Multi-layered effects of Panax notoginseng on immune system.

Recent research has demonstrated the immunomodulatory potential of Panax notoginseng in the treatment of chronic inflammatory diseases and cerebral hemorrhage, suggesting its significance in clinical practice. Nevertheless, the complex immune activity of various components has hindered a comprehensive understanding of the immune-regulating properties of Panax notoginseng, impeding its broader utilization. This review evaluates the effect of Panax notoginseng to various types of white blood cells, elucidates the underlying mechanisms, and compares the immunomodulatory effects of different Panax notoginseng active fractions, aiming to provide the theory basis for future immunomodulatory investigation.

Synthesis and biological evaluation of pyrazole-fused oleanolic acid derivatives as novel inhibitors of inflammatory and osteoclast differentiation.

A series of pyrazole-fused oleanolic acid derivatives were designed and synthesized. The modification of these analogues focused on the substituents screening on the pyrazole ring. The cytotoxicity of these compounds and their anti-inflammatory activities via inhibiting interleukin-1ß (IL-1ß) production were evaluated in RAW264.7 cells. Most of the derivatives showed significantly improved potency compared with oleanolic acid. Among them, compound 7n exhibited the most potent anti-inflammatory activity on decreasing IL-1ß production with low cytotoxicity. Moreover, the further study found 7n could inhibit RANKL-induced osteoclast differentiation on bone marrow-derived macrophages (BMMs). These findings may provide a potential direction for the drug development of osteoarthritis.

Detection and Mitigation of SYN Flooding Attacks through SYN/ACK Packets and Black/White Lists.

Software-defined networking (SDN) is a new network architecture that provides programmable networks, more efficient network management, and centralized control than traditional networks. The TCP SYN flooding attack is one of the most aggressive network attacks that can seriously degrade network performance. This paper proposes detection and mitigation modules against SYN flooding attacks in SDN. We combine those modules, which have evolved from the cuckoo hashing method and innovative whitelist, to get better performance compared to current methods Our approach reduces the traffic through the switch and improves detection accuracy, also the required register size is reduced by half for the same accuracy.

Ru-Catalyzed Defluorinative Alkylation or Catalyst-Free Hydroalkylation of gem-Difluoroalkenes Enabled by Visible Light.

A catalyst-induced defluorinative, alkylation or metal-free hydroalkylation of gem-difluoroalkenes enabled by visible light was developed. This protocol provided a mild and practical approach to important and novel monofluoroalkenes and difluoromethylene-containing compounds with moderate to excellent yields.

Design, synthesis and evaluation of the Brigatinib analogues as potent inhibitors against tertiary EGFR mutants (EGFRdel19/T790M/C797S and EGFRL858R/T790M/C797S).

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated encouraging clinical outcomes for patients with EGFR-mutated non-small cell lung cancer, a considerable number of patients will develop drug resistance and eventually undergo disease progression after taking EGFR-TKIs for a period of time. EGFRdel19/T790M/C797S and EGFRL858R/T790M/C797S are two most prevalent tertiary EGFR mutants identified in Osimertinib-resistant tumors and currently there is no therapy approved clinically targeting these mutants. In this study, we designed and synthesized a series of novel 4th generation EGFR inhibitors based on scaffold of Brigatinib. After extensive SAR studies, compound 23, the most promising candidate, exhibited strong biochemical potencies against EGFRdel19/T790M/C797S, EGFRL858R/T790M/C797S and other clinically relevant EGFR mutants while sparing wild type EGFR. In cellular assays, compound 23 potently inhibited proliferation of BaF3EGFR del19/T790M/C797S and PC-9EGFR del19/T790M/C797S. Moreover, compound 23 demonstrated good DMPK profile in mouse PK study.

Photoredox-catalysed regioselective synthesis of C-4-alkylated pyridines with N-(acyloxy)phthalimides.

A method of direct C-4 selective alkylation of pyridines under visible light irradiation at room temperature has been reported, using simple maleate-derived pyridinium salts as pyridine precursors and the readily available carboxylic acid-derived N-(acyloxy)phthalimides as alkyl radical precursors, affording good to excellent yields without using stoichiometric oxidants and acids. A broad range of primary, secondary, and tertiary carboxylates can be used as alkylation reagents. Oxidant and acid-sensitive functional groups can be tolerated well.

Identification of 2-substituted pyrrolo[1,2-b]pyridazine derivatives as new PARP-1 inhibitors.

A library of new 2-substituted pyrrolo[1,2-b]pyridazine derivatives were rapidly assembled and identified as PARP inhibitors. Structure-activity relationship for this class of inhibitor resulted in the discovery of most potent compounds 15a and 15b that exhibited about 29- and 5- fold selective activity against PARP-1 over PARP-2 respectively. The antiproliferative activity of the as-prepared compounds were demonstrated by further celluar assay in BRCA2-deficient V-C8 and BRCA1-deficient MDA-MB-436 cell lines, displaying that compound 15b could robustly reduce the corresponding cell proliferation and growth with CC50s of 340 and 106 nM respectively. The PK property of 15b was also investigated here.

