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ChemMedChem

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https://www.readbyqxmd.com/read/28815966/trifluoromethyl-oxetanes-synthesis-and-evaluation-as-a-tert-butyl-isostere
#1
Paramita Mukherjee, Martin Pettersson, Jason K Dutra, Longfei Xie, Christopher W Am Ende
The synthesis of a new trifluoromethyl oxetane was developed utilizing a Corey-Chaykovsky epoxidation/ring-expansion reaction of trifluoromethyl ketones. The reaction was shown to proceed under mild conditions and displays a broad substrate scope. The trifluoromethyl oxetane was also evaluated as a tert-butyl isostere in the context of the γ-secretase modulator (GSM) program. We demonstrate that the trifluoromethyl oxetane-containing GSM has reduced lipophilicity, improved lipophilic efficiency (LipE) and metabolic stability relative to the corresponding tert-butyl GSM analog, thus highlighting several benefits of trifluoromethyl oxetane as a more polar tert-butyl isostere...
August 16, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28815923/biophysical-screening-of-a-focused-library-for-the-discovery-of-cyp121-inhibitors-as-novel-antimycobacterials
#2
Christian Brengel, Andreas Thomann, Alexander Schifrin, Giuseppe Allegretta, Ahmed A M Kamal, Joerg Haupenthal, Isabell Schnorr, Sang Hyun Cho, Scott Gary Franzblau, Martin Empting, Jens Eberhard, Rolf W Hartmann
The development of novel antimycobacterial agents against Mycobacterium tuberculosis (Mtb) is urgently required due to the appearance of multi-drug resistance (MDR) combined with a complicated long-term treatment. CYP121 was shown to be a promising novel target for inhibition of mycobacterial growth. In this study, we describe the rational discovery of new CYP121 inhibitors by a systematic screening based on biophysical and microbiological methods. Best hits originating from only one structural class gave first information about molecular motifs required for binding and activity...
August 16, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28812327/design-and-synthesis-of-terephthalic-acid-based-histone-deacetylase-inhibitors-with-dual-stage-anti-plasmodium-activity
#3
Katharina Stenzel, Ming Jang Chua, Sandra Duffy, Yevgeniya Antonova-Koch, Stephan Meister, Alexandra Hamacher, Matthias U Kassack, Elizabeth A Winzeler, Vicky M Avery, Thomas Kurz, Katherine T Andrews, Finn Kristian Hansen
In this work we aimed to develop parasite-selective HDAC inhibitors with activity against the disease-causing asexual blood stages of Plasmodium as well as causal prophylactic and/or transmission blocking properties. We report the design, synthesis and biological testing of a series of 13 terephthalic acid-based histone deacetylase inhibitors. All compounds showed low cytotoxicity against human embryonic kidney (HEK293) cells (IC50 8 - >51 µM), with 11 also having sub-micromolar in vitro activity against drug-sensitive (3D7) and multi-drug resistant (Dd2) asexual blood stage Plasmodium falciparum parasites (IC50 ~ 0...
August 15, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28791799/reducing-the-flexibility-of-type-ii-dehydroquinase-enzyme-for-inhibition-a-fragment-based-approach-and-molecular-dynamics-simulation-study
#4
Antonio Peón, Adrián Robles, Beatriz Blanco, Marino Convertino, Paul Thompson, Alastair R Hawkins, Amedeo Caflisch, Concepcion Gonzalez-Bello
A multidisciplinary approach was used to identify and optimize a quinazolinedione-based ligand that would reduce the flexibility of the substrate-covering loop (catalytic loop) of the type II dehydroquinase from Helicobacter pylori. This enzyme, which is essential for the survival of this bacterium, is involved in the biosynthesis of the aromatic amino acids. A computer-aided fragment-based protocol (ALTA) was first employed to identify the aromatic fragments able to block the interface pocket that separates two neighbor enzyme subunits and is located at the active site entrance...
August 9, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28782186/application-of-the-pentafluorosulfanyl-group-as-a-bioisosteric-replacement
#5
Munia F Sowaileh, Robert Alan Hazlitt, David A Colby
The success of fluorinated molecules in drug design has led medicinal chemists to search for new fluorine-containing substituents. A major recently developed group is the pentafluorosulfanyl group. This group is stable under physiological conditions and displays unique physical and chemical properties. Currently, few synthetic methods exist that install the SF5 group, yet efforts to integrate this group into lead optimization continue unabated. Typically, the SF5 group has been used as a replacement for a trifluoromethyl, a tert-butyl, a halogen, or a nitro group...
