In silico approaches for the identification of novel ULK1 inhibitors: pharmacophore model, molecular docking and molecular dynamics simulations.

The serine/threonine kinase unc-51-like autophagy activating kinase 1 (ULK1) has been regarded as an attractive target for tumor therapy. In this study, in silico approaches, such as the pharmacophore-based virtual screening strategy, molecular docking and molecular dynamics (MD) simulations, were applied to develop novel potential ULK1 inhibitors. The pharmacophore models based on known aminopyrimidine ULK1 inhibitors were constructed to screen the dataset of 1.68 million compounds, which were obtained via screening the 2.30 million compounds in ChEMBL database by Lipinski's rule of five. Seven novel compounds and 1 known ULK1 inhibitor stand out for the strong virtual biological activity by molecular docking, cluster analysis, Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculation and Absorption Distribution Metabolism Excretion Toxicity (ADMET) prediction. Their results of MD included principal component analysis (PCA) and Free Energy Landscapes surface (FELs) indicated that the protein-ligand complex was stable in simulated trajectories of 100 ns. The binding free energy (BFE) calculations showed that a total of 6 novel compounds (CL130, CL834, CL961, CL966, CL163 and CL329) with the stable binding state and stronger BFE (-61.17 to -37.01 kcal/mol) than that of original ligand 3RF (-36.66 kcal/mol). With reference to the ULK1 inhibition of 3RF (IC50 = 160 nM), it can be inferred that these compounds could be used as a new type of potential ULK1 inhibitors and be worthy of further investigation for tumor treatments.Communicated by Ramaswamy H. Sarma.

Molecular Docking and Molecular Dynamics Simulation of New Potential JAK3 Inhibitors.

INTRODUCTION: JAK3 kinase inhibitor has become an effective means to treat tumors and autoimmune diseases. METHOD: In this study, molecular docking and molecular dynamics simulation were used to study the theoretical interaction mechanism between 1-phenylimidazolidine-2-one molecules and JAK3 protein. RESULT: The results of molecular docking showed that the six 1-phenylimidazolidine-2-one derivatives obtained by virtual screening were bound to the ATP pocket of JAK3 kinase, which were competitive inhibitors of ATP, and were mainly bound to the pocket through hydrogen bonding and hydrophobic interaction. Further, MM/GBSA based on molecular dynamics simulation sampling was used to calculate the binding energy between six molecules and the JAK3 kinase protein. Subsequently, the binding energy was decomposed into the contribution of each amino acid residue, of which Leu905, Lys855, Asp967, Leu956, Tyr904, and Val836 were the main energy-contributing residues. Among them, the molecule numbered LCM01415405 can interact with the specific amino acid Arg911 of JAK3 kinase, suggesting that the molecule may be a selective JAK3 kinase inhibitor. The root-mean-square fluctuation (RMSF) of JAK3 kinase pocket residues during molecular dynamics simulation showed that the combination of six new potential small molecule inhibitors with JAK3 kinase could reduce the flexibility of JAK3 kinase pocket residues. CONCLUSION: These findings reveal the mechanism of 1-phenylimidazolidine-2-one derivatives on JAK3 protein and provide a relatively solid theoretical basis for the development and structural optimization of JAK3 protein inhibitors.

Construction of 3,12-Diazatetracyclododecane-dienes through Unexpected Visible-Light-Induced Radical Cascade Cyclization.

A novel visible-light-induced cascade radical cyclization reaction of 3-cyano-4-aryl-1,4-dihydropyridines for the construction of 3,12-diazatetracyclododecane-diene derivatives is reported for the first time. In the presence of 410 nm blue LED lamp as the light source and ethanol as the solvent, the reactions proceed smoothly to afford photocyclization products in good yields. The process is carried out through the breaking of original C═C double bonds and the formation of three new single bonds in one pot and proved to be able to tolerate different substituents.

Straightforward synthesis of quinazolin-4(3H)-ones via visible light-induced condensation cyclization.

