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A number of the charge-density-wave materials reveala transitionto the macroscopic quantum state around 200 K. We used graphene-likemechanical exfoliation of TiSe2crystals to prepare a setof films with different thicknesses. The transition temperature tothe charge-density-wave state was determined via modification of Ramanspectra of TiSe2films. It was established that the transitiontemperature can increase from its bulk value to ∼240 K as thethickness of the van der Waals films reduces to the nanometer range.The obtained results are important for the proposed applications ofsuch materials in the collective-state information processing, whichrequire room-temperature operation. [ABSTRACT FROM AUTHOR]

The interaction of xanthine oxidase (XO), a key enzymein purinemetabolism, with cetyltrimethylammonium bromide (CTAB) and bis(cetyldimethylammonium)butanedibromide (C16C4C16Br2) has been studied using tensiometry, spectrofluorometry, spectrophotometry,and circular dichroism at pH 7.4 and 25 °C. The tensiometricprofiles of CTAB and C16C4C16Br2in the presence of XO exhibit a single break at a lower surfactantconcentration termed as C1compared to their CMC in thebuffered solution and show the existence of interaction between thesurfactants and the enzyme. The results of the multitechnique approachshowed that, although both CTAB as well as C16C4C16Br2interact with the XO, C16C4C16Br2interacts more stronglythan its conventional single chain counterpart. Fluorescence and absorptionmeasurements revealed that, compared to CTAB, C16C4C16Br2is more effective in unfoldingthe enzyme. Change in XO activity by the surfactants was in concurrencewith the structural alterations monitored by circular dichroism andshowed structural stabilization of XO at higher surfactant concentrations,consistent with the aggregation results. This stabilization has beenexplained in light of strong tendency of C16C4C16Br2for micellar growth and membrane/waterstabilization of proteins by membrane-like fragments provided by higherconcentrations of C16C4C16Br2. The results are related to the stronger electrostatic andhydrophobic forces in C16C4C16Br2, owing to the presence of two charged headgroups and twohydrophobic tails. [ABSTRACT FROM AUTHOR]

Neopetrothiazide ( 1 ), a pentacyclic isoquinoline quinone, was isolated from a Neopetrosia sp. sponge. The structure elucidation was facilitated by utilizing long-range heteronuclear single quantum multiple bond correlation (LR-HSQMBC) and heteronuclear multiple bond correlation (HMBC) nuclear magnetic resonance (NMR) pulse sequences optimized to detect four- and five-bond 1 H- 13 C heteronuclear correlations. These NMR experiments can help assign proton-deficient structural motifs like neopetrothiazide ( 1 ), which has 14 contiguous nonprotonated centers (C, N, and S). Neopetrothiazide ( 1 ), with an unprecedented thiazide-fused structural scaffold, is the first natural product containing a thiazide moiety.

Novel tricyclic analogues were designed, synthesized, and evaluated as RORγt inverse agonists. Several of these compounds were potent in an IL-17 human whole blood assay and exhibited excellent oral bioavailability in mouse pharmacokinetic studies. This led to the identification of compound 5 , which displayed dose-dependent inhibition of IL-17F production in a mouse IL-2/IL-23 stimulated pharmacodynamic model. In addition, compound 5 was studied in mouse acanthosis and imiquimod-induced models of skin inflammation, where it demonstrated robust efficacy comparable to a positive control. As a result of this excellent overall profile, compound 5 (BMS-986251) was selected as a clinically viable developmental candidate., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resistance, improve adherence, and mitigate toxicities. Active site inhibitors of HIV-1 integrase are clinically validated for the treatment of HIV-1 infection. Here we describe allosteric inhibitors of HIV-1 integrase that bind to the LEDGF/p75 interaction site and disrupt the structure of the integrase multimer that is required for the HIV-1 maturation. A series of pyrazolopyrimidine-based inhibitors was developed with a vector in the 2-position that was optimized by structure-guided compound design. This resulted in the discovery of pyrazolopyrimidine 3 , which was optimized at the 2- and 7-positions to afford 26 and 29 as potent allosteric inhibitors of HIV-1 integrase that exhibited low nanomolar antiviral potency in cell culture and encouraging PK properties.

RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.

Myeloperoxidase (MPO) generates reactive oxygen species that potentially contribute to many chronic inflammatory diseases. A recently reported triazolopyrimidine MPO inhibitor was optimized to improve acid stability and remove methyl guanine methyl transferase (MGMT) activity. Multiple synthetic routes were explored that allowed rapid optimization of a key benzyl ether side chain. Crystal structures of inhibitors bound to the MPO active site demonstrated alternate binding modes and guided rational design of MPO inhibitors. Thioether 36 showed significant inhibition of MPO activity in an acute mouse inflammation model after oral dosing., Competing Interests: The authors declare no competing financial interest.

