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Yongkai Cao, Ningning Sun, Jiumei Zhang, Zhiguo Liu, Yi-Zhe Tang, Zhengzhi Wu, Kyeong-Man Kim, Seung Hoon Cheon
[This corrects the article DOI: 10.1039/C8MD00237A.].
September 1, 2018: MedChemComm
Vinicius Vendrusculo, Vanessa P de Souza, Luiz Antônio M Fontoura, Marcelo G M D'Oca, Thais P Banzato, Paula A Monteiro, Ronaldo A Pilli, João Ernesto de Carvalho, Dennis Russowsky
A series of fifteen novel dihydropyrimidinone hybrid compounds were synthesized in good yields via a multicomponent reaction combined with the Huisgen reaction. The antiproliferative activity was investigated against nine tumor cell lines, and four hybrid compounds (TGI < 10 μM) showed promising antiproliferative activity against the tumor cell lines OVCAR-3 (ovarian), UACC-62 (melanoma) and U251 (glioma). Several hybrid compounds assayed have high TGI values (TGI 147.92-507.82) for the human keratinocyte cell line (HaCat), which reveals selectivity to cancer cells...
September 1, 2018: MedChemComm
William M Huggins, T Vu Nguyen, Nicholas A Hahn, James T Baker, Laura G Kuo, Darpan Kaur, Roberta J Melander, John S Gunn, Christian Melander
Serovars within the species Salmonella enterica are some of the most common food and water-borne pathogens worldwide. Some S. enterica serovars have shown a remarkable ability to persist both inside and outside the human body. Salmonella enterica serovar Typhi can cause chronic, asymptomatic infection of the human gallbladder. This organism's ability to survive inside the gallbladder centers around its ability to form biofilms on gallstone surfaces. Currently, chronic carriage of S. Typhi is treated by invasive methods, which are not well suited to areas where Salmonella carriage is prevalent...
September 1, 2018: MedChemComm
Jens-Alexander Fuchs, Francesca Grisoni, Michael Kossenjans, Jan A Hiss, Gisbert Schneider
Lipophilicity prediction is routinely applied to small molecules and presents a working alternative to experimental log  P or log  D determination. For compounds outside the domain of classical medicinal chemistry these predictions lack accuracy, advocating the development of bespoke in silico approaches. Peptides and their derivatives and mimetics fill the structural gap between small synthetic drugs and genetically engineered macromolecules. Here, we present a data-driven machine learning method for peptide log  D 7...
September 1, 2018: MedChemComm
Di Li, Rammohan R Yadav Bheemanaboina, Narsaiah Battini, Vijai Kumar Reddy Tangadanchu, Xian-Fu Fang, Cheng-He Zhou
A series of novel unique structural organophosphorus aminopyrimidines were developed as potential DNA-targeting membrane active inhibitors through an efficient one-pot procedure from aldehydes, phosphonate and aminopyrimidine. The biological assay revealed that some of the prepared compounds displayed antibacterial activities. In particular, imidazole derivative 2c exhibited more potent inhibitory activity against MRSA with an MIC value of 4 μg mL-1 in comparison with the clinical drugs chloromycin and norfloxacin...
September 1, 2018: MedChemComm
Alaaeldin M F Galal, Maha M Soltan, Esam R Ahmed, Atef G Hanna
A novel series of sulfonamide derivatives, coupled with a salicylamide scaffold, was designed and synthesized. The structures of the synthesized compounds were established using 1 H NMR, 13 C NMR and high-resolution mass spectroscopy. The synthesized compounds were tested in vitro against five types of human cell lines. Two were breast adenocarcinoma, including the hormone-dependent MCF-7 and the hormone-independent MDA-MB-231. The others were the colorectal adenocarcinoma Caco-2, the carcinoma HCT-116 and the immortalized retinal-pigmented epithelium, hTERT-RPE1...
