyzed asymmetric rearrangement of cyclopropylcarbinyl cations, leading to a series of chiral homoallylic sulfide products with good to excellent yields and enantioselectivities (up to 99% enantiomeric excess). In the presence of a chiral SPINOL-derived N -triflyl phosphoramide catalyst, the dehydration of prochiral cyclopropylcarbinols occurs rapidly to generate symmetrical cyclopropylcarbinyl cations, which are subsequently trapped by thione-containing nucleophiles. A subgram-scale experiment and multiple downstream transformations of the sulfide products are further pursued to demonstrate the synthetic utility. Notably, a few heteroaromatic sulfone derivatives could serve as “covalent warhead” in the enzymatic inhibition of severe acute respiratory syndrome coronavirus 2 main protease.

STAT3 is a critical transcription factor that transmits signals from the cell surface to the nucleus, thus influencing the transcriptional regulation of some oncogenes. The inhibition of the activation of STAT3 is considered a promising strategy for cancer therapy. Numerous STAT3 inhibitors bearing different scaffolds have been reported to date, with a few of them having been considered in clinical trials.This review summarizes the advances on STAT3 inhibitors with different structural skeletons, focusing on the structure-activity relationships in the related patent literature published from 2014 to date.Since the X-ray crystal structure of STAT3β homo dimer bound to DNA was solved in 1998, the development of STAT3 inhibitors has gone through a boom in recent years. However, none of them have been approved for marketing, probably due to the complex biological functions of the STAT3 signaling pathway, including its character and the poor drug-like physicochemical properties of its inhibitors. Nonetheless, targeting STAT3 continues to be an exciting field for the development of anti-tumor agents along with the emergence of new STAT3 inhibitors with unique mechanisms of action.

Bruton's tyrosine kinase (BTK) inhibitors suppressing the aberrant activation of BTK have led to a paradigm shift in the therapy of B-cell malignancies. However, there is an urgent need to discover more selective covalent BTK inhibitors owing to the off-target adverse effects of the approved inhibitor, ibrutinib. Herein, we disclose the discovery and preliminary activity studies of novel BTK inhibitors carrying 1-amino-1H-imidazole-5-carboxamide as a hinge binder. The most potent BTK inhibitor 26 demonstrates impressive selectivity, favorable pharmacokinetic properties, and robust antitumor efficacy in vivo, which indicates its potential as a novel therapeutic option for B-cell lymphomas. Importantly, to the best of our knowledge, this is the first example of a 1-amino-1H-imidazole-5-carboxamide scaffold used as the hinge binder of kinase inhibitors, which will largely expand the chemical diversity of kinase inhibitors.

Rosiglitazone has been reported to exert dual effects on liver steatosis, and it could exacerbate liver steatosis in obese animal models, which was suggested to be closely related to the elevated hepatic expression of FABP4. This study aimed to investigate whether combined treatment with FABP4 inhibitor I-9 could alleviate rosiglitazone-induced liver steatosis in obese diabetic db/db mice. Male C57BL/KsJ-db/db mice were orally treated with rosiglitazone, rosiglitazone combined with I-9 daily for 8 weeks. The liver steatosis was evaluated by triglyceride content and H&E staining. The expression of hepatic lipogenic genes or proteins in liver tissue or in FFA-treated hepatocytes and PMA-stimulated macrophages were determined by real-time quantitative polymerase chain reaction (RT-qPCR) or western blotting. Results showed that combined treatment with I-9 decreased rosiglitazone-induced increase in serum FABP4 level and expression of lipogenic genes in liver, especially FABP4, and ameliorated liver steatosis in db/db mice. Rosiglitazone-induced intracellular TG accumulation and increased expression of FABP4 in the cultured hepatocytes and macrophages were also suppressed by combined treatment. We concluded that combined treatment with FABP4 inhibitor I-9 could ameliorate rosiglitazone-exacerbated elevated serum FABP4 level and ectopic liver fat accumulation in obese diabetic db/db mice without affecting its anti-diabetic efficacy.

