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Bioorganic & Medicinal Chemistry Letters

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https://www.readbyqxmd.com/read/27923620/fluorescent-diphenylphosphonate-based-probes-for-detection-of-serine-protease-activity-during-inflammation
#1
Laura E Edgington-Mitchell, Nicholas Barlow, Luigi Aurelio, Aminath Samha, Monika Szabo, Bim Graham, Nigel Bunnett
Activity-based probes are small molecules that covalently bind to the active site of a protease in an activity-dependent manner. We synthesized and characterized two fluorescent activity-based probes that target serine proteases with trypsin-like or elastase-like activity. We assessed the selectivity and potency of these probes against recombinant enzymes and demonstrated that while they are efficacious at labeling active proteases in complex protein mixtures in vitro, they are less valuable for in vivo studies...
November 25, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27923618/novel-3-methylindoline-inhibitors-of-ezh2-design-synthesis-and-sar
#2
Amantullah Ansari, Sharad Satalkar, Varshavekumar Patil, Amit S Shete, Simranjeet Kaur, Ashu Gupta, Siddhartha Singh, Mohd Raja, Daniel L Severance, Sebastián Bernales, Sarvajit Chakravarty, David T Hung, Son M Pham, Francisco J Herrera, Roopa Rai
EZH2 (enhancer of zeste homologue 2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes the methylation of lysine 27 of histone H3 (H3K27). Dysregulation of EZH2 activity is associated with several human cancers and therefore EZH2 inhibition has emerged as a promising therapeutic target. Several small molecule EZH2 inhibitors with different chemotypes have been reported in the literature, many of which use a bicyclic heteroaryl core. Herein, we report the design and synthesis of EZH2 inhibitors containing an indoline core...
November 25, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27923617/novel-pyrazolo-1-5-a-pyridines-with-improved-aqueous-solubility-as-p110%C3%AE-selective-pi3-kinase-inhibitors
#3
Jackie D Kendall, Anna C Giddens, Kit Yee Tsang, Elaine S Marshall, Claire L Lill, Woo-Jeong Lee, Sharada Kolekar, Mindy Chao, Alisha Malik, Shuqiao Yu, Claire Chaussade, Christina Buchanan, Stephen M F Jamieson, Gordon W Rewcastle, Bruce C Baguley, William A Denny, Peter R Shepherd
As part of our investigation into pyrazolo[1,5-a]pyridines as novel p110α selective PI3 kinase inhibitors, we report a range of analogues with improved aqueous solubility by the addition of a basic amine. The compounds demonstrated comparable p110α potency and selectivity to earlier compounds but with up to 1000× greater aqueous solubility, as the hydrochloride salts. The compounds also displayed good activity in a cellular assay of PI3 kinase activity.
November 25, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27919655/novel-carbazole-sulfonamide-derivatives-of-antitumor-agent-synthesis-antiproliferative-activity-and-aqueous-solubility
#4
Lianqi Sun, Yanbin Wu, Yonghua Liu, Xiaofang Chen, Laixing Hu
The current optimization of IG-105 (3) on the carbazole-ring provided a series of new carbazole sulfonamides derivatives 13a-13m. All of the compounds have been evaluated against HepG2 cells (hepatoma cancer) for antiproliferative activity. Compounds that showed activity better or comparable to that of 3 versus HepG2 were evaluated against MCF-7 (breast cancer), MIA PaCa-2 (pancreatic cancer), and Bel-7402 (hepatoma/liver cancer) for antiproliferative activity. Of the seven compounds selected for further study five (13b, 13g, 13j, 13k and 13l) were found to give IC50 values against the four cell lines comparable to those for 3...
November 25, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27916489/synthesis-and-evaluation-of-the-anti-proliferative-activity-of-diaryl-3-pyrrolin-2-ones-and-fused-analogs
#5
Patricia Mowery, Fernando Banales Mejia, Courtney L Franceschi, Maeve H Kean, Deborah O Kwansare, Megan M Lafferty, Namita D Neerukonda, Carly E Rolph, Nathanyal J Truax, Erin T Pelkey
Analogs containing a central 3-pyrrolin-2-one core with different methoxyphenyl and/or indole substituents were prepared and tested for anti-proliferative activity in U-937 cells. The most efficacious analogs were non-rigid, (non-fused) contained methoxyaryl groups located at the 4-position, and contained either methoxyaryl or indole groups located at the 3-position. Both the number of methoxy groups contained in the substituents and the particular location of the indole rings with respect to the lactam carbonyl had significant affects on anti-proliferative activity...
