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Medicinal chemistry

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https://www.readbyqxmd.com/read/28531154/announcing-the-2017-pharmaceuticals-travel-award-for-young-post-doctoral-researchers
#1
EDITORIAL
Jean Jacques Vanden Eynde
Last year, for the first time in its history, our Journal was able to offer a travel grant of 800 CHF to a young researcher in the field of medicinal chemistry.
May 22, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/28527356/exceptional-release-kinetics-and-cytotoxic-selectivity-of-oxidised-mwcnts-double-functionalised-with-doxorubicin-and-prostate-homing-peptide
#2
Vedran Milosavljevic, Ludmila Krejcova, Roman Guran, Hana Buchtelova, Dorota Wawrzak, Lukas Richtera, Zbynek Heger, Pavel Kopel, Vojtech Adam
Multiwall carbon nanotubes (MWCNTs) are among the frequently studied carbon materials, particularly because of their physical and chemical properties and high potential for application in materials chemistry, industry, and medicine. MWCNTs are very promising as transporters of bioactive molecules because of their π electrons and large surface area, which can be easily modified, mostly by the application of inorganic acids for the introduction of carboxylic moieties on the surface. In the present study, we designed an oxidised MWCNTs (oMWCNTs) transporter for the targeted delivery of doxorubicin (Dox)...
May 3, 2017: Colloids and Surfaces. B, Biointerfaces
https://www.readbyqxmd.com/read/28527183/analytical-methods-in-tracing-honey-authenticity
#3
Jelena Trifković, Filip Andrić, Petar Ristivojević, Etil Guzelmeric, Erdem Yesilada
Honey is a precious natural product that is marketed with a wide range of nutritional and medicinal properties. However, it is also a product subjected to frequent adulteration through mislabeling and mixing with cheaper and lower-quality honeys and various sugar syrups. In that sense, honey authentication regarding its genuine botanical and geographical origins, as well as the detection of any adulteration, is essential in order to protect consumer health and to avoid competition that could create a destabilized market...
May 19, 2017: Journal of AOAC International
https://www.readbyqxmd.com/read/28525279/double-winged-3-hydroxypyrimidine-2-4-diones-potent-and-selective-inhibition-against-hiv-1-rnase-h-with-significant-antiviral-activity
#4
Sanjeev Kumar V Vernekar, Jing Tang, Bulan Wu, Andrew D Huber, Mary C Casey, Nataliya S Myshakina, Daniel J Wilson, Jayakanth Kankanala, Karen A Kirby, Michael A Parniak, Stefan G Sarafianos, Zhengqiang Wang
Human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function yet to be exploited as an antiviral target. One of the possible challenges may be that targeting HIV RNase H is confronted with a steep substrate barrier. We have previously reported a 3-hydroxypyrimidine-2,4-dione (HPD) subtype that potently and selectively inhibited RNase H without inhibiting HIV in cell culture. We report herein a critical redesign of the HPD chemotype featuring an additional wing at the C5 position that led to drastically improved RNase H inhibition and significant antiviral activity...
May 19, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28523098/incb24360-epacadostat-a-highly-potent-and-selective-indoleamine-2-3-dioxygenase-1-ido1-inhibitor-for-immuno-oncology
#5
Eddy W Yue, Richard Sparks, Padmaja Polam, Dilip Modi, Brent Douty, Brian Wayland, Brian Glass, Amy Takvorian, Joseph Glenn, Wenyu Zhu, Michael Bower, Xiangdong Liu, Lynn Leffet, Qian Wang, Kevin J Bowman, Michael J Hansbury, Min Wei, Yanlong Li, Richard Wynn, Timothy C Burn, Holly K Koblish, Jordan S Fridman, Tom Emm, Peggy A Scherle, Brian Metcalf, Andrew P Combs
A data-centric medicinal chemistry approach led to the invention of a potent and selective IDO1 inhibitor 4f, INCB24360 (epacadostat). The molecular structure of INCB24360 contains several previously unknown or underutilized functional groups in drug substances, including a hydroxyamidine, furazan, bromide, and sulfamide. These moieties taken together in a single structure afford a compound that falls outside of "drug-like" space. Nevertheless, the in vitro ADME data is consistent with the good cell permeability and oral bioavailability observed in all species (rat, dog, monkey) tested...
