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A facile synthetic route to an important intermediate 4-amino-2,6-dichloropyridine was developed. Oxidation of 2,6-dichloropyridine as a starting material gave pyridine N-oxide derivative which was subjected to nitration followed by reduction. Subsequent nitration of the product and nucleophilic displacement reaction were carried out to afford fully substituted energetic pyridine derivatives. Most of the synthetic reactions proceeded under mild conditions. [ABSTRACT FROM AUTHOR]

We have synthesized a series of 4 H ,6 H -[1,2,5]oxadiazolo[3,4- d ]pyrimidine-5,7-dione 1-oxide nucleoside and their anti-vesicular stomatitis virus (VSV) activities in Wish cell were also investigated in vitro. It was found that most compounds showed obvious anti-VSV activities and compound 9 with ribofuranoside improved the anti-VSV activity by approximately 10 times and 18 times compared to didanosine (DDI) and acyclovir, respectively. A quantitative structure–activity relationship (QSAR) study of these compounds as well as previous reported oxadiazolo[3,4- d ]pyrimidine nucleoside derivatives indicated that compounds with high activity should have small values of log P ( o / w ), vsurf_G and a large log S value. These findings and results provide a base for further investigations. [ABSTRACT FROM AUTHOR]

The nitro derivatives of symmetric benzo-dicycloureas were designed and optimized to obtain their molecular geometries and electronic structures at the DFT-B3LYP/6-31G** level. The theoretical molecular density, heat of formation, detonation velocity, and detonation pressure, estimated using Kamlet-Jacobs equations, showed that the detonation properties of compound 7 were excellent, while compounds 8 and 9 were unstable, and the molecular symmetry, steric hindrance, and hydrogen bonds were considered to be the three main factors contributing to molecular stability. These results provide basic information for the molecular design and synthesis of novel high energy density compounds. [ABSTRACT FROM AUTHOR]

Natural product mayamycin is the first example in the angucycline class featuring a C-glycoside linkage at the C5-position of the benz[ a]anthracenone core with remarkable biological activities. We successfully synthesized the two retrosynthetic fragments, but found that the final C-glycosylation did not occur. Alternatively, an A-ring saturated aglycon was prepared, but the proposed C-glycosylation still did not proceed. Finally, a simplified substrate was used and the subsequent C-glycosylation went through smoothly, giving a two-ring less analogue of mayamycin. [ABSTRACT FROM AUTHOR]

DMPAO has been found to be a powerful ligand to enable copper-catalyzed coupling of aryl halides with aliphatic acyclic secondary amines take place under relatively mild conditions, and coupling of aryl halides with primary amines and cyclic secondary amines proceeds at low catalyst loading. [ABSTRACT FROM AUTHOR]

A fused, tricyclic pyridine-based energetic material, 4-amino-5-nitro-[1,2,5]oxadiazolo[3,4-e]tetrazolo[1,5-a]pyridine-3-oxide (ANTP), was first synthesized through a two-step reaction from commercially available reagents with a total yield of 75%, namely the azidonation of 4-amino-2,6-dichloro-3,5-dinitropyridine with nitrogen elimination and ring closure, followed by another azidonation and azido–tetrazolo tautomerism. Its structure was determined by single X-ray diffraction. The crystal of ANTP is orthorhombic, with space group P212121 with crystal parameters of a = 8.9130(18) Å, b = 14.057(3) Å, c = 6.5730(13) Å, V = 823.5(3) Å3, and Z = 4, F(000) = 480. It exhibits a surprisingly high density (1.92 g cm−3 at 293 K), low thermal stability, a positive heat of formation and good detonation properties. [ABSTRACT FROM AUTHOR]