November 25, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27914798/antimycobacterial-activity-of-novel-hydrazide-hydrazone-derivatives-with-2h-chromene-and-coumarin-scaffold
#6
Violina T Angelova, Violeta Valcheva, Nikolay G Vassilev, Rosen Buyukliev, Georgi Momekov, Ivan Dimitrov, Luciano Saso, Mirjana Djukic, Boris Shivachev
This study reports the synthesis of new 2H-chromene or coumarin based acylhydrazones, which were evaluated for their in vitro antimycobacterial activity against reference strain Mycobacterium tuberculosis H37Rv and compared to the first-line antituberculosis drugs, isoniazid (INH) and ethambutol (EMB). The most active compounds 7m (MIC 0.13μM), 7o (MIC 0.15μM) and 7k (MIC 0.17μM) demonstrated antimycobacterial activity at submicromolar concentration level and remarkably minimal associated cytotoxicity in the human embryonic kidney cell line HEK-293T...
November 25, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27923619/synthesis-and-application-of-%C3%AE-carbolines-as-novel-multi-functional-anti-alzheimer-s-disease-agents
#7
William Horton, Abha Sood, Swarada Peerannawar, Nandor Kugyela, Aditya Kulkarni, Rekha Tulsan, Chris D Tran, Jessica Soule, Harry LeVine, Béla Török, Marianna Török
The design, synthesis and assessment of β-carboline core-based compounds as potential multifunctional agents against several processes that are believed to play a significant role in Alzheimer's disease (AD) pathology, are described. The activity of the compounds was determined in Aβ self-assembly (fibril and oligomer formation) and cholinesterase (AChE, BuChE) activity inhibition, and their antioxidant properties were also assessed. To obtain insight into the mode of action of the compounds, HR-MS studies were carried out on the inhibitor-Aβ complex formation and molecular docking was performed on inhibitor-BuChE interactions...
November 24, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27919659/synthesis-and-sar-study-of-novel-sarsasapogenin-derivatives-as-potent-neuroprotective-agents-and-no-production-inhibitors
#8
Hui Pan, Pham Van Khang, Dong Dong, Rui Wang, Lei Ma
Sarsasapogenin, isolated from rhizomes of Anemarrhena asphodeloides, was found to be able to enhance memory. On the basis of the structure of Sarsasapogenin, a series of derivatives were synthesized and evaluated for their neuroprotective activity in PC12 cells and NO production inhibitory activity in RAW264.7 cell lines. The preliminary structure-activity relationship of them indicated that introduction of carbamate groups at the 3-hydroxyl position of sarsasapogenin might improve neuroprotective activity...
November 24, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27919658/quinolizinium-as-a-new-fluorescent-lysosomotropic-probe
#9
Emmanouil Zacharioudakis, Tatiana Cañeque, Raúl Custodio, Sebastian Müller, Ana M Cuadro, Juan J Vaquero, Raphaël Rodriguez
We have synthesized a collection of quinolizinium fluorescent dyes for the purpose of cell imaging. Preliminary biological studies in human U2OS osteosarcoma cancer cells have shown that different functional groups appended to the cationic quinolizinium scaffold efficiently modulate photophysical properties but also cellular distribution. While quinolizinium probes are known nuclear staining reagents, we have identified a particular quinolizinium derivative salt that targets the lysosomal compartment. This finding raises the question of predictability of specific organelle targeting from structural features of small molecules...
November 24, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27919656/biotransformation-of-isofraxetin-6-o-%C3%AE-d-glucopyranoside-by-angelica-sinensis-oliv-diels-callus
#10
Di Zhou, Yuhua Zhang, Zhe Jiang, Yue Hou, Kun Jiao, Chunyan Yan, Ning Li
Isofraxetin-6-O-β-d-glucopyranoside, identified from traditional medicinal herbal Xanthoceras sorbifolia Bunge, has been demonstrated to be a natural neuroinflammatory inhibitor. In order to obtain more derivatives with potential anti-neuroinflammatory effects, biotransformation was carried out. According to the characteristics of coumarin skeleton, suspension cultures of Angelica sinensis (Oliv.) Diels callus (A. sinensis callus) were employed because of the presence of diverse phenylpropanoids biosynthetic enzymes...