September 1, 2018: MedChemComm
Wenfeng Liu, Shun Huang, Yonglian Li, Yanwen Li, Dongli Li, Panpan Wu, Quanshi Wang, Xi Zheng, Kun Zhang
Glycyrrhizinic acid (GA), a principal component derived from licorice which is used extensively as a natural sweetener and traditional folk herbal medicine, is attracting considerable attention because of its broad range of bioactivities. However, the anti-inflammatory mechanism of GA on 12- O -tetradecanoylphorbol-13-acetate (TPA)-mediated skin inflammation has not been elucidated. Herein, we investigated the anti-inflammatory activity of GA by using a TPA-induced mouse ear model. It was indicated that GA, applied topically onto mouse ears, effectively inhibited the TPA-mediated expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in a dose-dependent manner, respectively...
September 1, 2018: MedChemComm
Omar M Khdour, Indrajit Bandyopadhyay, Nishant P Visavadiya, Sandipan Roy Chowdhury, Sidney M Hecht
Friedreich's ataxia (FRDA) is a progressive neurodegenerative disease that is linked to transcriptional repression of the nuclear FXN gene encoding the essential mitochondrial protein frataxin (FXN). Compounds that increase frataxin levels may enable effective therapeutic intervention for blunting disease progression. Recently, we showed that lipophilic methylene violet (MV) and methylene blue (MB) analogues both conferred benefit to cultured FRDA cells in several regards, including ROS suppression, maintenance of mitochondrial membrane potential and increased ATP production...
September 1, 2018: MedChemComm
Triveni R Pardhi, Manishkumar S Patel, V Sudarsanam, Kamala K Vasu
Casein kinase 2 (CK2) and glycogen synthase kinase-3beta (GSK3β) are responsible for the phosphorylation of a tumor suppressor protein (PTEN) in a cooperative manner which causes its deactivation. Thus, it is essential to inhibit both kinases simultaneously to prevent PTEN deactivation more efficiently. In this study, we have designed a novel lead from Hit15 which was identified in silico as a dual kinase inhibitor against CK2 and GSK3β through our previous study. The dataset of structural analogs of the lead was designed and confirmed by pharmacophore mapping and molecular docking...
September 1, 2018: MedChemComm
Federica Castriconi, Marco Paolino, Giorgio Grisci, Cinzia Maria Francini, Annalisa Reale, Germano Giuliani, Maurizio Anzini, Gianluca Giorgi, Laura Mennuni, Chiara Sabatini, Marco Lanza, Gianfranco Caselli, Andrea Cappelli
Two small series of quinoline derivatives were designed starting from previously published quinoline derivatives 7a and b in order to obtain information about their interaction with the 5-HT4 R binding site. Initially, the structure of 7a and b was modified by replacing their basic moiety with that of partial agonist 4 (ML10302) or with that of reference ligand 6 (RS-67-333). Then, the aromatic moieties of 4-quinolinecarboxylates 7a , d-f , and h-k or 4-quinolinecarboxamides 7b , c , and g were modified into those of 2-quinolinecarboxamides 9a-e ...
September 1, 2018: MedChemComm
Yongkai Cao, Ningning Sun, Jiumei Zhang, Zhiguo Liu, Yi-Zhe Tang, Zhengzhi Wu, Kyeong-Man Kim, Seung Hoon Cheon
The dopamine D3 receptor (D3 R) is a proven therapeutic target for the treatment of neurological and neuropsychiatric disorders. In particular, D3 R-selective ligands that can eliminate side effects associated with dopamine D2 receptor (D2 R) therapeutics have been validated. However, the high homology in signaling pathways and the sequence similarity between D2 R and D3 R have rendered the development of D3 R-selective ligands challenging. Herein, we designed and synthesized a series of piperazine-phthalimide bitopic ligands based on a fragment-based and molecular docking inspired design...
September 1, 2018: MedChemComm
Kamaleddin H M E Tehrani, Nathaniel I Martin
Antibiotic resistance caused by β-lactamase production continues to present a growing challenge to the efficacy of β-lactams and their role as the most important class of clinically used antibiotics. In response to this threat however, only a handful of β-lactamase inhibitors have been introduced to the market over the past thirty years. The first-generation β-lactamase inhibitors (clavulanic acid, sulbactam and tazobactam) are all β-lactam derivatives and work primarily by inactivating class A and some class C serine β-lactamases...