Two series of novel 2-arylvinyl-naphtho[2,3- d ]imidazol-3-ium iodide derivatives and 2-arylvinyl-naphtho[2,3- d ]imidazol-3-ium bromide derivatives were designed and synthesized by the structural combination of YM155 with stilbenoids. All compounds were tested for anti-proliferative activity against PC-3, A375 and HeLa human cancer cell lines. Two of the compounds were selected for further investigation: 12b, which showed potent cytotoxicity against the three tested cell lines with IC 50 values in the range of 0.06–0.21 μM, and 7l , which displayed excellent selectivity for PC-3 cells with an IC 50 of only 22 nM. Western blot analysis results indicated that both 12b and 7l suppress the expression of Bcl-2 and Survivin proteins, which helps induce apoptosis. As determined by the percent of Annexin V-FITC-positive apoptotic cells, 12b was not only significantly more effective than 7l at a concentration of 100 nM in PC-3 cells but also induced apoptosis in a dose-dependent manner with more potency than 7l at a concentration of 1000 nM in A375 cells. Therefore, compound 12b was chosen for further in-depth studies investigating the mechanism of apoptosis. The results showed that it could activate caspase-3, hydrolyze PARP, and even inactivate ERK. Moreover, 12b arrested A375 cells at S phase in a time-dependent and dose-dependent manner, while having a visible effect on microtubule dynamics. In addition, ( E )-2-(2-(1 H -indol-3-yl)vinyl)-1-benzyl-3-(2-methoxyethyl)-4,9-dioxo-4,9-dihydro-1 H -naphtho[2,3-d]imidazol-3-ium bromide ( 12b ) exhibited significant antitumor activity when evaluated in a subcutaneous solid tumor model. Our study reveals that 2-arylvinyl-substituted naphtho[2,3-d]imidazolium scaffolding is a promising new entity for the development of multi-target anticancer drugs. [ABSTRACT FROM AUTHOR]

A number of N-heterocycles have been tested as directing group in the novel Ru-catalyzed regioselective ortho-selenylation of benzene featuring 2-pyridinyl and 1-pyrazolyl groups as most promising candidates that have been further examined in a broad variety of arenes. [ABSTRACT FROM AUTHOR]

An efficient approach for the synthesis of 2,2-disubstituted indolin-3-ones is described. From readily accessible aryl hydrazines and allyloxyketones, 2,2-disubstituted indolin-3-ones could be obtained in good to excellent yields under mild reaction conditions via a cascade Fischer indolization/Claisen rearrangement process. This protocol provides a facile entry to 2,2-disubstituted indolin-3-ones, which have been applied in the construction of the benzofuroindoline framework related to Phalarine. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinase-9 (MMP-9) is an attractive target for cancer therapy. In this study, the pharmacophore model of MMP-9 inhibitors is built based on the experimental binding structures of multiple receptor-ligand complexes. It is found that the pharmacophore model consists of six chemical features, including two hydrogen bond acceptors, one hydrogen bond donor, one ring aromatic regions, and two hydrophobic (HY) features. Among them, the two HY features are especially important because they can enter the S1′ pocket of MMP-9 which determines the selectivity of MMP-9 inhibitors. The reliability of pharmacophore model is validated based on the two different decoy sets and relevant experimental data. The virtual screening, combining pharmacophore model with molecular docking, is performed to identify the selective MMP-9 inhibitors from a database of natural products. The four novel MMP-9 inhibitors of natural products, NP-000686, NP-001752, NP-014331, and NP-015905, are found; one of them, NP-000686, is used to perform the experiment of in vitro bioassay inhibiting MMP-9, and the IC value was estimated to be only 13.4 µM, showing the strongly inhibitory activity of NP-000686 against MMP-9, which suggests that our screening results should be reliable. The binding modes of screened inhibitors with MMP-9 active sites were discussed. In addition, the ADMET properties and physicochemical properties of screened four compounds were assessed. The found MMP-9 inhibitors of natural products could serve as the lead compounds for designing the new MMP-9 inhibitors by carrying out structural modifications in the future. [ABSTRACT FROM AUTHOR]