A diastereo- and enantioselective rhodium(III)-catalyzed reductive cyclization of cyclohexadienone-tethered terminal alkenes and (E)-1,2-disubstituted alkenes (1,6-dienes) is reported, providing cis-bicyclic products bearing three contiguous stereocenters with good yields and high diastereo- and enantioselectivities. The kinetic resolution of the racemic precursor is also achieved with good efficiency. Moreover, a subgram-scale experiment, several transformations of the cyclization product, and one-pot preparation of bridged polycyclic frameworks are presented.

Among about 150 identified allenic natural products, the exocyclic allenes constitute a major subclass. Substantial efforts are devoted to the construction of axially chiral allenes, however, the strategies to prepare chiral exocyclic allenes are still rare. Herein, we show an efficient strategy for the asymmetric synthesis of chiral exocyclic allenes with the simultaneous control of axial and central chirality through copper(I)-catalyzed asymmetric intramolecular reductive coupling of 1,3-enynes to cyclohexadienones. This tandem reaction exhibits good functional group compatibility and the corresponding optically pure exocyclic allenes bearing cis-hydrobenzofuran, cis-hydroindole, and cis-hydroindene frameworks, are obtained with high yields (up to 99% yield), excellent diastereoselectivities (generally >20:1 dr) and enantioselectivities (mostly >99% ee). Furthermore, a gram-scale experiment and several synthetic transformations of the chiral exocyclic allenes are also presented., Substantial efforts have been devoted to the construction of axially chiral allenes, however, the strategies to prepare chiral exocyclic allenes are still rare. This work describes a copper-catalyzed asymmetric synthesis of exocyclic allenes by simultaneous control of axial and central chirality.

Introduction Traditional chemotherapy for ovarian cancer is limited due to drug resistance and systemic side effects. Although various targeted drug delivery strategies have been designed to enhance drug accumulation at the tumor site, simply improvement of targeting capability has not consistently led to satisfactory outcomes. Herein, AMD3100 was selected as the targeting ligand because of its high affinity to chemokine receptor 4 (CXCR4), which was highly expressed on ovarian cancer cells. Moreover, the AMD3100 has been proved having blockage capability of stromal cell-derived factor 1 (SDF-1 or CXCL12)/CXCR4 axis and to be a sensitizer of chemotherapeutic therapy. We designed a dual-functional targeting delivery system by modifying paclitaxel (PTX)-loaded PEGylation bovine serum albumin (BSA) nanoparticles (NPs) with AMD3100 (AMD-NP-PTX), which can not only achieve specific tumor-targeting efficiency but also enhance the therapeutic outcomes. Methods AMD3100 was chemically modified to Mal-PEG-NHS followed by reacting with BSA, then AMD-NP-PTX was synthesized and characterized. The targeting efficiency of AMD-NP was evaluated both in vitro and in vivo. The anticancer effect of AMD-NP-PTX was determined on Caov3 cells and ovarian cancer-bearing nude mice. Finally, the potential therapeutic mechanism was studied. Results AMD-NP-PTX was synthesized successfully and well characterized. Cellular uptake assay and in vivo imaging experiments demonstrated that NPs could be internalized by Caov3 cells more efficiently after modification of AMD3100. Furthermore, the AMD-NP-PTX exhibited significantly enhanced inhibition effect on tumor growth and metastasis compared with PTX, NP-PTX and free AMD3100 plus NP-PTX both in vitro and in vivo, and demonstrated improved safety profile. We also confirmed that AMD-NP-PTX worked through targeting CXCL12/CXCR4 axis, thereby disturbing its downstream signaling pathways including epithelial-mesenchymal transition (EMT) processes and nuclear factor κB (NF-κB) pathway. Conclusion The AMD-NP-PTX we designed would open a new avenue for dual-functional NPs in ovarian cancer therapy.

A highly enantioselective [3+2] annulation of isatin-derived Morita-Baylis-Hillman (MBH) carbonates and 3-nitroindoles was enabled by a chiral DMAP-thiourea bifunctional catalyst, affording the corresponding polycyclic spirooxindoles bearing three consecutive stereocenters with good to excellent yields and enantioselectivities. Transformations of the annulation product were subsequently elaborated and the preliminary biological assays demonstrated that these artificial spirooxindoles potentially inhibited pancreatic lipase in a dose-dependent manner.

