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MedChemComm

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https://www.readbyqxmd.com/read/29034069/scaffold-hopping-via-anchor-query-%C3%AE-lactams-as-potent-p53-mdm2-antagonists-%C3%A2
#1
S Shaabani, C G Neochoritis, A Twarda-Clapa, B Musielak, T A Holak, A Dömling
Using the pharmacophore-based virtual screening platform ANCHOR.QUERY, we morphed our recently described Ugi-4CR scaffold towards a β-lactam scaffold with potent p53-MDM2 antagonizing activities. 2D-HSQC and FP measurements confirm potent MDM2 binding. Molecular modeling studies are used to understand the observed SAR in the β-lactam series.
May 1, 2017: MedChemComm
https://www.readbyqxmd.com/read/28993794/antitrypanosomal-and-antileishmanial-activity-of-prenyl-1-2-3-triazoles
#2
Exequiel O J Porta, Sebastián N Jäger, Isabel Nocito, Galina I Lepesheva, Esteban C Serra, Babu L Tekwani, Guillermo R Labadie
A series of prenyl 1,2,3-triazoles were prepared from isoprenyl azides and different alkynes. The dipolar cycloaddition reaction provided exclusively primary azide products as regioisomeric mixtures that were separated by column chromatography and fully characterized. Most of the compounds displayed antiparasitic activity against Trypanosoma cruzi and Leishmania donovani. The most active compounds were assayed as potential TcCYP51 inhibitors.
May 1, 2017: MedChemComm
https://www.readbyqxmd.com/read/28798862/amiloride-as-a-new-rna-binding-scaffold-with-activity-against-hiv-1-tar
#3
Neeraj N Patwardhan, Laura R Ganser, Gary J Kapral, Christopher S Eubanks, Janghyun Lee, Bharathwaj Sathyamoorthy, Hashim M Al-Hashimi, Amanda E Hargrove
Diversification of RNA-targeted scaffolds offers great promise in the search for selective ligands of therapeutically relevant RNA such as HIV-1 TAR. We herein report the establishment of amiloride as a novel RNA-binding scaffold along with synthetic routes for combinatorial C(5)- and C(6)-diversification. Iterative modifications at the C(5)- and C(6)- positions yielded derivative 24, which demonstrated a 100-fold increase in activity over the parent dimethylamiloride in peptide displacement assays. NMR chemical shift mapping was performed using the 2D SOFAST- [(1)H-(13)C] HMQC NMR method, which allowed for facile and rapid evaluation of binding modes for all library members...
May 1, 2017: MedChemComm
https://www.readbyqxmd.com/read/28626548/nonomuraea-sp-atcc-55076-harbours-the-largest-actinomycete-chromosome-to-date-and-the-kistamicin-biosynthetic-gene-cluster
#4
Behnam Nazari, Clarissa C Forneris, Marcus I Gibson, Kyuho Moon, Kelsey R Schramma, Mohammad R Seyedsayamdost
Glycopeptide antibiotics (GPAs) have served as potent clinical drugs and as an inspiration to chemists in various disciplines. Among known GPAs, complestatin, chloropeptin, and kistamicin are unique in that they contain an unusual indole-phenol crosslink. The mechanism of formation of this linkage is unknown, and to date, the biosynthetic gene cluster of only one GPA with an indole-phenol crosslink, that of complestatin, has been identified. Here, we report the genome sequence of the kistamicin producer Nonomuraea sp...
April 1, 2017: MedChemComm
https://www.readbyqxmd.com/read/28890776/discovery-of-a-potent-protein-kinase-d-inhibitor-insights-in-the-binding-mode-of-pyrazolo-3-4-d-pyrimidine-analogues
#5
Klaas Verschueren, Mathias Cobbaut, Joachim Demaerel, Lina Saadah, Arnout R D Voet, Johan Van Lint, Wim M De Borggraeve
In this study, we set out to rationally optimize PKD inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold. The lead compound for this study was 1-NM-PP1, which was previously found by us and others to inhibit PKD. In our screening we identified one compound (3-IN-PP1) displaying a 10-fold increase in potency over 1-NM-PP1, opening new possibilities for specific protein kinase inhibitors for kinases that show sensitivity towards pyrazolo[3,4-d]pyrimidine derived compounds. Interestingly the observed SAR was not in complete agreement with the commonly observed binding mode where the pyrazolo[3,4-d]pyrimidine compounds are bound in a similar fashion as PKD's natural ligand ATP...