Drug delivery systems based on nanoparticles (nano-DDS) have aroused attentions for the treatment of glioblastoma (GBM), the most malignant brain cancer with a dismal prognosis. However, there are still numerous unmet challenges for traditional nano-DDS, such as the poor nanoparticle penetration, short retention in the GBM parenchyma and low glioma targeting ability. Herein, we used Pep-1 and CREKA peptides to construct a novel multifunctional GBM targeting nano-DDS (PC-NP). Pep-1 was used to overcome the blood–brain tumor barrier (BBTB) and home to glioma cells via interleukin-13 receptor-α2-mediated endocytosis, and CREKA was used to bind to fibrin–fibronectin complexes abundantly expressed in tumor microenvironment for enhanced retention in the GBM. Biological studies showed that the cellular uptake of PC-NP by U87MG cells was significantly enhanced compared with the non-targeting NP. Furthermore, CREKA modification increased the binding capacity of PC-NP to fibrin–fibronectin complexes as confirmed by the competition experiment. In accordance with the increased cellular uptake, PC-NP remarkably increased the cytotoxicity of its payload paclitaxel (PTX) against U87MG cells with an IC50of 0.176 μg/mL.In vivofluorescence imaging and antiglioma efficacy evaluation further confirmed that PC-NP accumulated effectively and penetrated deeply into GBM tissue. PC-NP-PTX exhibited a median survival time as long as 61 days in intracranial GBM-bearing mice. In conclusion, our findings indicated PC-NP as a promising nano-DDS for GBM targeting delivery of anticancer drugs. [ABSTRACT FROM AUTHOR]

Poria cocos is a saprophytic fungus that grows in diverse species of Pinus. Its sclerotium, called fu-ling or hoelen, has been used in various traditional Chinese medicines and health foods for thousands of years, and in several modern proprietary traditional Chinese medicinal products. It has extensive clinical indications, including sedative, diuretic, and tonic effects. Pachymic acid (PA) is the main lanostane-type triterpenoid in Poria cocos. Evidence suggests that PA has various biological properties such as cytotoxic, anti-inflammatory, antihyperglycemic, antiviral, antibacterial, sedative-hypnotic, and anti-ischemia/reperfusion activities. Although considerable advancements have been made, some fundamental and intricate issues remain unclear, such as the underlying mechanisms of PA. The present study aimed to summarize the biological properties and therapeutic potential of PA. The biosynthetic, pharmacokinetic, and metabolic pathways of PA, and its underlying mechanisms were also comprehensively summarized. [ABSTRACT FROM AUTHOR]

Four series of tetracyclic benzo[ b ]carbazolone compounds possessing more rotatable bonds and higher molecular flexibility were designed by either inserting a linker within the C8-side chain or by opening the middle ketone ring on the basis of compound 5 (Alectinib, CH5424802). Compound 15b was identified showing nearly identical high potency against both wild-type and the gatekeeper mutant ALK kinase (3.4 vs 3.9 nM). This compound has favorable PK profile with an oral bioavailability of 67.1% in rats. Moreover, compound 15b showed significant growth inhibition against ALK driven cancer cells and KARPAS-299 xenograft model. [ABSTRACT FROM AUTHOR]

N-(1-Oxy-pyridin-2-ylmethyl)oxalamic acid was identified as efficient ligand for CuI-catalyzed amination of aryl halides at room temperature. In our catalytic system, N-arylation of cyclic secondary amines, primary amines, amino acids, and ammonia proceeded with moderate to excellent yields and high functional group tolerance. [ABSTRACT FROM AUTHOR]

A series of 3-amino-benzo[ d ]isoxazole-/3-aminoindazole-based compounds were designed, synthesized and pharmacologically evaluated as tyrosine kinase c-Met inhibitors. The SAR study was conducted leading to identification of nine compounds ( 8d , 8e , 12 , 28a – d , 28h and 28i ) with IC 50 s less than 10 nM against c-Met. Compound 28a stood out as the most potent c-Met inhibitor displaying potent inhibitory effects both at enzymatic (IC 50 = 1.8 nM) and cellular (IC 50 = 0.18 μM on EBC-1 cells) levels. In addition, 28a had a relatively good selectivity compared to a panel of our in-house 14 RTKs. [ABSTRACT FROM AUTHOR]

A RhIII-catalysed ortho C-H amination of phenidones under mild conditions was developed using N-alkyl- O-benzoyl-hydroxylamines as aminating agents, and with a cyclic hydrazine moiety as a directing group, yields of up to 97 % and a high functional group tolerance were observed. This strategy offers an alternative route for the synthesis of amino analogues of the 5-lipoxygenase inhibitor phenidone, and the products are valuable for further functional group transformations. [ABSTRACT FROM AUTHOR]