Phosphoglycerate dehydrogenase (PHGDH) is abnormally expressed in numerous malignant tumor cells and catalyzes the first step of serine biosynthesis, thus becoming a key drug target for antitumor treatment. In this study, compound B2 bearing a benzene-1,3-diamine scaffold was identified by structure-based virtual screening as a novel PHGDH inhibitor with moderate enzymatic activity. The structure-activity relationship study led to the discovery of compound C25 possessing improved enzymatic inhibitory activity and potent inhibitory activity on the proliferation of cells overexpressing PHGDH. The enzyme kinetic assay confirmed that C25 inhibited PHGDH in a nicotinamide adenine dinucleotide (NAD

Bruton's tyrosine kinase (BTK) inhibitors suppressing the aberrant activation of BTK have led to a paradigm shift in the therapy of B-cell malignancies. However, there is an urgent need to discover more selective covalent BTK inhibitors owing to the off-target adverse effects of the approved inhibitor, ibrutinib. Herein, we disclose the discovery and preliminary activity studies of novel BTK inhibitors carrying 1-amino-1

Emerging evidence suggests that cancer metabolism is closely associated to the serine biosynthesis pathway (SSP), in which glycolytic intermediate 3-phosphoglycerate is converted to serine through a three-step enzymatic transformation. As the rate-limiting enzyme in the first step of SSP, phosphoglycerate dehydrogenase (PHGDH) is overexpressed in various diseases, especially in cancer. Genetic knockdown or silencing of PHGDH exhibits obvious anti-tumor response both in vitro and in vivo, demonstrating that PHGDH is a promising drug target for cancer therapy. So far, several types of PHGDH inhibitors have been identified as a significant and newly emerging option for anticancer treatment. Herein, this comprehensive review summarizes the recent achievements of PHGDH, especially its critical role in cancer and the development of PHGDH inhibitors in drug discovery.

Summary Bridged and fused polycyclic structures are found in a huge number of natural products. Significant progress has been made on their syntheses; however, facile and practical strategies to afford polycycles with tunable substituents and functional groups remain rare. Here, we report a practical rhodium(III)-catalyzed asymmetric borylative cyclization of cyclohexadienone-containing 1,6-enynes, affording highly enantioenriched cis-bicyclic frameworks with great functional group compatibility, and further extend it to construct bridged tricyclic and fused tetracyclic skeletons in one-pot protocols. The combination of borylative cyclization with a subsequent oxidation/aldol reaction sequence goes through an epimerization of the stereocenter adjacent to the acetyl group, yielding various tricyclic compounds. In addition, borylative cyclization is combined with a Suzuki-Miyaura coupling/Michael addition sequence, leading to diverse tetracyclic compounds. Starting from simple starting materials, both one-pot transformations yield complex products bearing several consecutive stereocenters with excellent enantioselectivities. Furthermore, an unnatural steroid-like compound is also readily prepared, demonstrating the potential of this methodology.

An efficient one-pot synthesis of multisubstituted 9,10-dihydrophenanthrenes from easily available 2-arylazaarenes and cyclohexadienone-tethered terminal alkynes (1,6-enynes) has been successfully achieved. This domino reaction proceeded smoothly through Cp*Rh(III)-catalyzed C-H activation, direct protonation of alkenyl-Rh intermediates, intramolecular Diels-Alder reaction, alkene isomerization, subsequent ring-opening aromatization, and acetylation. This strategy was pot-economical and tolerated a wide range of functional groups. Moreover, the potent anticancer activities against HepG2 cells were observed for these artificial 9,10-dihydrophenanthrene derivatives.

The rhodium(III)-catalyzed kinetic resolution of racemic nonactivated terminal alkene-tethered cyclohexadienones (1,6-dienes) has been developed with high to excellent selectivities (s up to 458) via asymmetric borylative cyclization, providing recovered cyclohexadienones and cis-hydrobenzofuranones with good to excellent yields and enantioselectivities (up to 99% ee). This reaction shows broad functional group tolerance and allows the further conversions of these two-type products to many optically active derivatives bearing multiple functionalities via Rh, Cu, Pd, and Ag catalysis.