March 1, 2017: MedChemComm
https://www.readbyqxmd.com/read/28533894/a-scaffold-merging-approach-to-hsp90-c-terminal-inhibition-synthesis-and-evaluation-of-a-chimeric-library
#6
Rachel E Davis, Zheng Zhang, Brian S J Blagg
Inhibition of the Hsp90 C-terminus is an attractive therapeutic paradigm for the treatment of cancer, however the developmental space of C-terminal inhibitors is limited. It was hypothesized that the combination of two previously identified scaffolds into a single structure could provide a platform for which to probe the three-dimensional space within the Hsp90 C-terminal binding pocket. The resulting chimeric compounds displayed anti-proliferative activity at low micromolar concentrations and manifested inhibitory activity in an Hsp90-dependent rematuration assay...
March 1, 2017: MedChemComm
https://www.readbyqxmd.com/read/28649316/discovery-of-decamidine-as-a-new-and-potent-prmt1-inhibitor
#7
Jing Zhang, Kun Qian, Chunli Yan, Maomao He, Brenson A Jassim, Ivaylo Ivanov, Yujun George Zheng
Protein arginine methyltransferase 1 (PRMT1) is a key player for the dynamic regulation of arginine methylation. Its dysregulation and aberrant expression are implicated in various pathological conditions, and a plethora of evidence suggests that PRMT1 inhibition is of significant therapeutic value. Herein, we reported the modification of a series of diamidine compounds with varied lengths in the middle alkyl linker for PRMT1 inhibition. Decamidine (2j), which possesses the longest linker in the series, displayed 2- and 4- fold increase in PRMT1 inhibition (IC50 = 13 μM), as compared with furamdine and stilbamidine...
February 1, 2017: MedChemComm
https://www.readbyqxmd.com/read/28670440/phenotype-based-variation-as-a-biomarker-of-sensitivity-to-molecularly-targeted-therapy-in-melanoma
#8
Kerem M Senses, Mehdi Ghasemi, Muhammad W Akbar, Murat Isbilen, Anna L Fallacara, Shoshana Frankenburg, Silvia Schenone, Michal Lotem, Maurizio Botta, Ali O Gure
Transcriptomic phenotypes defined for melanoma have been reported to correlate with sensitivity to various drugs. In this study, we aimed to define a minimal signature that could be used to distinguish melanoma sub-types in vitro, and to determine suitable drugs by which these sub-types can be targeted. By using primary melanoma cell lines, as well as commercially available melanoma cell lines, we find that the evaluation of MLANA and INHBA expression is as capable as one based on a combined analysis performed with genes for stemness, EMT and invasion/proliferation, in identifying melanoma subtypes that differ in their sensitivity to molecularly targeted drugs...
January 1, 2017: MedChemComm
https://www.readbyqxmd.com/read/28626547/structure-guided-optimization-of-quinoline-inhibitors-of-plasmodium-n-myristoyltransferase
#9
Victor Goncalves, James A Brannigan, Alice Laporte, Andrew S Bell, Shirley M Roberts, Anthony J Wilkinson, Robin J Leatherbarrow, Edward W Tate
The parasite Plasmodium vivax is the most widely distributed cause of recurring malaria. N-Myristoyltransferase (NMT), an enzyme that catalyses the covalent attachment of myristate to the N-terminal glycine of substrate proteins, has been described as a potential target for the treatment of this disease. Herein, we report the synthesis and the structure-guided optimization of a series of quinolines with balanced activity against both Plasmodium vivax and Plasmodium falciparum N-myristoyltransferase (NMT).
January 1, 2017: MedChemComm
https://www.readbyqxmd.com/read/28603600/synthesis-and-pharmacological-evaluation-of-novel-selective-mor-agonist-6%C3%AE-pyridinyl-amidomorphines-exhibiting-long-lasting-antinociception
#10
Ákos Urai, András Váradi, Levente Szőcs, Balázs Komjáti, Valerie Le Rouzic, Amanda Hunkele, Gavril W Pasternak, Susruta Majumdar, Sándor Hosztafi
It was previously reported that 6β-aminomorphinan derivatives show high affinity for opiate receptors. Novel 6β-heteroarylamidomorphinanes were designed based on the MOR selective antagonist NAP. The 6β-aminomorphinanes were prepared with stereoselective Mitsunobu reaction and subsequently acylated with nicotinic acid and isonicotinic acid chloride hydrochlorides. The receptor binding and efficacy were determined in vitro and the analgesic activity was studied in vivo. The in vitro studies revealed moderate selectivity for MOR...
