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Protein phosphorylation acts as an essential on/off switch in many cellular signaling pathways. This has led to ongoing interest in targeting kinases for therapeutic intervention. Computer-aided drug discovery has been proven a useful and cost-effective approach for facilitating prioritization and enrichment of screening libraries, but limited effort has been devoted providing insights on what makes a potent kinase inhibitor. To fill this gap, here we developed kinCSM, an integrative computational tool capable of accurately identifying potent cyclin-dependent kinase 2 (CDK2) inhibitors, quantitatively predicting CDK2 ligand-kinase inhibition constants (pKsubi/sub) and classifying different types of inhibitors based on their favorable binding modes. kinCSM predictive models were built using supervised learning and leveraged the concept of graph-based signatures to capture both physicochemical properties and geometry properties of small molecules. CDK2 inhibitors were accurately identified with Matthew's Correlation Coefficients (MCC) of up to 0.74, and inhibition constants predicted with Pearson's correlation of up to 0.76, both with consistent performances of 0.66 and 0.68 on a nonredundant blind test, respectively. kinCSM was also able to identify the potential type of inhibition for a given molecule, achieving MCC of up to 0.80 on cross-validation and 0.73 on the blind test. Analyzing the molecular composition of revealed enriched chemical fragments in CDK2 inhibitors and different types of inhibitors, which provides insights into the molecular mechanisms behind ligand-kinase interactions. kinCSM will be an invaluable tool to guide future kinase drug discovery. To aid the fast and accurate screening of CDK2 inhibitors, kinCSM is freely available at https://biosig.lab.uq.edu.au/kin_csm/.

Funder: Victorian Government, Funder: BBSRC, Nonhomologous end joining (NHEJ) is a DNA repair mechanism that religates double-strand DNA breaks to maintain genomic integrity during the entire cell cycle. The Ku70/80 complex recognizes DNA breaks and serves as an essential hub for recruitment of NHEJ components. Here, we describe intramolecular interactions of the Ku70 C-terminal domain, known as the SAP domain. Using single-particle cryo-electron microscopy, mass spectrometric analysis of intermolecular cross-linking and molecular modelling simulations, we captured variable positions of the SAP domain depending on DNA binding. The first position was localized at the DNA aperture in the Ku70/80 apo form but was not observed in the DNA-bound state. The second position, which was observed in both apo and DNA-bound states, was found below the DNA aperture, close to the helical arm of Ku70. The localization of the SAP domain in the DNA aperture suggests a function as a flexible entry gate for broken DNA. DATABASES: EM maps have been deposited in EMDB (EMD-11933). Coordinates have been deposited in Protein Data Bank (PDB 7AXZ). Other data are available from corresponding authors upon a request.

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Molten elemental sulfur was found to be an excellent reaction medium for oxidative coupling between bis-aza nucleophiles and cycloalkanones to the fused diaza heterocycles. No extensive aromatization was observed when cyclohexanone was used. These reaction conditions tolerate a wide range of functional groups and are applicable to oxidation sensitive o-phenylenediamines.

International audience; The disproportionation of elemental sulfur at moderate temperatures is investigated in the redox condensation involving o-halonitrobenzenes 1 and benzylamines 2. As a redox moderator, elemental sulfur plays the dual role of both electron donor and acceptor, generating its lowest and highest oxidation states: S(-2) (sulfide equivalent) in benzothiazole 3 and S(+6) (sulfate equivalent) in sulfamate 4, and filling the electron gap of the global redox condensation process. Along with this process, a cascade of reactions of reduction of the nitro group of 1, oxidation of the aminomethyl group of 2, metal-free aromatic halogen substitution, and condensation finally led to 2-arylbenzothiazoles 3.

Molecular iodine was found to be an excellent catalyst for reductive redox cyclization of o-nitro-t-anilines 1 into fused tricyclic or 1,2-disubtituted benzimidazoles 2. A range of functional groups such as halides (F, Cl, Br), methoxy, ester, trifluoromethyl, cyano, pyridine and even nitro groups were tolerated using formic acid as a clean, safe, user-friendly and complementary reductant. When iodine was used in a stoichiometric amount (50 mol%), the methodology allowed the direct synthesis of benzimidazole hydroiodides 2·HI in high yields by simple precipitation from the reaction mixture.