The new three-component Biginelli reaction of aromatic isocyanate, ethyl acetoacetate, and substituted urea (or thiourea as well as guanidine) is described for the first time. In this reaction,N4-aryl-5-carboxyl-6-methyl cytimidine derivatives were obtained in moderate to excellent yields by employing DBU as a highly effective catalyst. This methodology provides several advantages such as good functional group tolerance, excellent yields, atom efficiency, and experimental simplicity. [ABSTRACT FROM PUBLISHER]

Abstract: Eighteen symmetrical bis-Schiff base derivatives of isatin were synthesized by condensation of the natural or synthetic isatins with hydrazine and were evaluated for their in vitro and in vivo antitumor activities. More than half of the obtained compounds showed potent cytotoxicity according to the MTT assay on five different human cancer cell lines (i.e. HeLa, SGC-7901, HepG2, U251, and A549), with compound 3b 3,3′-(hydrazine-1,2-diylidene)bis (5-methylindolin-2-one) being the most potent compound on HepG2 (IC50 ∼ 4.23 μM). 3b was also found to be able to inhibit substantially the tumor growth on the HepS-bearing mice at a dose of 40 mg/kg. The real-time live cell imaging and tracking in the H2B-labeled HeLa cells revealed that 3b could induce mitosis interference and apoptosis-associated cell death. In mechanism study, 3b arrested the cell cycle at the G2/M phase in HepG2 cells by down-regulating the expression of cyclin B1 and cdc 2. [Copyright &y& Elsevier]

A tandem one-pot Friedel-Crafts alkylation/double cyclization process to conveniently assemble diaryl-fused 2,8-dioxabicyclo[3.3.1]nonanes with aryl substituents at the C-1 position was developed. 2-Hydroxychalcones and naphthol derivatives reacted in refluxing toluene with ( D, L)-10-camphorsulfonic acid (CSA) as the catalyst. The transformation conveniently provided the corresponding 2,8-dioxabicyclo[3.3.1]nonanes fused with one phenyl and one naphthyl group in moderate to good yields, and various substitutions on both reaction partners were tolerated. More importantly, aryl- and aza-aryl-fused 2,8-dioxabicyclo[3.3.1]nonanes were prepared for the first time using this procedure. [ABSTRACT FROM AUTHOR]

Anintermolecular C–H amination of 1-aryl-1H-pyrazol-5(4H)-ones was achieved under mild reactionconditions, using a low catalyst loading and with a broad scope ofaminating reagents. This protocol not only provides the first exampleof rhodium(III)-catalyzed intermolecular aromatic C–H aminationdirected by an intrinsic functionality of the substrate/product butalso features aminating an existing drug with either primary or secondary N-benzoate alkylamines as the coupling partners. [ABSTRACT FROM AUTHOR]

Facile synthetic routes for the preparation of some new 4-amino-3,5-dinitropyridine derivatives have been revealed. Nitration of 2-chloropyridin-4-amine ( 1) as a starting material, in an unexpected one-step reaction, to give dinitrated derivatives, followed by nucleophilic substitution reactions with sodium azide, potassium fluoride, ammonia, methylamine, and 4-nitroimidazol, respectively, gave substituted 4-amino-3,5-dinitropyridine derivatives. Meanwhile, its azide derivative underwent a ring closure conversion into 7-amino-6-nitro-[1,2,5]oxadiazolo[3,4- b]pyridine-1-oxide. It is of significance that all of the nucleophilic substitution reactions were carried out under mild conditions. [ABSTRACT FROM AUTHOR]

In this paper, a modified and facile Gewald reaction triggered by sodium polysulfide in the absence of catalytic base was developed. This approach involves a one-pot ultrasound-irritated aqueous reaction between ketones or aldehydes, malononitrile, and sodium polysulfide, which are converted into the corresponding 2-aminothiophene derivatives in moderate to high yields. In comparison with conventional methods, the prominent features of this sonocatalyzed procedure are experimental simplicity, good functional group tolerance, atom efficiency, and the use of water as a green solvent. [ABSTRACT FROM AUTHOR]