August 7, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28776965/silicon-phthalocyanines-axially-disubstituted-with-erlotinib-towards-small-molecular-target-based-photodynamic-therapy
#6
Juan-Juan Chen, Yi-Zhen Huang, Mei-Ru Song, Zhi-Hong Zhang, Jin-Ping Xue
Small molecular target-based photodynamic therapy-a promising targeted anticancer strategy-has been developed by the conjugation between zinc (II) phthalocyanine and small molecular target-based anticancer drug. To inhibit the self-aggregation and avoid the isomeride problem of phthalocyanine, two silicon phthalocyanines di-substituted axially with erlotinib have been synthesized and fully characterized. These conjugates exist as a monomeric form in different solvents and the culture media. Cellular experiments showed that these conjugates localize in lysosomes and mitochondria, and keep high photodynamic activities (IC₅₀ is as low as 8 nM under 1...
August 4, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28776962/simultaneous-multiple-ms-binding-assays-addressing-d%C3%A2-and-d%C3%A2-dopamine-receptors
#7
Marion Schuller, Georg Höfner, Klaus Theodor Wanner
MS Binding Assays represent a label-free alternative to radioligand binding assays. They provide basically the same capabilities as the latter, however, employ a nonlabelled reporter ligand instead of a radioligand. In contrast to radioligand binding assays, MS Binding Assays offer - due to the selectivity of mass spectrometric detection - basically the opportunity to monitor binding of different reporter ligands towards different targets simultaneously. The present study shows a proof of concept for this strategy as exemplified for MS Binding Assays addressing selectively D₁ and D₂ Dopamine receptors in a single binding experiment...
August 4, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28776959/development-of-substrate-derived-mechanistic-sirtuin-inhibitors-with-potential-anti-cancer-activity
#8
Michael Lammers, Nora Kuhlmann, Linda Baldus, Ines Neundorf, Constance Chollet
RhoGDIα is a key regulator for Rho-proteins coordinating their GTP/GDP- and membrane/cytosol-cycle. Recently, it was demonstrated by quantitative mass spectrometry that RhoGDIα is heavily targeted by post-translational lysine-acetylation. For one site in its N-terminal domain, namely K52, we reported that acetylation completely switches off RhoGDIα function. Here, we show that K52-acetylated RhoGDIα is specifically deacetylated by the sirtuin deacetylase Sirt2.. We show that acetylation at K52 decelerates cervical cancer cell proliferation, suggesting RhoGDIα acetylation to be a promising therapeutic target...
August 4, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28776949/structure-guided-design-of-peptides-as-tools-to-probe-the-protein-protein-interaction-between-cullin-2-and-elongin-bc-substrate-adaptor-in-cullin-ring-e3-ubiquitin-ligases
#9
Teresa Cardote, Alessio Ciulli
Cullin RING E3 ubiquitin ligases (CRLs) are large dynamic multi-subunit complexes that control the fate of many proteins in cells. CRLs constitute attractive drug targets for the development of small-molecule inhibitors and chemical inducers of protein degradation. Here we describe a structure-guided biophysical approach to probe the protein-protein interaction (PPI) between the Cullin-2 scaffold protein and the adaptor subunits Elongin BC within the context of the von Hippel-Lindau complex (CRL2VHL) using peptides...
August 3, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28771957/bridging-pharmaceutical-chemistry-with-drug-and-nanoparticle-targeting-to-investigate-the-role-of-the-18-kda-translocator-protein-tspo
#10
REVIEW
Rosa Maria Iacobazzi, Antonio Lopalco, Annalisa Cutrignelli, Valentino Laquintana, Angela Lopedota, Massimo Franco, Nunzio Denora
An interesting mitochondrial biomarker is the 18-kDa mitochondrial translocator protein (TSPO). Decades of study have shown that this protein plays an important role in a wide range of cellular functions, including opening of the mitochondrial permeability transition pore as well as programmed cell death and proliferation. Variations in TSPO expression have been correlated to different diseases, from tumors to endocrine and neurological disorders. TSPO has therefore become an appealing target for both early diagnosis and selective mitochondrial drug delivery...
