Potent Suppressive Effects of 1-Piperidinylimidazole Based Novel P2X7 Receptor Antagonists on Cancer Cell Migration and Invasion

Park, Jin-Hee,Williams, Darren R.,Lee, Ji-Hyung,Lee, So-Deok,Lee, Je-Heon,Ko, Hyojin,Lee, Ga-Eun,Kim, Sujin,Lee, Jeong-Min,Abdelrahman, Aliaa,Mü,ller, Christa E.,Jung, Da-Woon,Kim, Yong-Chul American Chemical Society 2016 Journal of medicinal chemistry Vol.59 No.16

<P>The P2X7 receptor (P2X7R) has been reported as a key mediator in inflammatory processes and cancer invasion/metastasis. In this study, we report the discovery of novel P2X7R antagonists and their functional activities as potential antimetastatic agents. Modifications of the hydantoin core-skeleton and the side chain substituents of the P2X7R antagonist 7 were performed. The structure activity relationships (SAR) and optimization demonstrated the importance of the sulfonyl group at the R-1 position and the substituted position and overall size of R-2 for P2X7R antagonism. The optimized novel analogues displayed potent P2X7 receptor antagonism (IC50 = 0.11-112 nM) along with significant suppressive effects on IL-1 beta release (IC50 = 0.32-210 nM). Moreover, representative antagonists (12g, 13k, and 17d) with imidazole and uracil core skeletons significantly inhibited the invasion of MDA-MB-231 triple negative breast cancer cells and cancer cell migration in a zebrafish xenograft model, suggesting the potential therapeutic application of these novel P2X7 antagonists to block metastatic cancer.</P>

Reconciling reported and unreported HFC emissions with atmospheric observations

Lunt, Mark F.,Rigby, Matthew,Ganesan, Anita L.,Manning, Alistair J.,Prinn, Ronald G.,O’Doherty, Simon,Mü,hle, Jens,Harth, Christina M.,Salameh, Peter K.,Arnold, Tim,Weiss, Ray F.,Saito, Takuya,Y National Academy of Sciences 2015 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.112 No.19

<P><B>Significance</B></P><P>Hydrofluorocarbons (HFCs) are among the atmosphere’s fastest growing, and most potent, greenhouse gases. Proposals have been made to phase down their use over the coming decades. Such initiatives may largely be informed by existing emissions inventories, which, we show, are the subject of significant uncertainty. In this work, we use atmospheric models and measurements to examine the accuracy of these inventories for five major HFCs. We show that, when aggregated together, reported emissions of these HFCs from developed countries are consistent with the atmospheric measurements, and almost half of global emissions now originate from nonreporting countries. However, the agreement between our results and the inventory breaks down for individual HFC emissions, suggesting inaccuracies in the reporting methods for individual compounds.</P><P>We infer global and regional emissions of five of the most abundant hydrofluorocarbons (HFCs) using atmospheric measurements from the Advanced Global Atmospheric Gases Experiment and the National Institute for Environmental Studies, Japan, networks. We find that the total CO<SUB>2</SUB>-equivalent emissions of the five HFCs from countries that are required to provide detailed, annual reports to the United Nations Framework Convention on Climate Change (UNFCCC) increased from 198 (175–221) Tg-CO<SUB>2</SUB>-eq⋅y<SUP>–1</SUP> in 2007 to 275 (246–304) Tg-CO<SUB>2</SUB>-eq⋅y<SUP>–1</SUP> in 2012. These global warming potential-weighted aggregated emissions agree well with those reported to the UNFCCC throughout this period and indicate that the gap between reported emissions and global HFC emissions derived from atmospheric trends is almost entirely due to emissions from nonreporting countries. However, our measurement-based estimates of individual HFC species suggest that emissions, from reporting countries, of the most abundant HFC, HFC-134a, were only 79% (63–95%) of the UNFCCC inventory total, while other HFC emissions were significantly greater than the reported values. These results suggest that there are inaccuracies in the reporting methods for individual HFCs, which appear to cancel when aggregated together.</P>

SchNetPack: A Deep Learning Toolbox For Atomistic Systems

Schu&#x308,tt, K. T.,Kessel, P.,Gastegger, M.,Nicoli, K. A.,Tkatchenko, A.,Mü,ller, K.-R. American Chemical Society 2019 Journal of chemical theory and computation Vol.15 No.1