May 11, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28522885/dynamically-tunable-cell-culture-platforms-for-tissue-engineering-and-mechanobiology
#6
Koichiro Uto, Jonathan H Tsui, Cole A DeForest, Deok-Ho Kim
Human tissues are sophisticated ensembles of many distinct cell types embedded in the complex, but well-defined, structures of the extracellular matrix (ECM). Dynamic biochemical, physicochemical, and mechano-structural changes in the ECM define and regulate tissue-specific cell behaviors. To recapitulate this complex environment in vitro, dynamic polymer-based biomaterials have emerged as powerful tools to probe and direct active changes in cell function. The rapid evolution of polymerization chemistries, structural modulation, and processing technologies, as well as the incorporation of stimuli-responsiveness, now permit synthetic microenvironments to capture much of the dynamic complexity of native tissue...
February 2017: Progress in Polymer Science
https://www.readbyqxmd.com/read/28521678/ipgk-pseaac-identify-lysine-phosphoglycerylation-sites-in-proteins-by-incorporating-four-different-tiers-of-amino-acid-pairwise-coupling-information-into-the-general-pseaac
#7
Li-Ming Liu, Yan Xu, Kuo-Chen Chou
BACKGROUND: Occurring at Lys residues, the PGK (lysine phosphoglycerylation) is a special kind of post-translational modification (PTM). It may invert the charge potential of the modified residue and change the protein structures and functions, causing various diseases in liver, brain, and kidney. OBJECTIVE: From the angles of both basic research and drug development, we are facing a critical challenging problem: for an uncharacterized protein sequence containing many Lys residues, which ones can be of phosphoglycerylation, and which ones cannot? METHOD: To address this problem, we have developed a predictor called iPGK-PseAAC by incorporating into the general PseAAC (pseudo amino acid composition) with four different tiers of amino acid pairwise coupling information, where tiers 1, 2, 3, and 4 refer to the amino acid pairwise couplings between all the 1st, 2nd, 3rd, and 4th most contiguous residues along a protein segment, respectively...
May 15, 2017: Medicinal Chemistry
https://www.readbyqxmd.com/read/28520403/integrated-strategy-for-unknown-ei-ms-identification-using-quality-control-calibration-curve-multivariate-analysis-ei-ms-spectral-database-and-retention-index-prediction
#8
Teruko Matsuo, Hiroshi Tsugawa, Hiromi Miyagawa, Eiichiro Fukusaki
Compound identification using unknown electron ionization (EI) mass spectra in gas chromatography coupled with mass spectrometry (GC-MS) is challenging in untargeted metabolomics, natural product chemistry, or exposome research. While the total count of EI-MS records included in publicly or commercially available databases is over 900,000, efficient use of this huge database has not been achieved in metabolomics. Therefore, we proposed a 'four-step' strategy for the identification of biologically significant metabolites using an integrated cheminformatics approach: (i) Quality control calibration curve to reduce background noise, (ii) variable selection by hypothesis testing in principal component analysis for the efficient selection of target peaks, (iii) searching the EI-MS spectral database, and (iv) retention index (RI) filtering in combination with RI predictions...
May 18, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28518069/modification-and-functionalization-of-the-guanidine-group-by-tailor-made-precursors
#9
Tobias G Kapp, Maximilian Fottner, Horst Kessler
The guanidine group is one of the most important pharmacophoric groups in medicinal chemistry. The only amino acid carrying a guanidine group is arginine. In this article, an easy method for the modification of the guanidine group in peptidic ligands is provided, with an example of RGD-binding integrin ligands. It was recently demonstrated that the distinct modification of the guanidine group in these ligands allows for the selective modulation of the subtype (e.g., between the subtypes αv and α5). Moreover, a formerly unknown strategy for the functionalization via the guanidine group was demonstrated, and the synthetic approach is reviewed in this document...
April 27, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28511907/potential-inhibitors-of-human-carbonic-anhydrase-isozymes-i-and-ii-design-synthesis-and-docking-studies-of-new-1-3-4-thiadiazole-derivatives
#10
Mehlika Dilek Altıntop, Belgin Sever, Ahmet Özdemir, Kaan Kucukoglu, Hicran Onem, Hayrunnisa Nadaroglu, Zafer Asım Kaplancıklı
In the last years, inhibition of carbonic anhydrase (CA) has emerged as a promising approach for pharmacologic intervention in a variety of disorders such as glaucoma, epilepsy, obesity, and cancer. As a consequence, the design of CA inhibitors (CAIs) is a highly dynamic field of medicinal chemistry. Due to the therapeutic potential of thiadiazoles as CAIs, new 1,3,4-thiadiazole derivatives were synthesized and investigated for their inhibitory effects on hCA I and hCA II. Although the tested compounds did not carry a sulfonamide group, an important pharmacophore for CA inhibitory activity, it was a remarkable finding that most of them were more effective on hCAs than acetazolamide (AAZ), the reference agent...
