journal
MENU ▼
Read by QxMD icon Read
search

Journal of Medicinal Chemistry

journal
https://www.readbyqxmd.com/read/28535350/activation-of-phenyl-4-2-oxo-3-alkylimidazolidin-1-yl-benzenesulfonates-prodrugs-by-cyp1a1-as-new-antimitotics-targeting-breast-cancer-cells
#1
Sébastien Fortin, Xavier Charest-Morin, Vanessa Turcotte, Coraline Lauvaux, Jacques Lacroix, Marie-France Côté, Stéphane Gobeil, Rene C-Gaudreault
Prodrug-mediated utilization of the cytochrome P450 (CYP) 1A1 to obtain the selective release of potent anticancer products within cancer tissues is a promising approach in chemotherapy. We herein report the rationale, preparation, biological evaluation and mechanism of action of phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs), that are antimicrotubule prodrugs activated by CYP1A1. Although PAIB-SOs are inert in most cells tested, they are highly cytocidal towards several human breast cancer cells, including hormone-independent and chemoresistant types...
May 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28535049/unusual-undergraduate-training-in-medicinal-chemistry-in-collaboration-between-academia-and-industry
#2
Thomas McInally, Simon J F Macdonald
Globalization has driven new paradigms for drug discovery and development. Activities previously carried out predominantly in the United States, Europe, and Japan are now carried out globally. This has caused considerable change in large pharma including how medicinal chemists are trained. Described here is the training of chemistry undergraduates in medicinal chemistry (as practiced in industry) in two modules developed in collaboration between the University of Nottingham (UoN) and GlaxoSmithKline (GSK). The students complete several design-synthesize-test iterations on medicinal chemistry projects where they carry out the design and synthesis, and GSK tests the compounds...
May 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28535045/bet-bromodomain-inhibitors-with-one-step-synthesis-discovered-from-virtual-screen
#3
Alex M Ayoub, Laura M L Hawk, Ryan J Herzig, Jiewei Jiang, Andrea J Wisniewski, Clifford T Gee, Peiliang Zhao, Jin-Yi Zhu, Norbert Berndt, Nana K Offei-Addo, Thomas G Scott, Jun Qi, James E Bradner, Timothy R Ward, Ernst Schönbrunn, Gunda I Georg, William C K Pomerantz
Chemical inhibition of epigenetic regulatory proteins BrdT and Brd4 is emerging as a promising therapeutic strategy in contraception, cancer, and heart disease. We report an easily synthesized dihydropyridopyrmidine pan-BET inhibitor scaffold, which was uncovered via a virtual screen followed by testing in a fluorescence anisotropy assay. Dihydropyridpyimidine 3 was subjected to further characterization and is highly selective for the BET family of bromodomains. Structure-activity relationship data and ligand deconstruction highlight the importance of the substitution of the uracil moiety for potency and selectivity...
May 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28505442/nitric-oxide-donor-based-cancer-therapy-advances-and-prospects
#4
Zhangjian Huang, Junjie Fu, Yihua Zhang
The increasing understanding of the role of nitric oxide (NO) in cancer biology has generated significant progress in the use of NO donor-based therapy to fight cancer. These advances strongly suggest the potential adoption of NO donor-based therapy in clinical practice, and this has been supported by several clinical studies in the past decade. In this review, we first highlight several types of important NO donors, including recently developed NO donors bearing a dinitroazetidine skeleton, represented by RRx-001, with potential utility in cancer therapy...
May 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28482151/trisubstituted-imidazoles-with-a-rigidized-hinge-binding-motif-act-as-single-digit-nm-inhibitors-of-clinically-relevant-egfr-l858r-t790m-and-l858r-t790m-c797s-mutants-an-example-of-target-hopping
#5
Michael Juchum, Marcel Günther, Eva Döring, Adrian Sievers-Engler, Michael Lämmerhofer, Stefan Laufer
The high genomic instability of non-small cell lung cancer tumors leads to the rapid development of resistance against promising EGFR tyrosine kinase inhibitors (TKIs). A recently detected triple mutation compromises the activity of the gold standard third-generation EGFR inhibitors. We have prepared a set of trisubstituted imidazoles with a rigidized 7-azaindole hinge binding motif as a new structural class of EGFR inhibitors by a target hopping approach from p38α MAPK inhibitor templates. On the basis of an iterative approach of docking, compound preparation, biological testing, and SAR interpretation, robust and flexible synthetic routes were established...