In this study, a novel immobilized TiO 2 /Ti film with exposed {001} facets was prepared via a facile one-pot hydrothermal route for the degradation of norfloxacin from aqueous media. The effects of various hydrothermal conditions (i.e., solution pH, hydrothermal time (H T ) and HF concentration) on the growth of {001} faceted TiO 2 /Ti film were investigated. The maximum photocatalytic performance of {001} faceted TiO 2 /Ti film was observed when prepared at pH 2.62, H T of 3 h and at HF concentration of 0.02 M. The as-prepared {001} faceted TiO 2 /Ti films were fully characterized by field-emission scanning electron microscope (FE-SEM), X-ray diffraction (XRD), high resolution transmission electron microscope (HR-TEM), and X-ray photoelectron spectroscopy (XPS). More importantly, the as-prepared {001} faceted TiO 2 /Ti film exhibited excellent photocatalytic performance toward degradation of norfloxacin in various water matrices (Milli-Q water, tap water, river water and synthetic wastewater). The individual influence of various anions (SO 4 2- , HCO 3 - , NO 3 - , Cl - ) and cations (K + , Ca 2+ , Mg 2+ , Cu 2+ , Na + , Fe 3+ ) usually present in the real water samples on the photocatalytic performance of as-prepared TiO 2 /Ti film with exposed {001} facet was investigated. The mechanistic studies revealed that • OH is mainly involved in the photocatalytic degradation of norfloxacin by {001} faceted TiO 2 /Ti film. In addition, norfloxacin degradation byproducts were investigated, on the basis of which degradation schemes were proposed.

JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.

Early hit to lead work on a pyrrolopyridine chemotype provided access to compounds with biochemical and cellular potency against Janus kinase 2 (JAK2). Structure-based drug design along the extended hinge region of JAK2 led to the identification of an important H-bond interaction with the side chain of Tyr 931, which improved JAK family selectivity. The 4,5-dimethyl thiazole analogue 18 demonstrated high levels of JAK family selectivity and was identified as a promising lead for the program.

High-affinity, functionally potent, urea-based antagonists of CCR1 have been discovered. Modulation of PXR transactivation has revealed the selective and orally bioavailable CCR1 antagonist BMS-817399 (29), which entered clinical trials for the treatment of rheumatoid arthritis.

MicroRNA 34a (miR-34a) is a potential tumor suppressor gene and has been identified as a miRNA component of the p53 network. To better understand the biological pathways involved in miR-34a action, a parallel global protein and mRNA expression profiling on miR-34a treated neuroblastoma cells (IMR32) was performed using isotope-coded affinity tags (ICAT) and Affymetrix U133plus2 microarray, respectively. Global profiling showed that miR-34a causes much smaller mRNA expression changes compared to changes at the protein level. A total of 1495 proteins represented by two or more peptides were identified from the quantitative ICAT analysis, of which 143 and 192 proteins are significantly up- or down-regulated by miR-34a, respectively. Pathway analysis of these differentially expressed proteins showed the enrichment of apoptosis and cell death processes in up-regulated proteins but DNA replication and cell cycle processes in the down-regulated proteins. Ribosomal proteins are the most significant set down-regulated by miR-34a. Additionally, biological network analysis to identify direct interactions among the differentially expressed proteins demonstrated that the expression of the ubiquitous transcription factor YY1, as well as its downstream proteins, is significantly reduced by miR-34a. We further demonstrated that miR-34a directly targets YY1 through a miR-34a-binding site within the 3' UTR of YY1 using a luciferase reporter system. YY1 is a negative regulator of p53, and it plays an essential role in cancer biology. Therefore, YY1 is another important direct target of miR-34a which closely regulates TP53 activities.

Neuroblastoma (NB) is a heterogeneous pediatric tumor. To better understand the biological pathways involved in the development of high-risk neuroblastoma, we performed parallel global protein and mRNA expression profiling on NB tumors of stage 4 MYCN-amplified (4+) and stage 1 MYCN-not-amplified (1-) using isotope-coded affinity tags (ICAT) and Affymetrix U133plus2 microarray, respectively. A total of 1461 proteins represented by 2 or more peptides were identified from the quantitative ICAT analysis, of which 433 and 130 proteins are up- or down-regulated, respectively, in 4+ tumor compared to the 1- tumor. Pathway analysis of the differentially expressed proteins showed the enrichment of glycolysis, DNA replication and cell cycle processes in the up-regulated proteins and cell adhesion, nervous system development and cell differentiation processes in the down-regulated proteins in 4+ tumor; suggesting a less mature neural and a more invasive phenotype of 4+ tumor. Myc targets and ribosomal proteins are overrepresented in the 4+ tumors as expected; functional gene sets reported to be enriched in neural and embryonic stem cells are significantly enriched in the 4+ tumor, indicating the existence of a stemness signature in MYCN-amplified stage 4 tumor. In addition, protein and mRNA expression are moderately correlated (r = 0.51, p < 0.0001), as approximately half of the up-regulated proteins in 4+ tumor have elevated mRNA level (n = 208), and one-third of down-regulated proteins have lower mRNA expression (n = 47). Further biological network analysis revealed that the differentially expressed proteins closely interact with other proteins of known networks; the important role of MYCN is confirmed and other transcription factors identified in the network may have potential roles in the biology of NB tumor. We used global genomic and proteomic analysis to identify biologically relevant proteins and pathways important to NB progression and development that may provide new insights into the biology of advanced neuroblastoma.