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The structure and reactivity of dammarenyl cation is studied to understand the factors governing the regio- and stereospecificity of triterpene synthesis. The dammarenyl cation represents the first branch point from which numerous mechanistic pathways of triterpene synthesis diverge.

Two new triterpenoids are uncovered while exploiting Arabidopsis thaliana genomic information. The compounds that have eluded classical methodologies can be uncovered by genome mining.

The N-acetylgalactosamine alpha-O-threonine can be genetically encoded in Escherichia coli using an evolved Methanococcus jannaschii Tyr-tRNA synthetase (MjTyrRS) pair. A general approach is developed to co-translationally incorporate glycosyl amino acids into proteins in vivo that provide an expedient route to prepare homogeneous glycoproteins.

Two mixed-ligand Ag(I) coordination polymers (CPs), namely, [Ag2(bipy)2(ox)·7H2O]n(1) and [Ag2(bipy)2(adip)·6H2O]n(2) (bipy = 4,4′-bipyridine, H2ox = oxalic acid, H2adip = adipic acid) have been synthesized and structurally characterized. Complex 1exhibits a three-dimensional (3D) framework constructed from ox pillared Ag−bipy sheets. Complex 2shows a stairlike two-dimensional (2D) structure composed of adip linked Ag−bipy double chains. Of particular interest, a 1D C4 water chain and a novel 1D T7(2) water tape constructed from edge-sharing heptamer water clusters coexist in complex 1, while a 1D C6 water chain exists in complex 2. Comparing the experimental results, it is comprehensible that the dicarboyxlates play crucial roles in the formation of the diverse structures and water aggregates. Additionally, results about thermogravimetric curves and photoluminescence spectra were discussed. [ABSTRACT FROM AUTHOR]

This article focuses on the role of glycosylation in many biological processes. Natural glycoproteins usually exist as heterogeneous glycoforms, and this complicates studies of their structure and function. Consequently, considerable effort has focused on the methods to generate homogeneous glycoproteins including chemical and enzymatic synthesis, in vitro translation, and pathway engineering. This process required the evolution of an orthogonal Methanococcus jannaschii. Future determination of the structures of the mutant synthetases may allow new libraries to be designed that lead to clones with improved specificities and activities.

Protein tyrosine phosphatase 1B (PTP1B) is an important target for type 2 diabetes. PTP1B inhibitors can reduce blood glucose levels by increasing insulin sensitivity. Anthocyanins often play a hypoglycemic effect, but the research about them have mainly focused on glucosidase. At present, the research about protein tyrosine phosphatase 1B (PTP1B) target is less, and the corresponding molecular mechanism is still unclear. Therefore, in this present study, anthocyanins isolated from blueberry were used to study the inhibitory activity on PTP1B. The isolated cyanidin-3-arabinoside (Cya-3-Ara) exhibited a better inhibitory activity with IC 50 = 8.91 ± 0.63 μM, which was higher than the positive control (oleanolic acid, IC 50 = 13.9 ± 1.01 μM), and the mechanism of PTP1B inhibition was reversible mixed pattern. The structure-activity relationship (SAR) between anthocyanins and PTP1B inhibition was investigated. The enzyme activity inhibition and molecular docking showed that anthocyanins had high selectivity for PTP1B inhibition. Further study showed that Cya-3-Ara could promote glycogen synthesis through ameliorating PTP1B-involved IRS-1/PI3K/Akt/GSK3β pathways. Cya-3-Ara could also be regarded as a synergistic inhibitor (CI ≤ 0.54) of oleanolic acid to obtain a better inhibitory effect on PTP1B. Taken together, our study clearly illustrates the SAR between anthocyanins and PTP1B inhibition and the mechanism of Cya-3-Ara in the insulin signaling pathway.

We report herein the design, synthesis, and evaluation of macrocyclic peptidomimetics that bind to WD repeat domain 5 (WDR5) and block the WDR5-mixed lineage leukemia (MLL) protein-protein interaction. Compound 18 (MM-589) binds to WDR5 with an IC 50 value of 0.90 nM (K i value <1 nM) and inhibits the MLL H3K4 methyltransferase (HMT) activity with an IC 50 value of 12.7 nM. Compound 18 potently and selectively inhibits cell growth in human leukemia cell lines harboring MLL translocations and is >40 times better than the previously reported compound MM-401. Cocrystal structures of 16 and 18 complexed with WDR5 provide structural basis for their high affinity binding to WDR5. Additionally, we have developed and optimized a new AlphaLISA-based MLL HMT functional assay to facilitate the functional evaluation of these designed compounds. Compound 18 represents the most potent inhibitor of the WDR5-MLL interaction reported to date, and further optimization of 18 may yield a new therapy for acute leukemia.