November 24, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27914799/computational-approach-for-the-assessment-of-inhibitory-potency-against-beta-amyloid-aggregation
#11
Marek Bajda, Sławomir Filipek
Beta-amyloid (Aβ) plaques are one of the hallmarks of Alzheimer's disease. Their presence in the brain leads to neurodegeneration and memory decline. Therefore, search for new drugs able to decrease formation of such deposits is of great interest. Our previously developed multifunctional compounds inhibited transformation of monomers into fibrils. Herein, we describe the computational approach for the assessment of inhibitory activity against Aβ aggregation. The influence of novel inhibitors on amyloid Aβ17-42 was studied by employing of molecular docking and all-atom molecular dynamics simulations...
November 24, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27914796/design-and-synthesis-of-new-piperidone-grafted-acetylcholinesterase-inhibitors
#12
Alireza Basiri, Michelle Xiao, Alec McCarthy, Debashis Dutta, Siddappa N Byrareddy, Martin Conda-Sheridan
Alzheimer's disease (AD) is a neurodegenerative disorder affecting 35million people worldwide. A common strategy to improve the well-being of AD patients consists on the inhibition of acetylcholinesterase with the concomitant increase of the neurotransmitter acetylcholine at cholinergic synapses. Two series of unreported N-benzylpiperidines 5(a-h) and thiazolopyrimidines 9(a-q) molecules were synthesized and evaluated in vitro for their acetylcholinesterase (AChE) inhibitory activities. Among the newly synthesized compounds, 5h, 9h, 9j, and 9p displayed higher AChE enzyme inhibitory activities than the standard drug, galantamine, with IC50 values of 0...
November 24, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27913183/nmr-strategies-to-support-medicinal-chemistry-workflows-for-primary-structure-determination
#13
Paul Oguadinma, Francois Bilodeau, Steven R LaPlante
Central to drug discovery is the correct characterization of the primary structures of compounds. In general, medicinal chemists make great synthetic and characterization efforts to deliver the intended compounds. However, there are occasions which incorrect compounds are presented, such as those reported for Bosutinib and TIC10. This may be due to a variety of reasons such as uncontrolled reaction schemes, reliance on limited characterization techniques (LC-MS and/or 1D 1H NMR spectra), or even the lack of availability or knowledge of characterization strategies...
November 24, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27914802/synthesis-and-in-vitro-antiproliferative-activity-of-c5-benzyl-substituted-2-amino-pyrrolo-2-3-d-pyrimidines-as-potent-hsp90-inhibitors
#14
Ju-Hyeon Lee, Sang Chul Shin, Seon Hee Seo, Young Ho Seo, Nakcheol Jeong, Chan-Wha Kim, Eunice EunKyeong Kim, Gyochang Keum
A novel series of heat shock protein 90 (Hsp90) inhibitors was identified by X-ray crystal analysis of complex structures at solvent-exposed exit pocket C. The 2-amino-pyrrolo[2,3-d]pyrimidine derivatives, 7-deazapurines substituted with a benzyl moiety at C5, showed potent Hsp90 inhibition and broad-spectrum antiproliferative activity against NCI-60 cancer cell lines. The most potent compound, 6a, inhibited Hsp90 with an IC50 of 36nM and showed a submicromolar mean GI50 value against NCI-60 cell lines. The interaction of 6a at the ATP-binding pocket of Hsp90 was confirmed by X-ray crystallography and Western blot analysis...
November 23, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27914797/design-synthesis-and-fungicidal-activity-of-novel-2-substituted-aminocycloalkylsulfonamides
#15
Caixiu Liu, Xiaojing Yan, Minlong Wang, Peiwen Qin, Zhiqiu Qi, Mingshan Ji, Xingyu Liu, P Vijaya Babu, Xinghai Li, Zi-Ning Cui
A series of novel 2-substituted aminocycloalkylsulfonamides were designed and synthesized by highly selective N-alkylation reaction, whose structures were characterized by (1)H NMR, (13)C NMR and HRMS. Among them, the configuration of compounds III12 and III20 were confirmed by X-ray single crystal diffraction. Bioassays demonstrated that the title compounds had considerable effects on different strains of Botrytis cinerea and Pyricularia grisea. Comparing with positive control procymidone (EC50=10.31mg/L), compounds III28, III29, III30 and III31 showed excellent fungicidal activity against a strain of B...