The epidemic coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now spread worldwide and efficacious therapeutics are urgently needed. 3-Chymotrypsin-like cysteine protease (3CLpro) is an indispensable protein in viral replication and represents an attractive drug target for fighting COVID-19. Herein, we report the discovery of 9,10-dihydrophenanthrene derivatives as non-peptidomimetic and non-covalent inhibitors of the SARS-CoV-2 3CLpro. The structure-activity relationships of 9,10-dihydrophenanthrenes as SARS-CoV-2 3CLpro inhibitors have carefully been investigated and discussed in this study. Among all tested 9,10-dihydrophenanthrene derivatives, C1 and C2 display the most potent SARS-CoV-2 3CLpro inhibition activity, with IC50 values of 1.55 ± 0.21 μM and 1.81 ± 0.17 μM, respectively. Further enzyme kinetics assays show that these two compounds dose-dependently inhibit SARS-CoV-2 3CLprovia a mixed-inhibition manner. Molecular docking simulations reveal the binding modes of C1 in the dimer interface and substrate-binding pocket of the target. In addition, C1 shows outstanding metabolic stability in the gastrointestinal tract, human plasma, and human liver microsome, suggesting that this agent has the potential to be developed as an orally administrated SARS-CoV-2 3CLpro inhibitor., Graphical abstract Image 1

Taxoids are a class of successful drugs and have been successfully used in chemotherapy for a variety of cancer types. However, despite the hope and promises that these taxoids have engendered, their utility is hampered by some clinic limitations. Extensive structure-activity relationship (SAR) studies of toxoids have been performed in many different laboratories. Whereas, SAR studies that based on the new-generation toxoid, larotaxel, have not been reported yet. In view of the advantages in preclinical and clinical data of larotaxel over former toxoids, new taxoids that strategicly modified at the C3'/C3'-N and C2 positions of larotaxel were designed, semi-synthesized, and examined for their potency and efficacy in vitro. As a result, it has been shown that the majority of these larotaxel analogues are exceptionally potent against both drug-sensitive tumor cells and tumor cells with drug resistance arising from P-glycoprotein over expression. Further in vivo antitumor efficacies investigations revealed A2 might be a potent antitumor drug candidate for further preclinical evaluation.

Fatty acid binding protein 4 (FABP4) plays a critical role in metabolism and inflammatory processes and therefore is a potential therapeutic target for immunometabolic diseases such as diabetes and atherosclerosis. Herein, we reported the identification of naphthalene-1-sulfonamide derivatives as novel, potent and selective FABP4 inhibitors by applying a structure-based design strategy. The binding affinities of compounds 16dk, 16do and 16du to FABP4, at the molecular level, are equivalent to or even better than that of BMS309403. The X-ray crystallography complemented by the isothermal titration calorimetry studies revealed the binding mode of this series of inhibitors and the pivotal network of ordered water molecules in the binding pocket of FABP4. Moreover, compounds 16dk and 16do showed good metabolic stabilities in liver microsomes. Further extensive in vivo study demonstrated that 16dk and 16do exhibited a dramatic improvement in glucose and lipid metabolism, by decreasing fasting blood glucose and serum lipid levels, enhancing insulin sensitivity, and ameliorating hepatic steatosis in obese diabetic (db/db) mice.

Polyvinyl acetate (PVA) adhesive is one of the most common types of adhesives has been used in the wood industry for decades. However, many drawbacks are still associated with this adhesive includi...

Fibroblast growth factor receptor (FGFR) is a potential target for cancer therapy because of its critical role in promoting cancer formation and progression. In a continuing effort to improve the cellular activity of hit compound 7r bearing an indazole scaffold, which was previously discovered by our group, several compounds harnessing fluorine substituents were designed, synthesized and biological evaluated. Besides, the region extended out to the ATP binding pocket toward solvent was also explored. Among them, compound 2a containing 2,6-difluoro-3-methoxyphenyl residue exhibited the most potent activities (FGFR1: less than 4.1nM, FGFR2: 2.0±0.8nM). More importantly, compound 2a showed an improved antiproliferative effect against KG1 cell lines and SNU16 cell lines with IC50 values of 25.3±4.6nM and 77.4±6.2nM respectively.