January 1, 2017: MedChemComm
https://www.readbyqxmd.com/read/28217276/synthesis-and-biological-evaluation-of-benzocyclooctene-based-and-indene-based-anticancer-agents-that-function-as-inhibitors-of-tubulin-polymerization
#11
Christine A Herdman, Tracy E Strecker, Rajendra P Tanpure, Zhi Chen, Alex Winters, Jeni Gerberich, Li Liu, Ernest Hamel, Ralph P Mason, David J Chaplin, Mary Lynn Trawick, Kevin G Pinney
The natural products colchicine and combretastatin A-4 (CA4) have been inspirational for the design and synthesis of structurally related analogues and spin-off compounds as inhibitors of tubulin polymerization. The discovery that a water-soluble phosphate prodrug salt of CA4 (referred to as CA4P) is capable of imparting profound and selective damage to tumor-associated blood vessels paved the way for the development of a new therapeutic approach for cancer treatment utilizing small-molecule inhibitors of tubulin polymerization that also act as vascular disrupting agents (VDAs)...
December 1, 2016: MedChemComm
https://www.readbyqxmd.com/read/28337336/sar-and-identification-of-2-quinolin-4-yloxy-acetamides-as-mycobacterium-tuberculosis-cytochrome-bc1-inhibitors
#12
Narisa Phummarin, Helena I Boshoff, Patricia S Tsang, James Dalton, Siouxsie Wiles, Clifton E Barry Rd, Brent R Copp
A previous phenotypic screen by GSK identified 2-(quinolin-4-yloxy)acetamides as potent growth inhibitors of Mycobacterium tuberculosis (Mtb). We report the results of a preliminary structure-activity relationship (SAR) study of the compound class which has yielded more potent inhibitors. An Mtb cytochrome bd oxidase deletion mutant (cydKO) was found to be hypersensitive to most members of the compound library, while strains carrying single-nucleotide polymorphisms of the qcrB gene, which encodes a subunit of the menaquinol cytochrome c oxidoreductase (bc1) complex, were resistant to the library...
November 1, 2016: MedChemComm
https://www.readbyqxmd.com/read/27840672/improved-antiviral-activity-of-a-polyamide-against-high-risk-human-papillomavirus-via-n-terminal-guanidinium-substitution
#13
C H Castaneda, M J Scuderi, T G Edwards, G D Harris, C M Dupureur, K J Koeller, C Fisher, J K Bashkin
We report the synthesis of two novel pyrrole-imidazole polyamides with N-terminal guanidinium or tetramethylguanidinium groups and evaluate their antiviral activity against three cancer-causing human papillomavirus strains. Introduction of guanidinium improves antiviral activity when compared to an unsubstituted analog, especially in IC90 values. These substitutions change DNA-binding preferences, while binding affinity remains unchanged.
November 1, 2016: MedChemComm
https://www.readbyqxmd.com/read/28948007/crosslinking-of-dna-linked-ligands-to-target-proteins-for-enrichment-from-dna-encoded-libraries
#14
Kyle E Denton, Casey J Krusemark
Achieving sufficient enrichment of ligands from DNA-encoded libraries for detection can be difficult, particularly for low affinity ligands within highly complex libraries. To address this challenge, we present an approach for crosslinking DNA-linked ligands to target proteins using electrophilic or photoreactive groups. The approach involves the teathering of a ssDNA oligonucleotide to a DNA-encoded molecule to enable attachment of a reactive group post-synthetically via DNA hybridization. Crosslinking traps ligand-protein complexes while in solution and allows for stringent washing conditions to be applied in the subsequent purification...
October 1, 2016: MedChemComm
https://www.readbyqxmd.com/read/27891211/from-linked-open-data-to-molecular-interaction-studying-selectivity-trends-for-ligands-of-the-human-serotonin-and-dopamine-transporter
#15
Barbara Zdrazil, Eva Hellsberg, Michael Viereck, Gerhard F Ecker
Retrieval of congeneric and consistent SAR data sets for protein targets of interest is still a laborious task to do if no appropriate in-house data set is available. However, combining integrated open data sources (such as the Open PHACTS Discovery Platform) with workflow tools now offers the possibility of querying across multiple domains and tailoring the search to the given research question. Starting from two phylogenetically related protein targets of interest (the human serotonin and dopamine transporters), the whole chemical compound space was explored by implementing a scaffold-based clustering of compounds possessing biological measurements for both targets...
