The indole ring, adamantane, and urea groups are important components of bioactive molecules. The orphan nuclear receptor Nur77 as a unique transcription factor encoded by an immediate early gene is a potential therapeutic target for cancer treatment. We synthesized a series of 1-(2-(adamantane-1-yl)-1H-indol-5-yl)-3-substituted urea/thiourea derivatives and identified which of these potential anticancer candidates could modulate the expression and activity of Nur77. The synthesized compounds were initially evaluated for their anti-proliferative activity against H460 lung cancer cells, HepG2 liver cancer cells, and MCF-7 breast cancer cells. Major compounds were found to be active against these tested cancer cell lines. The compounds with IC50 values down to 20 μM exhibited selective cytotoxicity effects on the human lung cancer cell line (H460) and the normal lung cell line (MCR-5). Compounds 7n, 7s, and 7w induced Nur77-expression in a time- and dose-dependent manner in H460 cells. Compounds 7n and 7s strongly induced Parp cleavage in H460 cells, but 7w resulted in a slight induction of apoptosis. The apoptotic effect of 7s was largely inhibited when the Nur77 was knocked down by shRNA. This indicated that Nur77 served as a critical mediator for the anticancer action of 7s. The molecular docking study between Nur77 and 7s revealed that compound 7s exhibited a promising binding affinity with Nur77. These findings will provide a direction for the developing Nur77 regulator as anticancer agents.

Human stimulator of interferon genes protein (hSTING) is an essential signaling adaptor and a cytosolic DNA sensor (CDS) that functions as a homodimer in innate immunity. Natural mutation V155M in hSTING can cause hSTING-associated vasculopathy with onset in infancy (SAVI) which is an autoinflammatory disease. However, the mechanisms between the variant and SAVI are poorly understood. To explore the mechanisms, we performed all-atom molecular dynamics (MD) simulations on the complexes of wild type (WT)/mutated (V155M) hSTING and endogenous agonist 2′3′-cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) to investigate whether the interaction between hSTING and 2′3′-cGAMP could be affected by natural mutation V155M, which plays a crucial role in SAVI disease. Based on the MD simulations, the dynamic cross-correlation analysis and principal component analysis indicated that the single point mutation on residue 155 from valine to methionine changed some residues' motions of hSTING. Furthermore, MM/PBSA calculation, hydrogen bond analysis and energy decomposition analysis showed that this single point mutation increased the binding affinity of 2′3′-cGAMP with hSTING. Finally, residual network analysis indicated the way that the V155M mutation around 17 Å from the binding site controlled the strength of binding interaction and the conformation change of the substructure. These results will help in the understanding of the mechanism of SAVI disease induced by hSTING mutation at the molecular level, and provide new ideas to design innovative drugs targeted on hSTING.

Human peroxisome proliferator-activated receptor alpha (hPPARα) is a ligand-dependent transcription factor that mainly controls lipid metabolism in the liver. It has drawn wide attention as a significant target for developing new hypoglycaemic drugs. However, a central and largely unresolved question in finding new drugs targeted on hPPARα concerns ligand action mechanism: what makes certain molecules act as antagonists while others behave as agonists in the same binding site? To understand this, we performed a total of 600 ns all-atom molecular dynamics (MD) simulations to explore how four small molecule ligands bind to the hPPARα and play opposite effects. We characterized and compared the protein backbone fluctuation, and investigated the interaction networks and the movements of helixes and loops near binding site during MD simulations. Moreover, by free energy calculation and phylogenetic tree analysis, 11 key residues favouring binding ligands and some other residues playing important roles in inducing the active conformation changing of hPPARα were discovered. The results could help to understand the activation/deactivation of hPPARα by agonists or antagonists, and provide insightful prospective into hPPARα targeted structure-based drug designs.

⿢A new separation workflow of microbial metabolites was proposed.⿢On-line separation based on application of analytical and preparative 2D-LC.⿢Unheated and oxygen-free sample post-treatment method kept compounds away from structural transformation.⿢Twelve cytochalasan derivatives, including two new compounds, were obtained with high purity in a short period of time.Microbial metabolites represent an important source of bioactive natural products, but always exhibit diverse of chemical structures or complicated chemical composition with low active ingredients content. Traditional separation methods rely mainly on off-line combination of open-column chromatography and preparative high performance liquid chromatography (HPLC). However, the multi-step and prolonged separation procedure might lead to exposure to oxygen and structural transformation of metabolites. In the present work, a new two-dimensional separation workflow for fast isolation and analysis of microbial metabolites from Chaetomium globosum SNSHI-5, a cytotoxic fungus derived from extreme environment. The advantage of this analytical comprehensive two-dimensional liquid chromatography (2D-LC) lies on its ability to analyze the composition of the metabolites, and to optimize the separation conditions for the preparative 2D-LC. Furthermore, gram scale preparative 2D-LC separation of the crude fungus extract could be performed on a medium-pressure liquid chromatograph ÿ preparative high-performance liquid chromatography system, under the optimized condition. Interestingly, 12 cytochalasan derivatives, including two new compounds named cytoglobosin Ab (3) and isochaetoglobosin Db (8), were successfully obtained with high purity in a short period of time. The structures of the isolated metabolites were comprehensively characterized by HR ESI⿿MS and NMR. To be highlighted, this is the first report on the combination of analytical and preparative 2D-LC for the separation of microbial metabolites. The new workflow exhibited apparent advantages in separation efficiency and sample treatment capacity compared with conventional methods.

A mild and efficient method was developed for the copper-catalyzed additions of H-phosphonate diesters to boronic acids under the copper catalyst system Cu2O/1,10-phenanthroline. To the best of our knowledge this finding is the first example of a copper-catalyzed synthesis of aryl phosphonates from arylboronic acids and H-phosphonate dialkyl esters.

The title compound, C14H23O5P, was synthesized by the reaction of 4-methoxybenzaldehyde and diisopropyl phosphite. Its structure was determined with X-ray crystallographic, NMR, MS, and elemental analysis (EA) techniques. The crystal belongs to monoclinic, space group P 21/n with the following crystallographic parameters: a = 10.529 (2) Å, b = 8.424 (2) Å, c = 19.448 (4) Å, α = 90°, β = 105.2 (3)°, γ = 90°, μ = 0.180 mm−1, V = 1664.1 (6) Å3, Z = 4, Dx = 1.207 mg/mm3, F (000) = 648, T = 293 (2) K, 2.00° ≤ θ ≤ 25.50°. The final residual factor is 0.049 for 1933 reflections with I > 2σ (I). Crystal packing is stabilized by interatomic hydrogen bond interactions between the doubly bonded phosphoryl O atom and the hydroxyl H atom which link the molecules into chains along the [011] plane of the unit cell.