Molecular iodine is shown to be an excellent catalyst for aerobic oxidative α,β-diamination of cyclohexanones with 2-aminopyrimidine/2-aminopyridines. This α,β-C–H functionalization is remarkable for its simplicity in both substrates and conditions, involving one and a half oxygen molecules and releasing three water molecules as the only byproduct. In addition, the functionalized products including protected 2-aminoimidazoles introduced without aromatization can serve as useful building blocks for natural product synthesis and medicinal chemistry.

A practical synthesis of fused benzimidazoles 5 has been developed by simply heating o-halonitrobenzenes 1 with tetrahydroisoquinolines 2. In this transformation, 2 played multiple roles as a building block, base and a double hydride donor in a cascade of uncatalyzed aromatic substitution, reduction of the nitro group, oxidation of the α-methylene group and condensation.

An efficient one-step synthesis of piperidin-2-yl and pyrrolidin-2-yl flavonoid alkaloids was achieved in good to excellent yields by a highly regioselective phenolic Mannich reaction of chrysin with cyclic imines or iminium salts. Performing the reaction in a mixture of H2O/THF in the absence of an external reagent afforded the C-6 alkylated product exclusively. The same reaction in water in the presence of NaOH provided the C-8 alkylated flavonoid as a major product. The reaction has been successfully extended to simple phenols.

The first enantioselective chiral phosphoric acid-catalyzed transfer hydrogenation of N-aryl-ortho-hydroxybenzophenone ketimines using a Hantzsch ester as hydrogen source was developed to afford, after removal of the N-aryl group, the corresponding chiral diarylmethylamines in high yields and enantioselectivities.

The stability of chitosan with a degree of deacetylation (DD) of 88 and 81% was investigated in solution during storage for 60 days at various temperatures (60, 28, and 5°C) and acid concentrations (0.8M, 0.2M, and 0.1M). The first-order rate constant of chain hydrolysis of 88%DD chitosan at 60°C was about 1.4 times higher than that of the 81%DD sample. At 28°C, the rates of hydrolysis for both chitosan samples were four to five times lower than those at 60°C and are similar. At 5°C, chain degradation was not significant. Although acetic acid caused significantly higher (P ≤ 0.05) chain scission than formic acid, no significant difference of rate change was observed among three different acid concentrations. Reprecipitation of dissolved chitosan was applied for its purification and to transfer dissolved chitosan to the solvent used to measure its molecular weight. Reprecipitation resulted in slightly lower molecular weight (P ≤ 0.05) for both 88%DD and 81%DD samples. The molecular weight of chitosan before and after reprecipitation had good linear relationship (r2 > 0.9). © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2008

Unbalanced redox condensation reaction between o-nitroanilines and alcohols, leading to benzimidazole and quinoxaline heterocycles can be efficiently promoted and catalyzed by sodium sulfide (40 mol%) in combination with iron(III) chloride hexahydrate (1 mol%). Beside the role as a precursor for the iron–sulfur (Fe/S) catalyst formation, hydrated sodium sulfide was shown to be an excellent noncompetitive, multi-electron reducing agent.

A wide range of 2-aroylbenzothiazoles 3 including some pharmacologically relevant derivatives can be obtained in high yields by simply heating o-halonitrobenzenes 1, acetophenones 2, elemental sulfur, and N-methylmorpholine. This three-component nitro methyl coupling was found to occur in an excellent atom-, step-, and redox-efficient manner in which elemental sulfur played the role of nucleophile building block and redox moderating agent to fulfill electronic requirements of the global reaction.

The presented reaction tolerates a variety of functional groups including aminobenzylamines, which react chemoselectively on the aliphatic amino group.

The disproportionation of elemental sulfur at moderate temperatures is investigated in the redox condensation involving o-halonitrobenzenes 1 and benzylamines 2. As a redox moderator, elemental sulfur plays the dual role of both electron donor and acceptor, generating its lowest and highest oxidation states: S(-2) (sulfide equivalent) in benzothiazole 3 and S(+6) (sulfate equivalent) in sulfamate 4, and filling the electron gap of the global redox condensation process. Along with this process, a cascade of reactions of reduction of the nitro group of 1, oxidation of the aminomethyl group of 2, metal-free aromatic halogen substitution, and condensation finally led to 2-arylbenzothiazoles 3.