May 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28463515/rational-design-of-bisubstrate-type-analogues-as-inhibitors-of-dna-methyltransferases-in-cancer-cells
#6
Ludovic Halby, Yoann Menon, Elodie Rilova, Dany Pechalrieu, Véronique Masson, Celine Faux, Mohamed Amine Bouhlel, Marie-Hélène David-Cordonnier, Natacha Novosad, Yannick Aussagues, Arnaud Samson, Laurent Lacroix, Fréderic Ausseil, Laurence Fleury, Dominique Guianvarc'h, Clotilde Ferroud, Paola B Arimondo
Aberrant DNA hypermethylation of promoter of tumor suppressor genes is commonly observed in cancer, and its inhibition by small molecules is promising for their reactivation. Here we designed bisubstrate analogues-based inhibitors, by mimicking each substrate, the S-adenosyl-l-methionine and the deoxycytidine, and linking them together. This approach resulted in quinazoline-quinoline derivatives as potent inhibitors of DNMT3A and DNMT1, some showing certain isoform selectivity. We highlighted the importance of (i) the nature and rigidity of the linker between the two moieties for inhibition, as (ii) the presence of the nitrogen on the quinoline group, and (iii) of a hydrophobic group on the quinazoline...
May 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28530834/a-facile-radiolabeling-of-18-f-fdpa-via-spirocyclic-iodonium-ylides-preliminary-pet-imaging-studies-in-preclinical-models-of-neuroinflammation
#7
Lu Wang, Ran Cheng, Masayuki Fujinaga, Jian Yang, Yiding Zhang, Akiko Hatori, Katsushi Kumata, Jing Yang, Neil Vasdev, Yunfei Du, Chongzhao Ran, Ming-Rong Zhang, Steven H Liang
A suitable TSPO PET ligand may visualize and quantify neuroinflammation in living brain. Herein we report a (18)F-ligand, [(18)F]2 ([(18)F]FDPA) is radiolabeled in high yield and high specific activity based on our spirocyclic iodonium ylide (SCIDY) strategy. [(18)F]2 demonstrated saturable specific binding to TSPO, substantially-elevated brain uptake and slow washout of bound PET signal in the preclinical models of brain neuroinflammation (cerebral ischemia and Alzheimer's disease).
May 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28530833/discovery-of-small-molecules-for-repressing-cap-independent-translation-of-human-vascular-endothelial-growth-factor-hvegf-as-novel-anti-tumor-agents
#8
Shi-Ke Wang, Yue Wu, Xiao-Qin Wang, Guo-Tao Kuang, Qi Zhang, Shu-Ling Lin, Hui-Yun Liu, Jia-Heng Tan, Zhi-Shu Huang, Tian-Miao Ou
Angiogenesis is important in tumorigenesis and tumor progression. Human vascular endothelial growth factor (hVEGF) is an angiogenic growth factor that plays a crucial role in tumor progression. The G-rich region within the 5'-untranslated region (5'-UTR) of hVEGF mRNA can form a 'switchable' RNA G-quadruplex structure that is essential for a cap-independent translation initiation. We screened our small-molecule library for binders of this G-tract. One novel quinazoline derivative, compound 1, showed a significant specific interaction with the G-tract and destabilized the G-quadruplex structure...
May 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28530811/multi-targeted-imidazoles-potential-therapeutic-leads-for-alzheimer-s-and-other-neurodegenerative-diseases
#9
Anne-Sophie Cornec, Ludovica Monti, Jane Kovalevich, Vishruti Makani, Michael J James, Krishna G Vijayendran, Killian Oukoloff, Yuemang Yao, Virginia M-Y Lee, John Q Trojanowski, Amos B Smith Iii, Kurt R Brunden, Carlo Ballatore
Alzheimer's disease (AD) is a complex, multifactorial disease in which different neuropathological mechanisms are likely involved, including those associated with pathological tau and Aβ species, as well as neuroinflammation. In this context, the development of single multi-targeted therapeutics directed against two or more disease mechanisms could be advantageous. Starting from a series of 1,5-diarylimidazoles with microtubule (MT)-stabilizing activity and structural similarities with known NSAIDs, we conducted structure-activity relationship studies that led to the identification of multi-targeted prototypes with activities as MT-stabilizing agents and/or inhibitors of the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways...