August 3, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28750143/characterization-of-small-molecule-scaffolds-that-bind-to-the-shigella-type-iii-secretion-system-protein-ipad
#11
Supratim Dey, Asokan Anbanandam, Ben E Mumford, Roberto N De Guzman
Many pathogens such as Shigella and other bacteria assemble the type III secretion system (T3SS) nanoinjector to inject virulence proteins into their target cells to cause infectious diseases in humans. The rise of drug resistance among pathogens that rely on the T3SS for infectivity, plus the dearth of new antibiotics require alternative strategies in developing new antibiotics. The Shigella T3SS tip protein IpaD is an attractive target for developing anti-infectives because of its essential role in virulence and its exposure on the bacterial surface...
July 27, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28749574/design-synthesis-pharmacological-evaluation-and-docking-studies-of-glun2b-selective-nmda-receptor-antagonists-with-a-benzo-7-annulen-7-amine-scaffold
#12
Sandeep Gawaskar, Louisa Temme, Julian A Schreiber, Dirk Schepmann, Alessandro Bonifazi, Dina Robaa, Wolfgang Sippl, Nathalie Strutz-Seebohm, Guiscard Seebohm, Bernhard Wünsch
Antagonists that selectively target GluN2B-subunit-containing N-methyl-d-aspartate (NMDA) receptors are of major interest for the treatment of various neurological disorders. In this study, relationships between variously substituted benzo[7]annulen-7-amines and their GluN2B affinity were investigated. 2-Nitro-5,6,8,9-tetrahydrobenzo[7]annulen-7-one (8) represents the central building block for the introduction of various substituents at the 2-position and various 7-amino moieties. N-(3-Phenylpropyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-amines with a 2-NO2 (7 c), 2-Cl (15 c), or 2-OBn group (22 c) show very high GluN2B affinity (Ki =1...
July 27, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28745428/what-do-we-miss-the-detergent-triton-x-100-added-to-avoid-compound-aggregation-can-affect-assay-results-in-an-unpredictable-manner
#13
Fabian G R Ehlert, Kerstin Linde, Wibke E Diederich
In this study we show that the detergent Triton X-100 being widely used in screening campaigns significantly reduces the binding affinities of some known specific inhibitors of HIV-1 protease and the well-established model protease endothiapepsin in a fluorescence-based assay. Surprisingly, other structurally related inhibitors remain entirely unaffected. In consequence, those compounds that were affected would most likely have been misclassified as unspecific binders although they actually are true positives, hence being considered excellent starting points for the further hit optimization...
July 26, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28741898/development-of-a-new-structural-class-of-broadly-acting-hcv-non-nucleoside-inhibitors-leading-to-the-discovery-of-mk-8876
#14
Casey C McComas, Anandan Palani, Wei Chang, M Katharine Holloway, Charles A Lesburg, Peng Li, Nigel Liverton, Peter T Meinke, David B Olsen, Xuanjia Peng, Richard M Soll, Ajay Ummat, Jie Wu, Jin Wu, Nicolas Zorn, Steven W Ludmerer
Studies directed at developing a broadly acting non-nucleoside inhibitor of HCV NS5B led to the discovery of a novel structural class of 5-aryl benzofurans that simultaneously interact with both the palm I and palm II binding regions. An initial candidate was potent in vitro against HCV GT1a and GT1b replicons, and induced multi-log reductions in HCV viral load when orally dosed to chronic GT1 infected chimpanzees. However, in vitro potency losses against clinically relevant GT1a variants prompted a further effort to develop compounds with sustained potency across a broader array of HCV genotypes and mutants...
July 25, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28741878/anticancer-gold-n-heterocyclic-carbene-complexes-a-comparative-in-vitro-and-ex-vivo-study
#15
Angela Casini, Natalia Estrada-Ortiz, Chiara Gabbiani, Federica Guarra, Geny Groothuis, Inge de Graaf, Marina de Jager, Lorella Marchetti
A series of organometallic Au(I) N-heterocyclic carbene (NHC) complexes was synthesized and characterized on anticancer activity in four human cancer cell lines. The compounds' toxicity in healthy tissue was determined using precision cut kidney slices (PCKS) as a tool to determine the potential selectivity of the Au complexes ex vivo. All evaluated compounds presented cytotoxic activity towards the cancer cells in the nano- or low micromolar range. The mixed Au(I) NHC complex - (ter-butylethynyl)-1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene gold(I), bearing an alkynyl moiety as ancillary ligand, showed high cytotoxicity in cancer cells in vitro, while being barely toxic in healthy rat kidney tissues...