Indoleamine 2,3-dioxygenase 1 (IDO1) plays a vital role in the catabolism of tryptophan along with the kynurenine pathway which is involved in many human diseases including cancer, Alzheimer's disease, etc. In this study, compound 1 bearing a 1-Indanone scaffold was identified as a novel IDO1 inhibitor by structure-based virtual screening, with moderate to good enzymatic and cellular inhibitory activities. Also, surface plasmon resonance analysis validated the direct interaction between compound 1 and IDO1 protein. The preliminary SAR was further explored and the binding mode with IDO1 protein was predicted by experiment along with molecular docking. Subsequent ADME properties of these active compounds were analyzed in silico, and the results showed good pharmacokinetic efficiencies. We believe this study contributes a lot to the structural diversity for the future development of highly potent IDO1 inhibitors.

This study focused on measuring the concentration of formaldehyde in furniture markets, malls, hotels, and restaurants in Guilin, Liuzhou, and Nanning in Guangxi China. Correlations between the indoor formaldehyde concentration and temperature, humidity, and air change rate were also obtained. The sixty sampled public places selected for this study represented the typical public indoor environment in Guangxi. The over standard rates of formaldehyde concentrations (0.1 mg m–3) measured in furniture markets, malls, and hotels were 94%, 87%, and 20%, respectively. The highest formaldehyde concentrations measured in furniture markets, malls, hotels and restaurants were 0.313 mg m–3, 0.231 mg m–3, 0.111 mg m–3, and 0.082 mg m–3. The overall mean formaldehyde concentrations in these four venues were found to be present in this descending order; furniture market (0.193 mg m–3) > mall (0.147 mg m–3) > hotel (0.079 mg m–3) > restaurant (0.058 mg m–3). This work showed that wood-related decorations and merchandises that contain high levels of formaldehyde, were the major sources of formaldehyde pollution in the indoor environment. Further analysis demonstrated that strong correlations (r > 0.80, p < 0.01) existed between the indoor formaldehyde concentration and temperature, humidity, and air change rate, which indicated that these indoor environmental factors appeared to be other key reasons for the high levels of indoor formaldehyde pollution. The results showed that a decrease in temperature and humidity, or an increase in air change rate in an indoor environment can effectively alleviate the level of indoor formaldehyde pollution. The findings of this study can further promote the development of measures to control indoor air pollution.

Based on the unique role of a common unit in a family of sulfur-containing natural histone deacetylases (HDACs) inhibitors, we have chosen largazole as an example of these inhibitors and adopted a "fluorine scan" strategy towards modification of this common unit. Thus a set of fluoro largazole analogues has been designed, synthesized and evaluated in enzymatic as well as cellular assays. The preliminary results indicate that introduction of fluorine at the various position of the unit has an important impact on the activity and selectivity of HDACs. Unlike other modifications which often led to significant reduction or complete loss of activity as reported in the literature, most of these fluoro thiols have displayed comparable or enhanced activity and selectivity in enzymatic assays. Two of the sulfhydryl esters have also exhibited excellent inhibitory activity in cellular assays with a few selected cell lines. The C19-fluorinated analogue has been further studied by immunoblot analysis, confirming that it is a potent selective class I HDAC inhibitor and supporting that the potent cellular antiproliferative activity is due to HDAC inhibition. The molecular docking study reveals that introducing fluorine at the C19 position does not change the original interactions, but might have made a subtle change in binding conformation, resulting in an obvious improvement in activity.

Although asymmetric phosphine catalysis is a powerful tool for the construction of various chiral carbon centers, its synthetic potential toward an enantioenriched atropisomer has not been explored yet. Reported herein is a phosphine-catalyzed atroposelective (4+2) annulation of δ-acetoxy allenoates and 2-hydroxyquinone derivatives. The reaction provides expedient access to aryl-naphthaquinone atropisomers by the de novo construction of a benzene ring. The two functionalities of the catalyst, a tertiary phosphine (Lewis base) and a tertiary amine (Bronsted base), cooperatively enable this process with high regio- and enantioselectivities.