May 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28530802/discovery-of-n-5-fluoropyridin-2-yl-6-methyl-4-pyrimidin-5-yloxy-picolinamide-vu0424238-a-novel-negative-allosteric-modulator-of-metabotropic-glutamate-receptor-subtype-5-selected-for-clinical-evaluation
#10
Andrew S Felts, Alice L Rodriguez, Anna L Blobaum, Ryan D Morrison, Brittney S Bates, Analisa Thompson Gray, Jerri M Rook, Mohammed N Tantawy, Frank W Byers, Sichen Chang, Daryl F Venable, Vincent B Luscombe, Gilles D Tamagnan, Colleen M Niswender, J Scott Daniels, Carrie K Jones, P Jeffrey Conn, Craig W Lindsley, Kyle A Emmitte
Preclinical evidence in support of the potential utility of mGlu5 NAMs for the treatment of a variety of psychiatric and neurodegenerative disorders is extensive, and multiple such molecules have entered clinical trials. Despite some promising results from clinical studies, no small molecule mGlu5 NAM has yet to reach market. Here we present the discovery and evaluation of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (27, VU0424238), a compound selected for clinical evaluation. Compound 27 is more than 900-fold selective for mGlu5 versus the other mGlu receptors, and binding studies established a Ki value of 4...
May 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28530407/a-gadolinium-complex-of-1-4-7-10-tetraazacyclododecane-1-4-7-trisacetic-acid-do3a-ethoxybenzyl-eob-conjugate-as-a-new-macrocyclic-hepatobiliary-mri-contrast-agent
#11
Ah Rum Baek, Hee-Kyung Kim, Subin Park, Gang Ho Lee, Hyo Jeung Kang, Jae Chang Jung, Joon-Suk Park, Hun-Kyu Ryeom, Tae-Jeong Kim, Yongmin Chang
We report the synthesis of a macrocyclic Gd chelate based on a 1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid (DO3A) coordination cage bearing an ethoxybenzyl (EOB) moiety and discuss its use as a T1 hepatobiliary magnetic resonance imaging (MRI) contrast agent. The new macrocyclic liver agent shows high chelation stability and high r1 relaxivity compared with linear-type Gd chelates, which are the current clinically approved liver agents. Our macrocyclic, liver-specific Gd chelate was evaluated in vivo through biodistribution analysis and liver MRI, which demonstrated its high tumor detection sensitivity and suggested that the new Gd complex is a promising contrast agent for liver cancer imaging...
May 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28485590/structure-activity-relationship-of-2-4-dichloro-n-3-5-dichloro-4-quinolin-3-yloxy-phenyl-benzenesulfonamide-int131-analogs-for-ppar%C3%AE-targeted-antidiabetics
#12
Rebecca L Frkic, Yuanjun He, Beatriz B Rodriguez, Mi Ra Chang, Dana Kuruvilla, Anthony Ciesla, Andrew D Abell, Theodore M Kamenecka, Patrick R Griffin, John B Bruning
Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor central to fatty acid and glucose homeostasis. PPARγ is the molecular target for type 2 diabetes mellitus (T2DM) therapeutics TZDs (thiazolidinediones), full agonists of PPARγ with robust antidiabetic properties, which are confounded with significant side effects. Partial agonists of PPARγ, such as INT131 (1), have displayed similar insulin-sensitizing efficacy as TZDs, but lack many side effects. To probe the structure-activity relationship (SAR) of the scaffold 1, we synthesized 14 analogs of compound 1 which revealed compounds with higher transcriptional potency for PPARγ and identification of moieties of the scaffold 1 key to high transcriptional potency...
May 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28463485/nitroimidazoles-molecular-fireworks-that-combat-a-broad-spectrum-of-infectious-diseases
#13
Chee Wei Ang, Angie M Jarrad, Matthew A Cooper, Mark A T Blaskovich
Infectious diseases claim millions of lives every year, but with the advent of drug resistance, therapeutic options to treat infections are inadequate. There is now an urgent need to develop new and effective treatments. Nitroimidazoles are a class of antimicrobial drugs that have remarkable broad spectrum activity against parasites, mycobacteria, and anaerobic Gram-positive and Gram-negative bacteria. While nitroimidazoles were discovered in the 1950s, there has been renewed interest in their therapeutic potential, particularly for the treatment of parasitic infections and tuberculosis...
May 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28525717/synthesis-and-biological-evaluation-of-novel-neuroprotective-pyridazine-derivatives-as-excitatory-amino-acid-transporter-2-eaat2-activators
#14
Alessia Chelini, Simone Brogi, Marco Paolino, Angela Di Capua, Andrea Cappelli, Gianluca Giorgi, Mersedeh Farzad, Lorenzo Di Cesare Mannelli, Laura Micheli, Carla Ghelardini, Maurizio Anzini
LDN-212320 (3) was found to be a potent EAAT2 activator at a translational level, restoring the normal clearance of glutamate and providing neuronal protection. Since the pharmacologic activation of EAAT2 represents a valuable strategy to relieve neuropathic pain, we synthesized novel activators (4a-f) of EAAT2. Among them 4f, analysed in comparison with compound 3 in different rat models of oxaliplatin-induced neuropathic pain, showed the better anti-hypersensitive profile being able to fully counteract the oxaliplatin-induced neuropathy...