Synthesis of 2-alkyl-chroman-4-ones via cascade alkylation-dechlorination of 3-chlorochromones.

An efficient and mild synthetic approach for 2-alkyl-substituted chroman-4-ones via zinc-mediated cascade decarboxylative ß-alkylation and dechlorination of 3-chlorochromones was developed. This transformation employed commercially available starting materials and was performed under mild conditions without heat, visible light, peroxide or heavy metals. Moreover, various alkyl NHPI esters with functional groups and differently substituted 3-chlorochromones were tolerated, affording the targeted products with moderate to excellent yields. This protocol could be utilized to construct a diverse library of 2-substituted chroman-4-one derivatives, which could be useful in the discovery of lead compounds for drug discovery in the future.

Design, synthesis and antiproliferative activity evaluation of a series of pyrrolo[2,1-f][1,2,4]triazine derivatives.

A series of 6-aminocarbonyl pyrrolo[2,1-f][1,2,4]triazine derivatives were designed by scaffold hopping strategy. The IC50 values of compound 14a against PI3Ks were measured, showing selective activity against p110α and p110δ with IC50s of 122 nM and 119 nM respectively. All the synthesized compounds were evaluated for their antiproliferative activity against human cancer cells by SRB assay. Compounds 14a, 14p and 14q exhibited potent antiproliferative activity against five types of human cancer cells and the PK property of 14q was also investigated here.

Regioselective synthesis of substituted thiazoles via cascade reactions from 3-chlorochromones and thioamides.

A facile and efficient strategy to synthesize substituted thiazoles via a cascade reaction from chromone derivatives and thioamides in an environmentally benign medium was developed. This cascade reaction involves a Michael addition/intramolecular cyclization process and a broad scope of reversed regioselectivity products was prepared in a short reaction time with excellent yields. The reversed regioselectivity was also explained by DFT calculations.

Correction: Regioselective synthesis of substituted thiazoles via cascade reactions from 3-chlorochromones and thioamides.

Correction for 'Regioselective synthesis of substituted thiazoles via cascade reactions from 3-chlorochromones and thioamides' by Tianzi Dai et al., Org. Biomol. Chem., 2020, 18, 6162-6170, DOI: .

Comparison of three-dimensional printing guides and double-layer guide plates in accurate bracket placement.

BACKGROUND: In the current study, we aimed to evaluate the accuracy of indirect bonding by either three-dimensional (3D) printing guides or double-layer guide plates. The results may serve as a clinical reference for bracket placements. METHODS: In total, 140 teeth were collected and arranged into five pairs of full dentition. The marking points were labeled on the buccal/labial surface of the crown in these orthodontic study models. (1) 3D printing guide: A digital profile was generated using an intraoral scanner. Two types of indirect bonding guide, namely the whole denture type and the single tooth type, were designed with the 3Shape TRIOS® Standard intraoral scanner and fabricated using 3D printing technology. (2) Double-layer guide plate: A working model was obtained by replicating the experimental models, and the double-layer guide plate was then made of the inner layer soft film (1.0 mm thickness) and the outer layer hard film (0.6 mm or 0.8 mm thickness). Brackets were transferred from working models to study models by the indirect bonding trays. We measured and analyzed the distance between marking points and bracket placement. Statistical analysis was done using SPSS 20.0 software. The accuracy of indirect bonding between 3D printing guide and double-layer guide plate was compared using paired t-test. RESULTS: According to our data, there was a significant difference between the 0.6 mm group and 0.8 mm group when the brackets were indirectly adhered using double-layer guide plates (p = 0.036). However, no statistical significance in bracket positioning accuracy was revealed between two types of 3D printing guide (p = 0.078), as well as between the 3D printing guide group and the 0.6 mm double-layer guide plate group (p = 0.069). CONCLUSIONS: When applying double-layer guide plates for indirect bonding, the 0.6 mm group is more accurate than the 0.8 mm group. When utilizing 3D printing guides for indirect bonding, whole denture type is more accessible than single tooth type but with no significant difference in accuracy. The accuracy of indirect bonding is comparable when using 3D printing guides (whole denture type) and double-layer guide plates (0.6 mm).

Substituent-Oriented Synthesis of Substituted Pyrazoles/Chromeno[3,2- c]pyrazoles via Sequential Reactions of Chromones/3-Chlorochromones and Tosylhydrazones.

A facile and efficient synthetic strategy for the chemoselective synthesis of monocyclic/tricyclic-fused pyrazoles was developed, and it was oriented by different 3-position substituents (H or Cl) on the chromones. The reaction proceeded in a one-pot sequential way with a broad substrate scope and moderate to excellent yields.

Convenient Synthesis of 6,7,12,13-Tetrahydro-5H-Cyclohepta[2,1-b:3,4-b']diindole Derivatives Mediated by Hypervalent Iodine (III) Reagent.

