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Cancer-specific inhibitors that reflect the unique metabolic needs of cancer cells are rare. Here we describe Gboxin, a small molecule that specifically inhibits the growth of primary mouse and human glioblastoma cells but not that of mouse embryonic fibroblasts or neonatal astrocytes. Gboxin rapidly and irreversibly compromises oxygen consumption in glioblastoma cells. Gboxin relies on its positive charge to associate with mitochondrial oxidative phosphorylation complexes in a manner that is dependent on the proton gradient of the inner mitochondrial membrane, and it inhibits the activity of F.sub.0F.sub.1 ATP synthase. Gboxin-resistant cells require a functional mitochondrial permeability transition pore that regulates pH and thus impedes the accumulation of Gboxin in the mitochondrial matrix. Administration of a metabolically stable Gboxin analogue inhibits glioblastoma allografts and patient-derived xenografts. Gboxin toxicity extends to established human cancer cell lines of diverse organ origin, and shows that the increased proton gradient and pH in cancer cell mitochondria is a mode of action that can be targeted in the development of antitumour reagents. Gboxin and its chemical derivatives inhibit the growth of primary human and mouse glioblastoma cells, but not of mouse embryonic fibroblasts or neonatal astrocytes, by targeting mitochondrial oxidative phosphorylation complexes., Author(s): Yufeng Shi [sup.1] [sup.2] , S. Kyun Lim [sup.3] [sup.4] [sup.8] , Qiren Liang [sup.3] , Swathi V. Iyer [sup.1] [sup.2] , Hua-Yu Wang [sup.3] , Zilai Wang [sup.1] [...]

Tethered photoswitches are molecules with two photo-dependent isomeric forms, each with different actions on their biological targets. They include reactive chemical groups capable of covalently binding to their target. Our aim was to develop a β-subunit-tethered propofol photoswitch (MAP20), as a tool to better study the mechanism of anesthesia through the GABAA α1β3γ2 receptor. We used short spacers between the tether (methanethiosulfonate), the photosensitive moiety (azobenzene), and the ligand (propofol), to allow a precise tethering adjacent to the putative propofol binding site at the β+α- interface of the receptor transmembrane helices (TMs). First, we used molecular modeling to identify possible tethering sites in β3TM3 and α1TM1, and then introduced cysteines in the candidate positions. Two mutant subunits [β3(M283C) and α1(V227C)] showed photomodulation of GABA responses after incubation with MAP20 and illumination with lights at specific wavelengths. The α1β3(M283C)γ2 receptor showed the greatest photomodulation, which decreased as GABA concentration increased. The location of the mutations that produced photomodulation confirmed that the propofol binding site is located in the β+α- interface close to the extracellular side of the transmembrane helices. Tethering the photoswitch to cysteines introduced in the positions homologous to β3M283 in two other subunits (α1W288 and γ2L298) also produced photomodulation, which was not entirely reversible, probably reflecting the different nature of each interface. The results are in agreement with a binding site in the β+α- interface for the anesthetic propofol. [ABSTRACT FROM AUTHOR]

Thefirst synthesis of the purported structure of Merremoside Dhas been achieved in 22 longest linear steps. The de novoasymmetric synthesis relied on the use of asymmetric catalysis toselectively install all 21 stereocenters in the final compounds fromcommercially available achiral starting materials. Adiabatic gradient2D NMR techniques (gHSQCAD, gHMBCAD, gH2BCAD, gHSQCTOXYAD, ROESYAD)were used to completely assign the structure of synthetic MerremosideD. Comparison of our assignments with the limited NMR data reportedfor natural Merremoside D allows for the tentative confirmation ofits structure. [ABSTRACT FROM AUTHOR]

A de novo asymmetric synthesis of α- ido-pyranosides, as well as several deoxy and amino variants, has been achieved. The procedure involves a palladium(0)-catalyzed glycosylation in combination with a Wharton rearrangement/epoxide-opening reaction sequence to access sugars with ido, manno, and colito stereochemistry as well as several azido analogues. [ABSTRACT FROM AUTHOR]

Authors combined the previous data and newly collected geothermal data, including temperature and rock thermal properties, to obtain present geothermal gradient, subsurface formation temperature at the depths of 1 000-5 000 m and the heat flow in the region. The results show that the present geothermal gradient of the Lower Yangtze area is 18-25 °C/km, while that of the Subei Basin is as high as 30 °C/km, and the heat flow ranges from 48 mW/m² to 80 mW/m² with a mean of 60 mW/m², approximating to that of the global continental areas. The prediction of deep subsurface formation temperature indicates that the formation temperature of the northern area is larger than 150 °C at 4 000 m depth, and the main Paleozoic marine hydrocarbon rocks are within high-over mature regime and the gas generation stage, suggesting this area is of suitable temperature condition for shale gas preservation. [ABSTRACT FROM AUTHOR]

A highly divergent synthesis of α-fuco-, α-6-deoxy-allo-, α-6-deoxy-altro-pyranosides has been achieved. This route utilizes a Wharton rearrangement as part of a new post-glycosylation transformation strategy. [ABSTRACT FROM AUTHOR]

Nicotinamide N-methyltransferase (NNMT) is a fundamental cytosolic biotransforming enzyme that catalyzes the N-methylation of endogenous and exogenous xenobiotics. We have identified small molecule inhibitors of NNMT with >1000-fold range of activity and developed comprehensive structure-activity relationships (SARs) for NNMT inhibitors. Screening of N-methylated quinolinium, isoquinolinium, pyrididium, and benzimidazolium/benzothiazolium analogues resulted in the identification of quinoliniums as a promising scaffold with very low micromolar (IC 50 ∼ 1 μM) NNMT inhibition. Computer-based docking of inhibitors to the NNMT substrate (nicotinamide)-binding site produced a robust correlation between ligand-enzyme interaction docking scores and experimentally calculated IC 50 values. Predicted binding orientation of the quinolinium analogues revealed selective binding to the NNMT substrate-binding site residues and essential chemical features driving protein-ligand intermolecular interactions and NNMT inhibition. The development of this new series of small molecule NNMT inhibitors direct the future design of lead drug-like inhibitors to treat several metabolic and chronic disease conditions characterized by abnormal NNMT activity.