May 19, 2017: Journal of Medicinal Chemistry
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
#15
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/28482155/targeting-the-receptor-for-advanced-glycation-endproducts-rage-a-medicinal-chemistry-perspective
#16
Salvatore Bongarzone, Vilius Savickas, Federico Luzi, Antony D Gee
The receptor for advanced glycation endproducts (RAGE) is an ubiquitous, transmembrane, immunoglobulin-like receptor that exists in multiple isoforms and binds to a diverse range of endogenous extracellular ligands and intracellular effectors. Ligand binding at the extracellular domain of RAGE initiates a complex intracellular signaling cascade, resulting in the production of reactive oxygen species (ROS), immunoinflammatory effects, cellular proliferation, or apoptosis with concomitant upregulation of RAGE itself...
May 19, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28481536/discovery-of-a-small-molecule-probe-that-post-translationally-stabilizes-the-survival-motor-neuron-protein-for-the-treatment-of-spinal-muscular-atrophy
#17
Anne Rietz, Hongxia Li, Kevin M Quist, Jonathan J Cherry, Christian L Lorson, Barrington G Burnett, Nicholas L Kern, Alyssa N Calder, Melanie Fritsche, Hrvoje Lusic, Patrick J Boaler, Sungwoon Choi, Xuechao Xing, Marcie A Glicksman, Gregory D Cuny, Elliot J Androphy, Kevin J Hodgetts
Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. We previously developed a high-throughput assay that employs an SMN2-luciferase reporter allowing identification of compounds that act transcriptionally, enhance exon recognition, or stabilize the SMN protein. We describe optimization and characterization of an analog suitable for in vivo testing. Initially, we identified analog 4m that had good in vitro properties but low plasma and brain exposure in a mouse PK experiment due to short plasma stability; this was overcome by reversing the amide bond and changing the heterocycle...
May 19, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28520415/design-and-synthesis-of-soluble-and-cell-permeable-pi3k%C3%AE-inhibitors-for-long-acting-inhaled-administration
#18
Matthew W D Perry, Karin Björhall, Britta K Bonn, Johan Carlsson, Yunhua Chen, Anders Eriksson, Linda Fredlund, Hai'e Hao, Neil S Holden, Kostas Karabelas, Helena Lindmark, Feifei Liu, Nils Pemberton, Jens Petersen, Sandra Rodrigo Blomqvist, Reed W Smith, Tor Svensson, Ina Terstiege, Christian Tyrchan, Wenzhen Yang, Shuchun Zhao, Linda Öster
PI3Kδ is a lipid kinase that is believed to be important in the migration and activation of cells of the immune system. Inhibition is hypothesised to provide a powerful yet selective immunomodulatory effect that may be beneficial for the treatment of conditions such as asthma or rheumatoid arthritis. In this work we describe the identification of inhibitors based on a thiazolopyridone core structure and their subsequent optimisation for inhalation. The initially identified compound (13) had good potency and isoform selectivity but was not suitable for inhalation...
May 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28520410/proteolytically-stable-cyclic-decapeptide-for-breast-cancer-cell-targeting
#19
Yogita Raghuwanshi, Hashem Rajab Etayash, Rania Soudy, Igor Paiva, Afsaneh Lavasanifar, Kamaljit Kaur
Starting with a previously reported linear breast cancer targeting decapeptide WxEAAYQkFL, here we report the synthesis of a novel cyclic peptide analogue cyclicWXEAAYQkFL. The N- to C-terminus amide cyclized peptide with one D-amino acid (k) displayed higher uptake by breast cancer cells, with minimal uptake by the non-cancerous cells compared to the linear peptide with two D-amino acids (x and k), and was stable toward proteolytic degradation. When immobilized on gold microcantilever surface, the cyclic peptide was able to capture breast cancer cells specifically and sense samples with ≥25 cancer cells/mL...
May 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28517931/correction-to-synthesis-antiviral-potency-in-vitro-admet-and-x-ray-structure-of-potent-cd4-mimics-as-entry-inhibitors-that-target-the-phe43-cavity-of-hiv-1-gp120
#20
Francesca Curreli, Young Do Kwon, Dmitry S Belov, Ranjith R Ramesh, Alexander V Kurkin, Andrea Altieri, Peter D Kwong, Asim K Debnath
No abstract text is available yet for this article.
May 18, 2017: Journal of Medicinal Chemistry
journal
journal
32885
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"