July 25, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28741876/discovery-of-novel-potent-muscarinic-m3-receptor-antagonists-with-proper-plasma-stability-by-structural-recombination-of-marketed-m3-antagonists
#16
Zuojuan Xiang, Jun Liu, Hongbin Sun, Xiaoan Wen
The marketed long-acting M3 antagonists for treatment of chronic obstructive pulmonary disease have inappropriate plasma stability (either overstable or excessively unstable), which causes substantial systemic exposure or poor patient compliance. To discover novel M3 antagonists with proper plasma stability, we synthesized and biologically evaluated a series of chiral quaternary ammonium salts of pyrrolidinol esters, which were designed by structural recombination of the marketed M3 antagonists. As a result, two novel potent M3 antagonists, (R/S)-3-[2-hydroxy-2,2-di(thiophen-2-yl)acetoxy]-1,1-dimethylpyrrolidinium bromides (1 a: Ki =0...
July 25, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28741867/targeting-of-a-helix-loop-helix-transcriptional-regulator-by-a-short-helical-peptide
#17
Cornelia Roschger, Saskia Neukirchen, Brigitta Elsässer, Mario Schubert, Nicole Maeding, Thomas Verwanger, Barbara Krammer, Chiara Cabrele
The Id proteins (Id1-4) are cell cycle regulators that play a key role during development, in cancer and vascular disorders. They contain a conserved helix-loop-helix (HLH) domain that folds into a parallel four-helix bundle upon self- or heteroassociation with basic-HLH transcription factors. By using such protein-protein interactions, the Id proteins inhibit cell differentiation and promote cell cycle progression. Accordingly, their supporting role in cancer has been convincingly demonstrated, which makes these proteins interesting therapeutic targets...
July 25, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28741844/regulated-drug-release-abilities-of-calcium-carbonate-gelatin-hybrid-nanocarriers-fabricated-via-a-self-organizational-process
#18
Kazuki Murai, Kazuya Kurumisawa, Yoshihiro Nomura, Mutsuyoshi Matsumoto
In this study, we investigated the drug-releasing behavior of a calcium carbonate (CaCO3)-gelatin hybrid nanocarrier, fabricated via a single process using biomimetic mineralization. The organic scaffold (gelatin) of the fabricated nanocarrier is responsible for its ability to load anionic drugs and for controlling the morphology of the inorganic matrix (CaCO3). We studied the drug-releasing properties of the nanocarrier by investigating the response of the CaCO3 matrix to acidic conditions. We found that under neutral conditions, drug release from the nanocarrier was inhibited, while under acidic conditions, the drug was efficiently released...
July 25, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28737008/design-and-synthesis-of-new-4-alkylidene-beta-lactams-benzyl-and-phenethyl-carbamate-as-key-fragments-to-switch-on-the-antibacterial-activity
#19
Daria Giacomini, Giulia Martelli, Miriam Piccichè, Enrico Calaresu, Clementina Elvezia Anna Cocuzza, Rosario Musumeci
The emergence of multidrug resistant bacterial strains is particularly important in some chronic pathologies such as cystic fibrosis (CF), where persistent colonization and selection of resistant strains being favoured by the frequent and repeated use of antibacterial agents. Staphylococcus aureus is a common pathogen in CF patients with an associated increased multidrug resistance. In a previous research we demonstrated that the presence of a 4-alkylidene side chain directly linked to a beta-lactam appeared to strengthen the potency against S...
July 23, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28724198/direct-and-topoisomerase-ii-mediated-dna-damage-by-bis-3-chloropiperidines-the-importance-of-being-an-earnest-g
#20
Alice Sosic, Ivonne Zuravka, Nina-Katharina Schmitt, Angelica Miola, Richard Göttlich, Dan Fabris, Barbara Gatto
Bis-3-chloropiperidines are a new class of DNA-active compounds capable of alkylating nucleobases and inducing strand cleavage. In this report, we investigated the reactivity of these mustard-based agents with both single- and double-stranded DNA constructs. Polyacrylamide gel electrophoresis (PAGE) and electrospray ionization mass spectrometry (ESI-MS) were employed to obtain valuable insights into their mechanism at the molecular level and to investigate their time- and concentration-dependence. The results revealed the preferential formation of mono- and bifunctional adducts at nucleophilic guanine sites...
July 19, 2017: ChemMedChem
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