• In this study, we employed virtual screening method combined with drug repurposing. • Optimization of the pharmacophore model combined with molecular dynamics simulation. • The pharmacophore is constructed based on HDAC2 crystals with selective inhibitors. • One of the screened compounds, the antiviral drug DB13696, showed obvious anti-proliferative ability on HepG2 cells with high HDAC2 expression. Histone deacetylase 2 (HDAC2) is a vital therapeutic target for cancer and neurodegenerative diseases. Although some highly effective HDAC2 inhibitors were developed, their serious side effects and toxicity have not been well resolved. Currently, drug repurposing has been an efficient strategy in drug discovery. In this study, a series of in silico simulations and drug repurposing approaches were employed to identify promising HDAC2 inhibitors. We first constructed a receptor-ligand pharmacophore model. Notably, we combined pharmacophore model construction with molecular dynamics simulation, and used dynamic interatomic distances to evaluate the stability of the interactions and the importance of features in pharmacophore. In addition, molecular docking and molecular dynamics simulations were used to perform further screening. The results suggested that compounds DB08464, DB00731 (Nateglinide), DB13930 (Ulixertinib) and DB13696 (Salifungin) stably bound to HDAC2 and produced many favorable interactions. The MTT assay pointed out that one of the screened compounds, the antiviral drug DB13696 , showed obvious anti-proliferative ability on HepG2 cells with high HDAC2 expression, indicating that the calculated methods performed in this study should be reliable. [ABSTRACT FROM AUTHOR]

Indirubin is the crucial ingredient of Danggui Longhui Wan and Qing-Dai, traditional Chinese medicine herbal formulas used for the therapy of chronic myelocytic leukemia in China for hundreds of years. Although the monomeric indirubin has been used in China for the treatment human chronic myelocytic leukemia. However, due to low water solubility, poor pharmacokinetic properties and low therapeutic effects are the major obstacle, and had significantly limited its clinical application. Consequently, the attractive anticancer profile of indirubin has enthused numerous researchers to discover novel indirubin derivatives with improved pharmacodynamic activity as well as good pharmacokinetic property. In this paper, we comprehensively review the recent progress of anticancer potential of indirubins, structural modification and structure-activity relationship, which may provide useful direction for the further development of novel indirubins with improved pharmacological profiles for the treatment of various types of cancer. This review covers the recent advances of anticancer potential of indirubins, structural modification and structure-activity relationship, which may provide useful direction for the further development of novel indirubins with improved pharmacological profiles. [Display omitted] • Indirubin is an important natural bisindole alkaloid for anticancer drug exploration. • The recent advances of structural modification of indirubin were comprehensively summarized. • The multiple mechanisms underlying the anticancer action were included. • The structure-activity relationship was discussed. • The review will be conducive to the medicinal research of indirubin. [ABSTRACT FROM AUTHOR]

It is found that CuI/DMPAO efficiently promotes the N-arylation of acyclic secondary amines. [ABSTRACT FROM AUTHOR]

Abstract: Two series of new analogues were designed by replacing the quinoline scaffold of our earlier lead 2 (zgwatinib) with quinoxaline and pyrido[2,3-d]pyrimidine frameworks. Moderate c-Met inhibitory activity was observed in the quinoxaline series. Among the pyrido[2,3-d]pyrimidine series, compounds 13a–c possessing an O-linkage were inactive, whilst the N-linked analogues 15a–c retained c-Met inhibitory potency. Highest activity was observed in the 3-nitrobenzyl analog 15b that showed an IC50 value of 6.5nM. Further structural modifications based on this compound were undergoing. [Copyright &y& Elsevier]

Abstract: Guided by the metabolism information of SQ109, derivatives with substituted geranylamine moiety or substituted admantane ring of SQ109 were synthesized and evaluated as antituberculosis agents. Among all tested compounds, compound 11c showed the most potent antituberculosis activity with MIC value of 0.3μM against Mycobacterium tuberculosis H37Rv. [Copyright &y& Elsevier]