<P>SchNetPack is a toolbox for the development and application of deep neural networks that predict potential energy surfaces and other quantum-chemical properties of molecules and materials. It contains basic building blocks of atomistic neural networks, manages their training, and provides simple access to common benchmark datasets. This allows for an easy implementation and evaluation of new models. For now, SchNetPack includes implementations of (weighted) atom-centered symmetry functions and the deep tensor neural network SchNet, as well as ready-to-use scripts that allow one to train these models on molecule and material datasets. Based on the PyTorch deep learning framework, SchNetPack allows one to efficiently apply the neural networks to large datasets with millions of reference calculations, as well as parallelize the model across multiple GPUs. Finally, SchNetPack provides an interface to the Atomic Simulation Environment in order to make trained models easily accessible to researchers that are not yet familiar with neural networks.</P> [FIG OMISSION]</BR>

First-Principles Modeling of the Polycyclic Aromatic Hydrocarbons Reduction

Boukhvalov, D. W.,Feng, X.,Mü,llen, K. American Chemical Society 2011 The Journal of Physical Chemistry Part C Vol.115 No.32

<P>Density functional theory modeling of the reduction of realistic nanographene molecules (C<SUB>42</SUB>H<SUB>18</SUB>, C<SUB>48</SUB>H<SUB>18</SUB>, and C<SUB>60</SUB>H<SUB>24</SUB>) by molecular hydrogen evidence of the presence of limits in the hydrogenation process. These limits caused the contentions between three-fold symmetry of polycyclic aromatic hydrocarbon molecules and two-fold symmetry of adsorbed hydrogen pairs. Increase in the binding energy between nanographenes during reduction is also discussed as a possible cause of the experimentally observed limited hydrogenation of studied nanographenes.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jpccck/2011/jpccck.2011.115.issue-32/jp2024928/production/images/medium/jp-2011-024928_0002.gif'></P>

Many-Body Descriptors for Predicting Molecular Properties with Machine Learning: Analysis of Pairwise and Three-Body Interactions in Molecules

Pronobis, Wiktor,Tkatchenko, Alexandre,Mü,ller, Klaus-Robert American Chemical Society 2018 Journal of chemical theory and computation Vol.14 No.6

<P>Machine learning (ML) based prediction of molecular properties across chemical compound space is an important and alternative approach to efficiently estimate the solutions of highly complex many-electron problems in chemistry and physics. Statistical methods represent molecules as descriptors that should encode molecular symmetries and interactions between atoms. Many such descriptors have been proposed; all of them have advantages and limitations. Here, we propose a set of general two-body and three-body interaction descriptors which are invariant to translation, rotation, and atomic indexing. By adapting the successfully used kernel ridge regression methods of machine learning, we evaluate our descriptors on predicting several properties of small organic molecules calculated using density-functional theory. We use two data sets. The GDB-7 set contains 6868 molecules with up to 7 heavy atoms of type CNO. The GDB-9 set is composed of 131722 molecules with up to 9 heavy atoms containing CNO. When trained on 5000 random molecules, our best model achieves an accuracy of 0.8 kcal/mol (on the remaining 1868 molecules of GDB-7) and 1.5 kcal/mol (on the remaining 126722 molecules of GDB-9) respectively. Applying a linear regression model on our novel many-body descriptors performs almost equal to a nonlinear kernelized model. Linear models are readily interpretable: a feature importance ranking measure helps to obtain qualitative and quantitative insights on the importance of two- and three-body molecular interactions for predicting molecular properties computed with quantum-mechanical methods.</P> [FIG OMISSION]</BR>

Synthesis and Characterization of Novel Ethylene-<i>graft</i>-Ethylene/Propylene Copolymers

Stadler, Florian J.,Arikan-Conley, Burc&#x327,ak,Kaschta, Joachim,Kaminsky, Walter,Mü,nstedt, Helmut American Chemical Society 2011 Macromolecules Vol.44 No.12

<P>A sequential metallocene-catalyzed synthesis of ethylene/propylene macromers, which are subsequently incorporated into growing polyethylene chains, leads to comb-like polymers. After the synthesis, a Soxhlet extraction ensures the purity of the sample. The GPC-MALLS analysis reveals narrowly distributed samples with a non-negligible degree of branching. The comb polymers show a very high viscosity, which significantly differs from conventional long-chain branched metallocene polyethylenes (LCB-mPE) but is in agreement with findings on comb model polymers. The zero shear rate viscosity η<SUB>0</SUB> lies significantly above the relation between <I>M</I><SUB>w</SUB> and η<SUB>0</SUB> for linear and for conventional LCB-mPE. The thermorheological behavior is complex and differs from that observed for LCB-mPE but also does not resemble an LDPE-like thermorheological behavior.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/mamobx/2011/mamobx.2011.44.issue-12/ma200588r/production/images/medium/ma-2011-00588r_0007.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/ma200588r'>ACS Electronic Supporting Info</A></P>