Fatty acid binding protein 4 (FABP4) has been demonstrated to be secreted from adipocytes in an unconventional pathway associated with lipolysis. Circulating FABP4 is elevated in metabolic disorders and has been shown to affect various peripheral cells such as pancreatic β-cells, hepatocytes and macrophages, but its effects on adipocytes remains unclear. The aim of this study was to investigate the effects of exogenous FABP4 (eFABP4) on adipocyte differentiation and function. 3T3-L1 pre-adipocytes or mature adipocytes were treated with recombinant FABP4 in the absence or presence of FABP4 inhibitor I-9/p38 MAPK inhibitor SB203580; Meanwhile male C57BL/6J mice were subcutaneously injected twice a day with recombinant FABP4 (0.35 mg/kg) with or without I-9 (50 mg/kg) for 2 weeks. The effects of eFABP4 on differentiation, lipolysis and inflammation were determined by triglyceride measurement or lipolysis assay, western blotting, or RT-qPCR analysis. eFABP4 treatment significantly reduced intracellular triglyceride content and decreased expression of adipogenic markers peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer binding protein alpha (C/EBPα), intracellular FABP4, and adiponectin in 3T3-L1 cells. Besides, eFABP4 promoted lipolysis and inflammation in differentiated 3T3-L1 adipocytes as well as in adipose tissue of eFABP4-treated C57BL/6J mice, with elevated gene expression of monocyte chemoattractant protein (MCP)-1, tumor necrosis factor (TNF)-α, and elevated protein expression of adipose triglyceride lipase (ATGL), phosphorylation of hormone-sensitive lipase (HSL) (Ser-660), p38, and nuclear factor-kappa B (NF-κB). The pro-inflammatory and pro-lipolytic effects of eFABP4 could be reversed by SB203580/I-9. These findings indicate that eFABP4 interferes with adipocyte differentiation, induces p38/HSL mediated lipolysis and p38/NF-κB mediated inflammation in adipocytes in vitro and in vivo.

The cumulative evidence supports STAT3, a transcriptional mediator of oncogenic signaling, as a therapeutic target in cancer. The development of STAT3 inhibitors remain an active area of research as no inhibitors have yet to be approved for cancer treatment. In a continuing effort to develop more potent STAT3 inhibitors based on our previously identified hit compound 16w, a series of benzothiazole derivatives with unique binding mode in SH2 domain of STAT3 were designed, synthesized and biologically evaluated. Of note, compound B19 demonstrated excellent activity against IL-6/STAT3 signaling pathway with the IC50 value as low as 0.067 μM as determined by a luciferase reporter assay. Moreover, multiple compounds displayed potent antiproliferative activity against MDA-MB-468 and JAK2 mutant HEL cell lines. Further biochemical study using Western blot assay indicated that B19 blocked the phosphorylation of STAT3 at Tyr 705 and Ser 727 and thus suppressed STAT3-mediated gene expression of c-MYC and MCL-1. Simultaneously, it induced cancer cell G2/M phase arrest and apoptosis both in MDA-MB-468 and HEL cell lines. Finally, molecular docking study along with surface plasmon resonance (SPR) and fluorescence polarization (FP) assays disclosed the binding mode of B19 in STAT3 SH2 domain. Taken together, our finding suggests that B19 is a promising therapeutic STAT3 inhibitor for cancer treatment.

The high antibacterial and photocatalytic activities of Cu2O/ZnO composite films were synthesized through the electrodeposition method. The crystalline phase and microstructure of the film samples were analyzed based on X-ray diffraction and scanning electron microscopy. The Cu2O/ZnO composite film-50 min has uniform and compact film structure with a large surface area. Compared with neat Cu2O film, the spectral response range of Cu2O/ZnO composite film was clearly enlarged to 265–560 nm, indicating that it had stronger spectral response ability in both UV and visible light. Among all the photocatalytic film samples, the Cu2O/ZnO composite film-50 min showed a better antibacterial activity against Escherichia coli (90.23 %) and Staphylococcus aureus (88.78 %) under fluorescent light. In addition, the Cu2O/ZnO composite film-50 min also exhibited the optimal photocatalytic property for the degradation of formaldehyde (80.33 %) under LED light irradiation. Moreover, the high photocatalytic and antibacterial stability in the cycle experiment indicate that Cu2O/ZnO composite film-50 min could be an excellent semiconductor photocatalytic material with high usability in practical applications.

STAT3 signaling pathway has been validated as a vital therapeutic target for cancer therapy. Based on the novel STAT3 inhibitor of a benzyloxyphenyl-methylaminophenol scaffold hit (1) discovered through virtual screening, a series of analogues had been designed and synthesized for more potent inhibitors. The preliminary SAR had been discussed and the unique binding site in SH2 domain was predicted by molecular docking. Among them, compounds 4a and 4b exhibited superior activities than hit compound (1) against IL-6/STAT3 signaling pathway with IC50 values as low as 7.71μM and 1.38μM, respectively. Compound 4a also displayed potent antiproliferative activity against MDA-MB-468 cell line with an IC50 value of 9.61μM. We believe that these benzyloxyphenyl-methylaminophenol derivatives represent a unique mechanism for interrogating STAT3 as well as a potential structure type for further exploration.