September 14, 2016: MedChemComm
https://www.readbyqxmd.com/read/28093576/synthetic-%C3%AE-hydroxytropolones-as-inhibitors-of-hiv-reverse-transcriptase-ribonuclease-h-activity
#16
Ryan P Murelli, Michael P D'Erasmo, Danielle R Hirsch, Christine Meck, Takashi Masaoka, Jennifer A Wilson, Baofeng Zhang, Rajat K Pal, Emilio Gallicchio, John A Beutler, Stuart F J Le Grice
HIV Reverse Transcriptase-associated ribonuclease H activity is a promising enzymatic target for drug development that has not been successfully targeted in the clinic. While the α-hydroxytropolone-containing natural products β-thujaplicinol and manicol have emerged as some of the most potent leads described to date, structure-function studies have been limited to the natural products and semi-synthetic derivatives of manicol. Thus, a library of α-hydroxytropolones synthesized through a convenient oxidopyrylium cycloaddition/ring-opening sequence have been tested in in vitro and cell-based assays, and have been analyzed using computational support...
September 1, 2016: MedChemComm
https://www.readbyqxmd.com/read/28090282/traceless-solid-phase-%C3%AE-hydroxytropolone-synthesis
#17
Michael P D'Erasmo, Takashi Masaoka, Jennifer A Wilson, Errol M Hunte, John A Beutler, Stuart F J Le Grice, Ryan P Murelli
α-Hydroxytropolones are established inhibitors of several therapeutically relevant binuclear metalloenzymes, and thus lead drug targets for various human diseases. We have leveraged a recently-disclosed three-component oxidopyrylium cycloaddition in the first solid-phase synthesis of α-hydroxytropolones. We also showed that, while minor impurities exist after cleavage and aqueous wash, the semi-crude products display activity in HIV RT-associated RNaseH enzymatic and cell-based assays consistent with pure molecules made in solution phase...
September 1, 2016: MedChemComm
https://www.readbyqxmd.com/read/28042453/design-and-synthesis-of-selective-small-molecule-inhibitors-of-coactivator-associated-arginine-methyltransferase-1-carm1
#18
H Ü Kaniskan, M S Eram, J Liu, D Smil, M L Martini, Y Shen, V Santhakumar, P J Brown, C Arrowsmith, M Vedadi, J Jin
Coactivator-associated arginine methyltransferase 1 (CARM1) is a type I protein arginine methyltransferase (PRMT) that catalyzes the conversion of arginine into monomethylarginine (MMA) and further into asymmetric dimethylarginine (ADMA). CARM1 methylates histone 3 arginines 17 and 26, as well as numerous non-histone proteins including CBP/p300, SRC-3, NCOA2, PABP1, and SAP49, while also functioning as a coactivator for various proteins that have been linked to cancer such as p53, NF-κβ, β-catenin, E2F1 and steroid hormone receptor ERα...
September 1, 2016: MedChemComm
https://www.readbyqxmd.com/read/28042452/anticancer-agents-interacting-with-membrane-glucose-transporters
#19
C Granchi, S Fortunato, F Minutolo
The altered metabolism observed in cancer cells generally consists in increased glucose uptake and glycolytic activity. This is associated with an overexpression of glucose transporter proteins (GLUTs), which facilitate glucose uptake across the plasma membrane and play a crucial role in the survival of cancer cells. Therefore GLUTs are considered as suitable targets for the treatment of cancer. Herein we review some of the most relevant GLUT inhibitors that have been recently developed as prospective anticancer agents...
September 1, 2016: MedChemComm
https://www.readbyqxmd.com/read/27642504/recent-advances-in-the-rational-design-and-optimization-of-antibacterial-agents
#20
Jesse A Jones, Kristopher G Virga, Giuseppe Gumina, Kirk E Hevener
This review discusses next-generation antibacterial agents developed using rational, or targeted, drug design strategies. The focus of this review is on small-molecule compounds that have been designed to bypass developing bacterial resistance, improve the antibacterial spectrum of activity, and/or to optimize other properties, including physicochemical and pharmacokinetic properties. Agents are discussed that affect known antibacterial targets, such as the bacterial ribosome, nucleic acid binding proteins, and proteins involved in cell-wall biosynthesis; as well as some affecting novel bacterial targets which do not have currently marketed agents...
September 1, 2016: MedChemComm
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