Sulfur versus Iron Oxidation in an Iron−Thiolate Model Complex

McDonald, Aidan R.,Bukowski, Michael R.,Farquhar, Erik R.,Jackson, Timothy A.,Koehntop, Kevin D.,Seo, Mi Sook,De Hont, Raymond F.,Stubna, Audria,Halfen, Jason A.,Mü,nck, Eckard,Nam, Wonwoo,Que, American Chemical Society 2010 JOURNAL OF THE AMERICAN CHEMICAL SOCIETY - Vol.132 No.48

<P>In the absence of base, the reaction of [Fe<SUP>II</SUP>(TMCS)]PF<SUB>6</SUB> (<B>1</B>, TMCS = 1-(2-mercaptoethyl)-4,8,11-trimethyl-1,4,8,11-tetraazacyclotetradecane) with peracid in methanol at −20 °C did not yield the oxoiron(IV) complex (<B>2</B>, [Fe<SUP>IV</SUP>(O)(TMCS)]PF<SUB>6</SUB>), as previously observed in the presence of strong base (KO<SUP>t</SUP>Bu). Instead, the addition of 1 equiv of peracid resulted in 50% consumption of <B>1</B>. The addition of a second equivalent of peracid resulted in the complete consumption of <B>1</B> and the formation of a new species <B>3</B>, as monitored by UV−vis, ESI-MS, and Mössbauer spectroscopies. ESI-MS showed <B>3</B> to be formulated as [Fe<SUP>II</SUP>(TMCS) + 2O]<SUP>+</SUP>, while EXAFS analysis suggested that <B>3</B> was an O-bound iron(II)−sulfinate complex (Fe−O = 1.95 Å, Fe−S = 3.26 Å). The addition of a third equivalent of peracid resulted in the formation of yet another compound, <B>4</B>, which showed electronic absorption properties typical of an oxoiron(IV) species. Mössbauer spectroscopy confirmed <B>4</B> to be a novel iron(IV) compound, different from <B>2</B>, and EXAFS (Fe?O = 1.64 Å) and resonance Raman (ν<SUB>Fe?O</SUB> = 831 cm<SUP>−1</SUP>) showed that indeed an oxoiron(IV) unit had been generated in <B>4</B>. Furthermore, both infrared and Raman spectroscopy gave indications that <B>4</B> contains a metal-bound sulfinate moiety (ν<SUB>s</SUB>(SO<SUB>2</SUB>) ≈ 1000 cm <SUP>−1</SUP>, ν<SUB>as</SUB>(SO<SUB>2</SUB>) ≈ 1150 cm <SUP>−1</SUP>). Investigations into the reactivity of <B>1</B> and <B>2</B> toward H<SUP>+</SUP> and oxygen atom transfer reagents have led to a mechanism for sulfur oxidation in which <B>2</B> could form even in the absence of base but is rapidly protonated to yield an oxoiron(IV) species with an uncoordinated thiol moiety that acts as both oxidant and substrate in the conversion of <B>2</B> to <B>3</B>.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jacsat/2010/jacsat.2010.132.issue-48/ja1045428/production/images/medium/ja-2010-045428_0015.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/ja1045428'>ACS Electronic Supporting Info</A></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/ja1045428'>ACS Electronic Supporting Info</A></P>

Versatile Tandem Ring-Opening/Ring-Closing Metathesis Polymerization: Strategies for Successful Polymerization of Challenging Monomers and Their Mechanistic Studies

Park, Hyeon,Kang, Eun-Hye,Mü,ller, Laura,Choi, Tae-Lim American Chemical Society 2016 JOURNAL OF THE AMERICAN CHEMICAL SOCIETY - Vol.138 No.7