May 5, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28510452/rational-optimization-of-mechanism-based-inhibitors-through-determination-of-the-microscopic-rate-constants-of-inactivation
#11
Carter G Eiden, Kimberly M Maize, Barry C Finzel, John D Lipscomb, Courtney C Aldrich
Mechanism-based inhibitors (MBIs) are widely employed in chemistry, biology, and medicine because of their exquisite specificity and sustained duration of inhibition. Optimization of MBIs is complicated because of time-dependent inhibition resulting from multistep inactivation mechanisms. The global kinetic parameters kinact and KI have been used to characterize MBIs, but they provide far less information than is commonly assumed, as shown by derivation and simulation of these parameters. We illustrate an alternative and more rigorous approach for MBI characterization through determination of the individual microscopic rate constants...
May 18, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28509362/developing-polyamine-based-peptide-amphiphiles-with-tunable-morphology-and-physicochemical-properties
#12
Mehdi Bin Samad, Yashpal Singh Chhonker, Jacob I Contreras, Alec McCarthy, Megan M McClanahan, Daryl J Murry, Martin Conda-Sheridan
The ability to tune supramolecular properties such as size, morphology, or metabolic stability is of paramount importance in the field of supramolecular chemistry. Peptide amphiphiles (PAs) are a family of functional self-assembling biomaterials that have garnered widespread attention due to their broad applicability in medicine. PAs are generally comprised of an amino acid sequence connected to lipid tail(s) allowing them to self-assemble into supramolecular structures with diverse morphologies. Herein, this study describes the synthesis of a new class of polyamine-based "hybrid" PAs (PPAs) as novel self-assembling systems...
May 16, 2017: Macromolecular Bioscience
https://www.readbyqxmd.com/read/28508381/visualization-of-metallodrugs-in-single-cells-by-secondary-ion-mass-spectrometry-imaging
#13
REVIEW
Kui Wu, Feifei Jia, Wei Zheng, Qun Luo, Yao Zhao, Fuyi Wang
Secondary ion mass spectrometry, including nanoscale secondary ion mass spectrometry (NanoSIMS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS), has emerged as a powerful tool for biological imaging, especially for single cell imaging. SIMS imaging can provide information on subcellular distribution of endogenous and exogenous chemicals, including metallodrugs, from membrane through to cytoplasm and nucleus without labeling, and with high spatial resolution and chemical specificity. In this mini-review, we summarize recent progress in the field of SIMS imaging, particularly in the characterization of the subcellular distribution of metallodrugs...
May 15, 2017: Journal of Biological Inorganic Chemistry: JBIC
https://www.readbyqxmd.com/read/28506751/recent-progress-towards-clinically-relevant-atp-competitive-akt-inhibitors
#14
REVIEW
Bayard R Huck, Igor Mochalkin
The frequency of PI3K/Akt/mTOR (PAM) Pathway mutations in human cancers sparked interest to determine if the pathway is druggable. The modest clinical benefit observed with mTOR rapalogs (temsirolimus and everolimus) provided further motivation to identify additional nodes of pathway inhibition that lead to improved clinical benefit. Akt is a central signaling node of the PAM pathway and could be an ideal target for improved pathway inhibition. Furthermore, inhibitors of Akt may be especially beneficial in tumors with Akt1 mutations...
April 29, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28504917/modulating-5-ht4-and-5-ht6-receptors-in-alzheimer-s-disease-treatment
#15
Julien Lalut, Delphine Karila, Patrick Dallemagne, Christophe Rochais
Alzheimer's disease (AD) is the most common form of dementia affecting millions of patients worldwide which can only be treated with symptomatic drugs. Among the numbers of biological targets which are today explored in order to prevent or limit the progression of AD, the modulation of 5-HT6R and 5-HT4R appeared to be promising. This modulation has been proved to enhance the cognition in AD through modulation of the neurotransmitter system but could also be beneficial in order to limit the amyloid pathology...