We have designed and synthesized 9H-pyrimido[4,5-b]indole-containing compounds to obtain potent and orally bioavailable BET inhibitors. By incorporation of an indole or a quinoline moiety to the 9H-pyrimido[4,5-b]indole core, we identified a series of small molecules showing high binding affinities to BET proteins and low nanomolar potencies in inhibition of cell growth in acute leukemia cell lines. One such compound, 4-(6-methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethylisoxazole (31) has excellent microsomal stability and good oral pharmacokinetics in rats and mice. Orally administered, 31 achieves significant antitumor activity in the MV4;11 leukemia and MDA-MB-231 triple-negative breast cancer xenograft models in mice. Determination of the cocrystal structure of 31 with BRD4 BD2 provides a structural basis for its high binding affinity to BET proteins. Testing its binding affinities against other bromodomain-containing proteins shows that 31 is a highly selective inhibitor of BET proteins. Our data show that 31 is a potent, selective, and orally active BET inhibitor.

Shelterin, a six-protein complex, plays a fundamental role in protecting both the length and the stability of telomeres. Repressor activator protein 1 (RAP1) and telomeric repeat-binding factor 2 (TRF2) are two subunits in shelterin that interact with each other. Small-molecule inhibitors that block the RAP1/TRF2 protein-protein interaction can disrupt the structure of shelterin and may be employed as pharmacological tools to investigate the biology of shelterin. On the basis of the cocrystal structure of RAP1/TRF2 complex, we have developed first-in-class triazole-stapled peptides that block the protein-protein interaction between RAP1 and TRF2. Our most potent stapled peptide binds to RAP1 protein with a Ki value of 7 nM and is >100 times more potent than the corresponding wild-type TRF2 peptide. On the basis of our high-affinity peptides, we have developed and optimized a competitive, fluorescence polarization (FP) assay for accurate and rapid determination of the binding affinities of our designed compounds and this assay may also assist in the discovery of non-peptide, small-molecule inhibitors capable of blocking the RAP1/TRF2 protein-protein interaction.

Small-molecule inhibitors of bromodomain and extra terminal proteins (BET), including BRD2, BRD3, and BRD4 proteins have therapeutic potential for the treatment of human cancers and other diseases and conditions. In this paper, we report the design, synthesis, and evaluation of γ-carboline-containing compounds as a new class of small-molecule BET inhibitors. The most potent inhibitor (compound 18, RX-37) obtained from this study binds to BET bromodomain proteins (BRD2, BRD3, and BRD4) with Ki values of 3.2-24.7 nM and demonstrates high selectivity over other non-BET bromodomain-containing proteins. Compound 18 potently and selectively inhibits cell growth in human acute leukemia cell lines harboring the rearranged mixed lineage leukemia 1 gene. We have determined a cocrystal structure of 18 in complex with BRD4 BD2 at 1.4 Å resolution, which provides a solid structural basis for the compound's high binding affinity and for its further structure-based optimization. Compound 18 represents a promising lead compound for the development of a new class of therapeutics for the treatment of human cancer and other conditions.

TiO2 nanoparticles were successfully fabricated on electrospun polyacrylonitrile (PAN) nanofibers via the coupling of electrospinning and hydrothermal pathway. A straightforward photocatalysis oxidation process has been developed for simultaneous desulfurization and denitrification of flue gas using the TiO2-PAN photocatalyst. Also, the influences of some important operating parameters, such as titanium loading content of catalyst, flue gas humidity, flue gas flow, and inlet flue gas temperature on removal efficiencies of SO2 and NO were investigated. The results demonstrated that removal efficiencies of 99.3% for SO2 and 71.2% for NO were attained under the following optimal experiment conditions: titanium loading content, 6.78 At %; gas flow rate, 200 mL/min; flue gas humidity, 5%; inlet flue gas temperature, 40 °C. Furthermore, the presumed reaction mechanism of SO2 and NO removal using TiO2-PAN photocatalyst under UV light was proposed.