To overcome the drug-resistance of first generation EGFR inhibitors and the nonselective toxicities of second generation inhibitors among NSCLC patients, a series of 5-(methylthio)pyrimidine derivatives were discovered as novel EGFR inhibitors, which harbored not only potent enzymatic and antiproliferative activities against EGFRL858R/T790M mutants, but good selectivity over wide-type form of the receptor. This goal was achieved by employing structure-based drug design and traditional optimization strategies, based on WZ4002 and CO1686. These derivatives inhibited the enzymatic activity of EGFRL858R/T790M mutants with IC50 values in subnanomolar ranges, while exhibiting hundreds of fold less potency on EGFRWT. These compounds also strongly inhibited the proliferation of H1975 non-small cell lung cancer cells bearing EGFRL858R/T790M, while being significantly less toxic to A431 human epithelial carcinoma cells with overexpressed EGFRWT. The EGFR kinase inhibitory and antiproliferative activities were further validated by Western blot analysis for activation of EGFR and the downstream signaling in cancer cells.

Signal transducer and activator of transcription 3 (STAT3) is identified as a promising target for multiple cancer therapy and attracts widespread concern. Herein, we reported the discovery of a series of 2-acetyl-7-phenylamino benzofuran derivatives as STAT3 inhibitors using scaffold fusion strategy. Further structure activity relationship study led to the discovery of compound C6, which displayed the most potent anti-proliferation activities against MDA-MB-468 cells (IC50 = 0.16 μM). Western blot assay demonstrated that C6 inhibited the activation of STAT3 (Tyr705) without influencing the phosphorylation of STAT1 (Tyr701). Further mechanistic studies indicated that C6 caused a notable G2/M cycle-arresting and early apoptosis in a concentration-dependent manner in MDA-MB-468 cells. Finally, molecular modelling study elucidated the binding mode of C6 in STAT3 SH2 domain.

Persistently activated signal transducer and activator of transcription 3 (STAT3) plays an important role in the development of multiple cancers, and therefore is a potential therapeutic target for cancer prevention. Herein, we report the rational design, synthesis, and biological evaluation of novel potent STAT3 inhibitors based on BBI608. Among them, compound A11 exhibited the most potent in vitro tumor cell growth inhibitory activities toward MDA-MB-231, MDA-MB-468 and HepG2 cells with IC50 values as low as 0.67 ± 0.02 μM, 0.77 ± 0.01 μM and 1.24 ± 0.16 μM, respectively. Fluorescence polarization (FP) assay validated the binding of compound A11 in STAT3 SH2 domain with the IC50 value of 5.18 μM. Further mechanistic studies indicated that A11 inhibited the activation of STAT3 (Y705), and thus reduced the expression of STAT3 downstream genes CyclinD1 and C-Myc. Simultaneously, it induced cancer cell S phase arrest and apoptosis in a concentration-dependent manner. An additional in vivo study revealed that A11 suppressed the MDA-MB-231 xenograft tumor growth in mice at the dose of 10 mg/kg (i.p.) without obvious body-weight loss. Finally, molecular docking study further elucidated the binding mode of A11 in STAT3 SH2 domain.

This study focused on measuring the pollution characteristics, the monthly and seasonal variation rule of formaldehyde in the teaching machine room of Guangxi Normal University from March 2016 to February 2018, and the correlation between formaldehyde concentration and temperature or humidity were also analyzed. The results indicated that seasonal and monthly variation rule of formaldehyde changed with temperature and humidity in the teaching machine room. The concentration of formaldehyde was higher in summer and autumn, while was lower in winter and spring. Further analysis indicated that there was a strongly positive correlation (R2>0.87, R2>0.85, R2>0.81, p3, 0.445mg/m3 and 0.184mg/m3, 0.213mg/m3 in July 2016, 2017, respectively. After eleven years, the formaldehyde in the teaching machine room was still seriously exceeded the standard (0.1mol/L), and decreased the temperature or humidity could effective alleviate the level of indoor formaldehyde concentration.