To determine the effects of equivalent diet- or exercise-induced weight loss and exercise without weight loss on subcutaneous fat, visceral fat, and insulin sensitivity in obese women.Fifty-four premenopausal women with abdominal obesity [waist circumference 110.1 +/- 5.8 cm (mean +/- SD)] (BMI 31.3 +/- 2.0 kg/m2) were randomly assigned to one of four groups: diet weight loss (n = 15), exercise weight loss (n = 17), exercise without weight loss (n = 12), and a weight-stable control group (n = 10). All groups underwent a 14-week intervention.Body weight decreased by approximately 6.5% within both weight loss groups and was unchanged in the exercise without weight loss and control groups. In comparison with controls, cardiorespiratory fitness improved within the exercise groups only (p0.01). Reduction in total, abdominal, and abdominal subcutaneous fat within the exercise weight loss group was greater (p0.001) than within all other groups. The reduction in total and abdominal fat within the diet weight loss and exercise without weight loss groups was greater than within controls (p0.001) but not different from each other (p0.05). Visceral fat decreased within all treatment groups (p0.008), and these changes were not different from each other. In comparison with the control group, insulin sensitivity improved within the exercise weight loss group alone (p0.001).Daily exercise without caloric restriction was associated with substantial reductions in total fat, abdominal fat, visceral fat, and insulin resistance in women. Exercise without weight loss was also associated with a substantial reduction in total and abdominal obesity.

A general, straightforward, and atom-economical three-component synthesis of thioamides from alkynes, elemental sulfur, and aliphatic amines has been developed.

A wide variety of functionalized 2-aryl benzimidazoles can be prepared by a solvent-free cobalt- or iron-catalyzed redox condensation of 2-nitroanilines and benzylamines. The cascade including benzylamine oxidation, nitro reduction, condensation, and aromatization occurs without any added reducing or oxidizing agent. The method can be extended to other alkylamines as reducing components or 2-nitrobenzamides as oxidizing components when using an iron/sulfur catalyst to afford various diazaheterocycles.

Benzotriazole is used as an efficient catalyst for transamidation reactions of amides, imides, and urea.

The proposed reaction mechanism includes a spontaneous formation of catalytically active iron-sulfur clusters.

A green and remarkably simple synthesis of nitrogen heterocycles from benzylamines and anilines o-substituted by a cyclizable group has been developed based on selective uncatalyzed autoxidation of benzylamines.

A simple, straightforward, and atom-economic multicomponent synthesis of different substituted benzothiazoles from readily available starting materials is developed.

The reaction does not require any oxidizing or reducing agent and proceeds without any solvent.

A novel remarkably simple solvent-free and catalyst-free synthesis of benzazoles from alkylamines and o-hydroxy/amino/mercaptan anilines using elemental sulfur as traceless oxidizing agent has been developed.

An efficient and selective multicomponent oxidative coupling of two different aliphatic primary amines into thioamides by elemental sulfur under solvent-free conditions has been developed.

Heating o-hydroxyacetophenones and anilines under solvent-free conditions afforded the corresponding aryl ketimines in good to excellent yields.

A novel method of transamidation of carboxamides with amines using catalytic amounts of readily available boric acid under solvent-free conditions has been developed. The scope of the methodology has been demonstrated with (i) primary, secondary, and tertiary amides and phthalimide and (ii) aliphatic, aromatic, cyclic, acyclic, primary, and secondary amines.

1,3-dipolar cycloadditions (1,3-DC) reactions involving nitrones as dipole have met a recent growing interest 1 – 8 especially in their diastereoselective and enantioselective versions. 9 - 10 This...

The title reaction of chrysin (I) can be controlled by the conditions: simply running in a solvent mixture, the process affords C-6 substituted products, whereas in the presence of aqueous NaOH, C-8 substitution takes place.

Keywords: amines ; chirality ; enantioselectivity ; Hantzsch ester ; hydrogenation ; phosphoric acid ; Asymmetric Transfer Hydrogenation ; Alpha-Imino Esters ; Organocatalytic Transfer Hydrogenation ; Friedel-Crafts Reaction ; Bronsted Acid ; Arylboronic Acids ; Organometallic Reagents ; Reductive Amination ; Cetirizine Hydrochloride ; 3-Component Reaction Reference EPFL-ARTICLE-168571doi:10.1002/chem.201101694View record in Web of Science Record created on 2011-08-31, modified on 2017-05-12

Transfer hydrogenation of title ketimines (I) with Hantzsch ester proceeds efficiently in the presence of a chiral BINOL-derived phosphoric acid catalyst to give the corresponding diarylmethylamines (II) in good yields and enantioselectivities (up to 91% e.e.).

Unprotected substrates are converted in a highly efficient manner concerning yields and enantioselectivities.

Cycloaddition reactions occupy a special place in organic synthesis because of the simultaneous creation of several bonds and generation of new stereogenic centers in often highly stereocontrolled ...