November 23, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27913182/virtual-screening-and-biophysical-studies-lead-to-hsp90-inhibitors
#16
Renjie Huang, Daniel M Ayine-Tora, M Nasri Muhammad Rosdi, Yu Li, Jóhannes Reynisson, Ivanhoe K H Leung
Heat shock protein 90 (HSP90) is a molecular chaperone that plays important functional roles in cells. The chaperone activity of HSP90 is regulated by the hydrolysis of ATP at the protein's N-terminal domain. HSP90, in particular the N-terminal domain, is a current inhibition target for therapeutic treatments of cancers. This paper describes an application of virtual screening, thermal shift assaying and protein NMR spectroscopy leading to the discovery of HSP90 inhibitors that contain the resorcinol structure...
November 23, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27913181/squarate-based-carbocyclic-nucleosides-syntheses-computational-analyses-and-anticancer-antiviral-evaluation
#17
Meijun Lu, Qing-Bin Lu, John F Honek
Squaric acid and its derivatives are versatile synthons and have demonstrated applications in medicinal chemistry, notably as non-classical bioisosteric replacements for functional groups such as carboxylic acids, alpha-amino acids, urea, guanidine, peptide bonds and phosphate/pyrophosphate linkages. Surprisingly, no reports have appeared concerning its possible application as a nucleobase substitute in nucleosides. A preliminary investigation of such an application is reported herein. 3-Amino-4-((1R,4S)-4-(hydroxymethyl)cyclopent-2-en-1-yl)amino-cyclobut-3-ene-1,2-dione, 3-((1R,4S)-4-(hydroxymethyl)cyclopent-2-en-1-yl)amino-4-methoxycyclobut-3-ene-1,2-dione, and 3-hydroxy-4-((1R,4S)-4-(hydroxymethyl)cyclopent-2-en-1-yl)amino-cyclobut-3-ene-1,2-dione sodium salt were synthesized...
November 23, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27913179/phytochemical-and-cytotoxic-studies-on-the-roots-of-euphorbia-fischeriana
#18
Qun Shi, Yi-Wei Sun, Dali Meng
With the aim of supporting the folk applications of Euphorbia fischeriana, a phytochemical study was performed, which led to the discovery of 9 compounds, including three new ones (1-3) and six known ones (4-9). Their structures were determined by 1D, 2D NMR, and HRESIMS analysis. In the cytotoxic assays on Hep-3B cell line, 2 showed stronger inhibitory effects (IC50 8.1μmol/L) than that of positive control, and 1, 8 and 9 also gave inhibitory effects in a certain degree with IC50 values of 12.5, 12.0 and 18...
November 23, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27914801/new-bithiazolyl-hydrazones-novel-synthesis-characterization-and-antitubercular-evaluation
#19
Mahendra B Bhalerao, Sambhaji T Dhumal, Amarsinh R Deshmukh, Laxman U Nawale, Vijay Khedkar, Dhiman Sarkar, Ramrao A Mane
New bithiazolyl hydrazones (6a-l) have been first time synthesized by carrying novel one pot cyclocondensation of 5-acyl thiazoles (1a-b), thiosemicarbazide (2) and substituted phenacyl chlorides (4a-f) in freshly prepared ionic liquid, diisopropyl ethyl ammonium acetate (DIPEAc) at room temperature. The newly synthesized compounds have been evaluated for their antitubercular activity and the compounds 3b, 6a, 6b, 6d, 6e, 6f, 6g, and 6l have displayed noticeable antitubercular activity compared to Rifampicin with tolerable cytotoxicity...
November 22, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27908764/discovery-and-initial-optimization-of-alkoxyanthranilic-acid-derivatives-as-inhibitors-of-hcv-ns5b-polymerase
#20
Kyle Parcella, Andrew Nickel, Brett R Beno, Steven Sheriff, Changhong Wan, Ying-Kai Wang, Susan B Roberts, Nicholas A Meanwell, John F Kadow
Alkoxyanthranilic acid derivatives have been identified to inhibit HCV NS5B polymerase, binding in an allosteric site located at the convergence of the palm and thumb regions. Information from co-crystal structures guided the structural design strategy. Ultimately, two independent structural modifications led to a similar shift in binding mode that when combined led to a synergistic improvement in potency and the identification of inhibitors with sub-micromolar HCV NS5B binding potency.
November 22, 2016: Bioorganic & Medicinal Chemistry Letters
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