Bisindolyl alkaloids represent a large family of natural and synthetic products that display various biological activities. Among the bisindole compounds, 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b']diindoles have received little attention. Only two methods have been developed for the construction of the 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b']diindole scaffold thus far, including the classical Fischer indole synthesis conducted by reacting indole-fused cycloheptanone and hydrazines, and the condensation reaction to build the seven-membered ring. Here, we report for the first time a new route to synthesize 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b']diindoles through intramolecular oxidative coupling of 1,3-di(1H-indol-3-yl)propanes in the presence of PIFA, DDQ and TMSCl with moderate to excellent yields.

One Pot and Metal-Free Approach to 3-(2-Hydroxybenzoyl)-1-aza-anthraquinones.

Herein, a direct strategy to synthesize 3-(2-hydroxybenzoyl)-1-aza-anthraquinones with excellent efficiency, mild conditions, and benign functional group compatibility was reported. A variety of 3-formylchromone compounds were employed as compatible substrates and this protocol gave the 3-(2-hydroxybenzoyl)-1-aza-anthraquinone derivatives in good to excellent yields without inert gas and expensive transition metal catalysts. Some compounds displayed good anti-proliferative activities.

C-H Trifluoromethylation of 2-Substituted/Unsubstituted Aminonaphthoquinones at Room Temperature with Bench-Stable (CF3SO2)2Zn: Synthesis and Antiproliferative Evaluation.

A direct C-H trifluoromethylation of 2-amino-1,4-naphthoquinone analogues is described. This reaction proceeds under mild conditions at open atmosphere, providing a range of CF3-containing naphthoquinones with good yield and functional group compatibility. All synthetic compounds were screened for antiproliferative activity against three human cancer cell lines. Notably, some of those trifluoromethyl analogs, such as 3a, 3g, 3j, and 3t, showed good antiproliferative profiles.

Feasibility of Shape-Memory Ni/Ti Alloy Wire Containing Tube Elevators for Transcrestal Detaching Maxillary Sinus Mucosa: Ex Vivo Study.

BACKGROUND: Osteotome sinus floor elevation is a less invasive approach to augment an insufficient alveolar bone at the posterior maxilla for dental implantation. However, this approach has some limitations due to the lack of sinus lift tools available for clinical use and the small transcrestal access to the maxillary sinus floor. We recently invented shape-memory Ni/Ti alloy wire containing tube elevators for transcrestal detaching maxillary sinus mucosa, and developed goat ex vivo models for direct visualizing the effectiveness of detaching sinus mucosa in real time during transcrestal maxillary sinus floor elevation. METHODS: We evaluated our invented elevators, namely elevator 012 and elevator 014, for their effectiveness for transcrestal detaching maxillary sinus mucosa using the goat ex vivo models. We measured the length of sinus mucosa detached in mesial and distal directions or buccal and palatal directions, and the space volume created by detaching maxillary sinus mucosa in mesial, distal, buccal and palatal directions using the invented elevators. RESULTS: Elevator 012 had a shape-memory Ni/Ti alloy wire with a diameter of 0.012 inch, while elevator 014 had its shape-memory Ni/Ti alloy wire with a diameter of 0.014 inch. Elevator 012 could detach the goat maxillary sinus mucosa in the mesial or distal direction for 12.1±4.3 mm, while in the buccal or palatal direction for 12.5±6.7 mm. The elevator 014 could detach the goat maxillary sinus mucosa for 23.0±4.9 mm in the mesial or distal direction, and for 19.0±8.1 mm in the buccal or palatal direction. An average space volume of 1.7936±0.2079 ml was created after detaching the goat maxillay sinus mucosa in both mesial/distal direction and buccal/palatal direction using elevator 012; while the average space volume created using elevator 014 was 1.8764±0.2366 ml. CONCLUSION: Both two newly invented tube elevators could effectively detach the maxillary sinus mucosa on the goat ex vivo sinus models. Moreover, elevator 014 has advantages over the elevator 012 for the capability to detach sinus mucosa.

Efficient Pd-catalyzed domino synthesis of 1-phenyl-1H-indol-2-amine and 5-amino-indolo[1,2-a]quinazoline derivatives.

An efficient and practical one-pot domino synthesis of 1-phenyl-1H-indol-2-amine and 5-amino-indolo[1,2-a]quinazoline derivatives from readily available 2-(2-bromophenyl)acetonitriles was developed. The overall protocol involves a Buchwald-Hartwig type coupling and a base-promoted intramolecular nucleophilic reaction. The reaction scope, advantages and limitations are discussed.

An efficient and practical approach to trifluoromethylthiolation of α-haloketones/α-haloarylmethanes.

An efficient and practical approach to trifluoromethylthiolation of α-haloketones/α-haloarylmethanes was developed. The transformation employs only AgSCF3 and KI in situ generated active nucleophilic trifluoromethylthio species and cleanly occurs in up to quantitative yield at room temperature, thereby providing an unprecedentedly easy entry to various α-SCF3-substituted ketones/arylmethanes.