A green, simple and efficient method is developed for the synthesis of quinazolin-4(3H)-ones via visible light-induced condensation cyclization of 2-aminobenzamides and aldehydes under visible light irradiation. The reaction proceeds using fluorescein as a photocatalyst in the presence of TBHP without the need for a metal catalyst. In addition, this reaction tolerates a broad scope of substrates and could afford a variety of desirable products in good to excellent yields. Thus, the present synthetic method provides a straightforward strategy for the synthesis of quinazolin-4(3H)-ones.

Asymmetric Synthesis of Spiropyrazolones via Chiral Pd(0)/Ligand Complex-Catalyzed Formal [4+2] Cycloaddition of Vinyl Benzoxazinanones with Alkylidene Pyrazolones.

In the presence of the chiral Pd(0)/ligand complex, vinyl benzoxazinanones underwent the [4+2] cycloaddition with alkylidene pyrazolones smoothly and delivered spiropyrazolones in reasonable yields, diastereoselectivities, and eneantioselectivities (up to >99% yield, >99:1 dr and 99% ee). The absolute configuration of the obtained spiropyrazolones was unambiguously characterized with the use of X-ray single-crystal structure analysis. Moreover, the reaction mechanism was assumed to interpret the formation of the target compounds.

Photocatalyst-Free Singlet Oxygen-Induced Oxygenation: A Strategy for the Preparation of 5-Cyano-2-pyridones Driven by Blue-Light Irradiation.

A mild, catalyst- and metal-free photochemical protocol for the oxygenation of 3-cyano-1,4-dihydropyridines to 5-cyano-2-pyridones was developed. Utilizing molecular oxygen from the air as the oxidant and a cheap blue LED lamp as the light source, a variety of 3-cyano-1,4-dihydropyridines were converted into the corresponding 5-cyano-2-pyridones in moderate to excellent yields. Exploration of the substrate scope revealed that 3-cyano and 4-aryl groups play an important role in the formation of 2-pyridone.

Visible-Light-Induced C-C Coupling Reaction to Synthesize Bipyridine From 3-Cyano-1,4-Dihydropyridines.

A concise and efficient photocatalytic C-C coupling of 1-benzyl-3-cyano-1, 4-dihydropyridine for synthesis of 1,1'-dibenzyl-3, 3'-dicyano-1,1',4,4'-tetrahydro-4, 4'-bipyridine is described. The reporter system provides a novel technique that facilitates synthesis of C-C coupling derivatives without addition of transition metals and oxidants or other additives. A plausible synthetic pathway is proposed, and the coupling product was characterized via nuclear magnetic resonance spectroscopy (1H and 13C NMR), high-resolution electrospray ionization mass spectrometry (ESI-HRMS) and X-ray analyses.

Crystal structure of 1-benzyl-4-formyl-1H-pyrrole-3-carb-oxamide.

In the title compound, C13H12N2O2 (I), the mean planes of the pyrrole and benzyl rings are approximately perpendicular, forming a dihedral angle of 87.07 (4) °. There is an intra-molecular N-H⋯O hydrogen bond forming an S(7) ring motif. In the crystal, mol-ecules are linked via a pair of N-H⋯O hydrogen bonds forming inversion dimers. C-H⋯O hydrogen bonds link the dimers into chains along direction [10-1]. The chains are further linked by weak C-H⋯π inter-actions forming layers parallel to the ac plane.

Preparation of 4,7-diphenyl-1,10-phenanthroline-2,9-dicarboxylic acid catalyzed by iron(III)porphyrins with (diacetoxyiodo)benzene.

Using iron(III)porphyrins in combination with (diacetoxyiodo)benzene allows for the conversion of 2,9-bis(bromomethyl)-4,7-diphenyl-1,10-phenanthroline into 4,7-diphenyl-1,10-phenanthroline-2,9-dicarboxylic acid. This method provides a cost-effective and environmentally-friendly oxidation procedure using less toxic PhI(OAc)2 and biologically relevant iron(III)porphyrins. The catalytic activity of five kinds of iron-metallated functional porphyrins were investigated using different oxidants, including air, H2O2, PhI(OAc)2, PhIO and NaClO. Our results showed that the use of T(p-NO2)PPFeCl with PhI(OAc)2 as the oxidant in the presence of water displays remarkable activity for the desired oxidation reaction. The generality of this method was examined by synthesizing the carboxylic acids of pyridines and quinolines.