Fatty acid binding protein 4 (FABP4) is a potential drug target for diabetes and atherosclerosis. For discovering new chemical entities as FABP4 inhibitors, structure-based virtual screening (VS) was performed, bioassay demonstrated that 16 of 251 tested compounds are FABP4 inhibitors, among which compound m1 are more active than endogenous ligand linoleic acid (LA). Based on the structure of m1, new derivatives were designed and prepared, leading to the discovery of two more potent inhibitors, compounds 9 and 10. To further explore the binding mechanisms of these new inhibitors, we determined the X-ray structures of the complexes of FABP4-9 and FABP4-10, which revealed similar binding conformations of the two compounds. Residue Ser53 and Arg126 formed direct hydrogen bonding with the ligands. We also found that 10 could significantly reduce the levels of lipolysis on mouse 3T3-L1 adipocytes. Taken together, in silico, in vitro and crystallographic data provide useful hints for future development of novel inhibitors against FABP4.

Based on the unique role of a common unit in a family of sulfur-containing natural histone deacetylases (HDACs) inhibitors, we have chosen largazole as an example of these inhibitors and adopted a "fluorine scan" strategy towards modification of this common unit. Thus a set of fluoro largazole analogues has been designed, synthesized and evaluated in enzymatic as well as cellular assays. The preliminary results indicate that introduction of fluorine at the various position of the unit has an important impact on the activity and selectivity of HDACs. Unlike other modifications which often led to significant reduction or complete loss of activity as reported in the literature, most of these fluoro thiols have displayed comparable or enhanced activity and selectivity in enzymatic assays. Two of the sulfhydryl esters have also exhibited excellent inhibitory activity in cellular assays with a few selected cell lines. The C19-fluorinated analogue has been further studied by immunoblot analysis, confirming that it is a potent selective class I HDAC inhibitor and supporting that the potent cellular antiproliferative activity is due to HDAC inhibition. The molecular docking study reveals that introducing fluorine at the C19 position does not change the original interactions, but might have made a subtle change in binding conformation, resulting in an obvious improvement in activity.

Fatty acid binding protein 4 (FABP4) and fatty acid binding protein 5 (FABP5) are mainly expressed in adipocytes and/or macrophages and play essential roles in energy metabolism and inflammation. When FABP4 function is diminished, FABP5 expression is highly increased possibly as a functional compensation. Dual FABP4/5 inhibitors are expected to provide beneficial synergistic effect on treating diabetes, atherosclerosis, and inflammation-related diseases. Starting from our previously reported selective FABP4 inhibitor 8, structural biology information was used to modulate the selectivity profile and to design potent dual FABP4/5 inhibitors with good selectivity against FABP3. Two compounds A16 and B8 were identified to show inhibitory activities against both FABP4/5 and good selectivity over FABP3, which could also reduce the level of forskolin-stimulated lipolysis in mature 3T3-L1 adipocytes. Compared with compound 8, these two compounds exhibited better anti-inflammatory effects in lipopolysaccharide-stimulated RAW264.7 murine macrophages, with decreased levels of pro-inflammatory cytokines TNFα and MCP-1 and apparently inhibited IKK/NF-κB pathway.

In this study, the structures and thermal stability of pure urea-formaldehyde resin (PR) and modified urea-formaldehyde (UF) resin are investigated by differential thermal gravity (TG/DTG), and differential scanning calorimetry (DSC) supported by data from Fourier transform infrared spectroscopy. FTIR analysis indicate that the modifiers such as polydimethylsiloxane, dicyclohexylcarbodiimide and phenol have actively participated in the curing reactions. TG/DTG and DSC curve of UF resin show that its pyrolysis process is conducted in three steps: desiccation and dehydration, flash pyrolysis and slow decomposition. Compared with pure urea-formaldehyde resin (PR), modified UF resin exhibited good thermal stability. The activation energy (E) of modified UF resin acquired by Kissinger and Ozawa method was higher than that of PR. ΔH > 0, ΔS > 0 and ΔG > 0 in the thermal decomposition process of UF resin means that the decomposition reaction of UF resin before and after modification is a process of unnatural decalescence and entropy increase.