Herein, we describe the design, synthesis and structure−activity relationships of a series of novel s-triazine compounds can induce methuotic phenotype in various types of cancer cells. (E)-1-(4-Chlorophenyl)-3-(4-((4-morpholino-6-styryl-1,3,5-triazine-2-yl)amino)phenyl)urea, compound V6 , exhibited a striking methuotic phenotype with a minimal effective concentration of less than 10 nM in U87 glioblastoma cells. Based on structure−activity relationship studies, we designed and synthesized an active probe P1 that retained the full potential of V6 in inducing the methuotic phenotype in U87 glioblastoma cells. Using this probe following affinity-based proteomic profiling strategy, we identified vimentin as the specific target protein of compound V6. Molecular docking revealed that V6 can form hydrogen bonds with vimentin at 273R and 276Y in its rod domain. Image 1 • Design and synthesis of a series of novel s-triazine compounds inducing methuotic phenotype are reported. • Compound V6 exhibited a striking methuotic phenotype with <10 nM in U87 glioblastoma cells. • Probe (P1) of the most interesting compound V6 was designed and synthesized. • Vimentin was identified as the specific target protein of V6 following affinity-based proteomic profiling strategy. [ABSTRACT FROM AUTHOR]

A palladium-catalyzed dual C–H activation to construct C–C/C–N bonds for one-pot synthesis of benzo[c]pyrazolo[1,2-a]cinnolin-1-ones is successfully developed. This approach involves using a pyrazolone moiety as an internal directing group for C–H activation, and provides a flexible strategy to access this polycyclic skeleton. [ABSTRACT FROM AUTHOR]

Abstract: The low bioavailability of SQ109 in rats, resulting from first-pass effect in the liver, may be remedied by prodrug strategy. Based on esterase-sensitive carbamate prodrug strategy, a novel series of prodrugs of SQ109 has been reported. Bioavailability of SQ109 after administration of prodrug 7a was 91.4% compared with 21.4% after oral administration of SQ109. After oral administration of compound 7a, the parent drug SQ109 exhibited preferential tissue distribution into lung and spleen, the target organs of tubercular infection and replication. [Copyright &y& Elsevier]

An efficient method for the asymmetric bromo-oxycyclization of a broad range of (2-alkenyl)phenylsilanols is described which provides benzoxazoles with a quarternary carbon centre in generally high yields and with high enantiomeric purity. [ABSTRACT FROM AUTHOR]

An abstract of the article "N-(1-Oxy-2-picolyl)oxalamic Acid as an Efficient Ligand for Copper-Catalyzed Amination of Aryl Iodides at Room Temperature" by Y. Wang, J. Ling and colleagues is presented.

Multisubstituted phenols are efficiently obtained by dienone-phenol rearrangement of 4,4-disubstituted cyclohexadienones. [ABSTRACT FROM AUTHOR]

A green process for the cross-coupling of azoles and aryl halides in water with low catalyst loading is reported. [ABSTRACT FROM AUTHOR]

An abstract of the article "RhIII-Catalyzed Hydrazine-Directed C(sp²)-H Amination of Phenidones with N-Alkyl-O-benzoyl-hydroxylamines" by Y. Xue and colleagues is presented.

The article presents chemical equations related to the article Base-Mediated Biginelli-Like Reaction Ignited by Aromatic Isocyanate by C. Liang, and others, published in the periodical "Synthetic Communications" in 2014.

For the first time, aryl- and aza-aryl-fused 2,8-dioxabicyclo[3.3.1]nonanes are prepared using a tandem one-pot Friedel-Crafts alkylation/double cyclization process. [ABSTRACT FROM AUTHOR]

The article presents chemical equations related to the article "Rh(III)-Catalyzed Intermolecular C-H Amination of 1-Aryl-1H-pyrazol-5(4H)-ones with Alkylamines" by K. Wu, Z. Fan and colleagues, published in the periodical "Organic Letters" in 2014.

The structure of the product (Ve) is confirmed by X-ray analysis. [ABSTRACT FROM AUTHOR]

Substrate (I), prepared by nitration of 2-chloropyridine-4-amine, is treated with various reagents to give the corresponding 2-substituted products. [ABSTRACT FROM AUTHOR]