<P>Tandem ring-opening/ring-closing metathesis (RO/RCM) results in extremely fast living polymerization; however, according to previous reports, only monomers containing certain combinations of cycloalkenes, terminal alkynes, and nitrogen linkers successfully underwent tandem polymerization. After examining the polymerization pathways, we proposed that the relatively slow intramolecular cyclization might lead to competing side reactions such as intermolecular cross metathesis reactions to form inactive propagating species. Thus, we developed two strategies to enhance tandem polymerization efficiency. First, we modified monomer structures to accelerate tandem RO/RCM cyclization by enhancing the Thorpe-Ingold effect. This strategy increased the polymerization rate and suppressed the chain transfer reaction to achieve controlled polymerization, even for challenging syntheses of dendronized polymers. Alternatively, reducing the reaction concentration facilitated tandem polymerization, suggesting that the slow tandem RO/RCM cyclization step was the main reason for the previous failure. To broaden the monomer scope, we used monomers containing internal alkynes and observed that two different polymer units with different ring sizes were produced as a result of nonselective alpha-addition and beta-addition on the internal alkynes. Thorough experiments with various monomers with internal alkynes suggested that steric and electronic effects of the alkyne substituents influenced alkyne addition selectivity and the polymerization reactivity. Further polymerization kinetics studies revealed that the rate-determining step of monomers containing certain internal alkynes was the six-membered cyclization step via beta-addition, whereas that for other monomers was the conventional intermolecular propagation step, as observed in other chain-growth polymerizations. This conclusion agrees well with all those polymerization results and thus validates our strategies.</P>

Self-Assembly Behavior of Alkylated Isophthalic Acids Revisited: Concentration in Control and Guest-Induced Phase Transformation

Park, Kwang-Won,Adisoejoso, Jinne,Plas, Jan,Hong, Jongin,Mü,llen, Klaus,De Feyter, Steven American Chemical Society 2014 Langmuir Vol.30 No.50

<P>The engineering of two-dimensional crystals by physisorption-based molecular self-assembly at the liquid–solid interface is a powerful method to functionalize and nanostructure surfaces. The formation of high-symmetry networks from low-symmetry building blocks is a particularly important target. Alkylated isophthalic acid (ISA) derivatives are early test systems, and it was demonstrated that to produce a so-called porous hexagonal packing of plane group <I>p</I>6, i.e., a regular array of nanowells, either short alkyl chains or the introduction of bulky groups within the chains were mandatory. After all, the van der Waals interactions between adjacent alkyl chains or alkyl chains and the surface would dominate the ideal hydrogen bonding between the carboxyl groups, and therefore, a close-packed lamella structure (plane group <I>p</I>2) was uniquely observed. In this contribution, we show two versatile approaches to circumvent this problem, which are based on well-known principles: the “concentration in control” and the “guest-induced transformation” methods. The successful application of these methods makes ISA suitable building blocks to engineer a porous pattern, in which the distance between the pores can be tuned with nanometer precision.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/langd5/2014/langd5.2014.30.issue-50/la5040849/production/images/medium/la-2014-040849_0006.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/la5040849'>ACS Electronic Supporting Info</A></P>

Source Identification and Apportionment of Halogenated Compounds Observed at a Remote Site in East Asia

Li, Shanlan,Kim, Jooil,Park, Sunyoung,Kim, Seung-Kyu,Park, Mi-Kyung,Mü,hle, Jens,Lee, Gangwoong,Lee, Meehye,Jo, Chun Ok,Kim, Kyung-Ryul American Chemical Society 2014 Environmental science & technology Vol.48 No.1

<P>The sources of halogenated compounds in East Asia associated with stratospheric ozone depletion and climate change are relatively poorly understood. High-precision in situ measurements of 18 halogenated compounds and carbonyl sulfide (COS) made at Gosan, Jeju Island, Korea, from November 2007 to December 2011 were analyzed by a positive matrix factorization (PMF). Seven major industrial sources were identified from the enhanced concentrations of halogenated compounds observed at Gosan and corresponding concentration-based source contributions were also suggested: primary aluminum production explaining 37% of total concentration enhancements, solvent usage of which source apportionment is 25%, fugitive emissions from HCFC/HFC production with 11%, refrigerant replacements (9%), semiconductor/electronics industry (9%), foam blowing agents (6%), and fumigation (3%). Statistical trajectory analysis was applied to specify the potential emission regions for seven sources using back trajectories. Primary aluminum production, solvent usage and fugitive emission sources were mainly contributed by China. Semiconductor/electronics sources were dominantly located in Korea. Refrigerant replacement, fumigation and foam blowing agent sources were spread throughout East Asian countries. The specified potential source regions are consistent with country-based consumptions and emission patterns, verifying the PMF analysis results. The industry-based emission sources of halogenated compounds identified in this study help improve our understanding of the East Asian countries’ industrial contributions to halogenated compound emissions.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/esthag/2014/esthag.2014.48.issue-1/es402776w/production/images/medium/es-2013-02776w_0003.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/es402776w'>ACS Electronic Supporting Info</A></P>