May 15, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28503695/cp-co-iii-catalyzed-directed-c-h-trifluoromethylthiolation-of-2-phenylpyridines-and-6-arylpurines
#16
Misaki Yoshida, Kentaro Kawai, Ryo Tanaka, Tatsuhiko Yoshino, Shigeki Matsunaga
Cp*Co(III)-catalyzed directed C-H trifluoromethylthiolation using N-trifluoromethylthiodibenzenesulfonimide as an electrophilic SCF3 source is described. 6-Arylpurines, an important structural motif in medicinal chemistry, and 2-phenylpyridines selectively afforded mono-trifluoromethylthiolated products in moderate to good yields using an inexpensive first-row transition metal catalyst.
May 15, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28501516/is-dual-inhibition-of-metalloenzymes-hdac-8-and-mmp-2-a-potential-pharmacological-target-to-combat-hematological-malignancies
#17
REVIEW
Sk Abdul Amin, Nilanjan Adhikari, Tarun Jha
For the last three decades, metalloenzymes such as histone deacetylases (HDACs) and matrix metalloproteinases (MMPs) have been identified in promoting solid as well as hematological carcinogenesis. Histone deacetylase 8 (HDAC-8), a class I HDAC enzyme, may serve as 'epigenetic player' that affects in the regulation of transcription factors and alters the structure of chromosome associated with tumorigenesis. It is established that the influence of MMP-2 in invasion, metastasis and angiogenenic events of hematological malignancies may be suppressed by HDAC inhibitors through reversion-inducing-cysteine-rich protein with kazal motifs (RECK) protein...
May 10, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28501511/identification-of-quinazoline-based-inhibitors-of-irak4-for-the-treatment-of-inflammation
#18
Graham F Smith, Michael D Altman, Brian Andresen, James Baker, Jason D Brubaker, Hongmin Chen, Yiping Chen, Matthew Childers, Anthony Donofrio, Heidi Ferguson, Christian Fischer, Thierry O Fischmann, Craig Gibeau, Alexander Hicks, Sue Jin, Sam Kattar, Melanie A Kleinschek, Erica Leccese, Charles Lesburg, Chaomin Li, Jongwon Lim, Duan Liu, John K F Maclean, Faruk Mansoor, Lilly Y Moy, Erin F Mulrooney, Antoaneta S Necheva, Jeremy Presland, Larissa Rakhilina, Ruojing Yang, Luis Torres, Jie Zhang-Hoover, Alan Northrup
Interleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity...
April 18, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28498658/discovery-of-clinical-candidate-1-2s-3s-4s-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl-methoxy-7-methoxyisoquinoline-6-carboxamide-pf-06650833-a-potent-selective-inhibitor-of-interleukin-1-receptor-associated-kinase-4-irak4-by-fragment-based-drug-design
#19
Katherine L Lee, Catherine M Ambler, David R Anderson, Brian P Boscoe, Andrea G Bree, Joanne I Brodfuehrer, Jeanne S Chang, Chulho Choi, Seung Won Chung, Kevin J Curran, Jacqueline E Day, Christoph M Dehnhardt, Ken Dower, Susan E Drozda, Richard K Frisbie, Lori Krim Gavrin, Joel A Goldberg, Seungil Han, Martin Hegen, David Hepworth, Heidi R Hope, Satwik Kamtekar, Iain C Kilty, Arthur Lee, Lih-Ling Lin, Frank E Lovering, Michael D Lowe, John P Mathias, Heidi M Morgan, Elizabeth A Murphy, Nikolaos Papaioannou, Akshay Patny, Betsy S Pierce, Vikram R Rao, Eddine Saiah, Ivan J Samardjiev, Brian M Samas, Marina W H Shen, Julia H Shin, Holly H Soutter, Joseph W Strohbach, Peter T Symanowicz, Jennifer R Thomason, John D Trzupek, Richard Vargas, Fabien Vincent, Jiangli Yan, Christoph W Zapf, Stephen W Wright
Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40)...
May 12, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28497493/natural-and-synthetic-flavonoids-as-potent-mycobacterium-tuberculosis-ugm-inhibitors
#20
Stephane Vincent, Sydney Villaume, Jian Fu, Inès N'Go, Huayong Lou, Hui Liang, Laurent Kremer, Weidong Pan
This study reports a novel class of inhibitors of UDP-galactopyranose mutase (UGM) derived from a screening of natural products. This enzyme is an essential biocatalyst involved in the cell wall biosynthesis of Mycobacterium tuberculosis. Flavonoids were found to be potent inhibitors of UGM. The synthesis of novel methylated flavonoids allowed to perform a structure-activity relationship analysis and to determine which functional groups and structural elements are required for UGM inhibition.The binding mode of one of the best inhibitor was found to be non-competitive...
May 11, 2017: Chemistry: a European Journal
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