September 1, 2018: MedChemComm
Georges Vauquelin
Review articles on binding kinetics essentially focus on drugs that dissociate slowly from their target since this is required for the successful treatment of many pathophysiological conditions. Recently, the therapeutic benefit of a high k on ( i.e. the second order association rate constant) has also been linked to fast association and to a fast clinical action. Other studies, however, called this assertion into question since additional factors, like the dosing paradigm and the binding mechanism, are important as well...
September 1, 2018: MedChemComm
M Damen, A J J Groenen, S F M van Dongen, R J M Nolte, B J Scholte, M C Feiters
Diseases that are linked to defective genes or mutations can in principle be cured by gene therapy, in which damaged or absent genes are either repaired or replaced by new DNA in the nucleus of the cell. Related to this, disorders associated with elevated protein expression levels can be treated by RNA interference via the delivery of siRNA to the cytoplasm of cells. Polynucleotides can be brought into cells by viruses, but this is not without risk for the patient. Alternatively, DNA and RNA can be delivered by transfection, i...
September 1, 2018: MedChemComm
Shogo Mori, Sylvie Garneau-Tsodikova
You might have heard the expression "a figure is worth a thousand words". But, how important really is it to make nice, complete, and clear figures? Actually… extremely important! Taking the extra time and effort to optimize the quality and visibility of your figures is totally worth it. Figures can most rapidly catch the attention of readers and influence their decision to read or not read your manuscript. This opinion article provides insight into ways to maximize the visibility and impact of your figures! We hope you will find value in the tips provided and can't wait to see all your beautiful figures...
September 1, 2018: MedChemComm
Derek Lowe
We're going to need a bigger compound deck….
September 1, 2018: MedChemComm
Xiaojuan Xu, Senzhen Wang, Yuan Chang, Chaochao Ge, Xinna Li, Yongli Feng, Songqiang Xie, Chaojie Wang, Fujun Dai, Wen Luo
Naphthalenetetracarboxylic diimide (NDI) is widely used as a photoelectric material in the field of medicine. A series of asymmetric naphthalene diimide derivatives were synthesized and evaluated for their anticancer properties by various experimental assays. As the representative compound, 3c exerted significantly greater inhibitory effects on hepatoma cells SMMC-7721 and Hep G2 with an IC50 value of 1.48 ± 0.43 μM and 1.70 ± 0.53 μM, respectively, than normal hepatocytes QSG-7701 with an IC50 value of 7...
August 1, 2018: MedChemComm
Brooke A Andrews, R Brian Dyer
Lactate dehydrogenase (LDH) has recently garnered attention as an attractive target for cancer therapies, owing to the enzyme's critical role in cellular metabolism. Current inhibition strategies, employing substrate or cofactor analogues, are insufficiently specific for use as pharmaceutical agents. The possibility of allosteric inhibition of LDH was postulated on the basis of theoretical docking studies of a small molecule inhibitor to LDH. The present study examined structural analogues of this proposed inhibitor to gauge its potency and attempt to elucidate the molecular mechanism of action...
August 1, 2018: MedChemComm
Jieen Pan, Chenglong Huang, Gang Chen, Zhenhai Cai, Zhongwei Zhang
Background: senile osteoporosis researchers are now seeking to promote osteoblastogenesis and resultant bone formation to directly counteract age-related bone loss. Targeting microRNA (miRNA) activity in adult osteoblasts may be a successful therapeutic strategy for age-related bone loss. We investigated the mechanism(s) by which miRNAs negatively regulate osteoblastogenesis and bone formation in vitro and in vivo . Methods: we performed a miRNA microarray screen followed by PCR validation in adult bone marrow-derived mesenchymal stem cells during the proliferation-to-mineralization transition to identify downregulated miRNAs, most notably miR-451...
August 1, 2018: MedChemComm
K V Yogesh, Toshiya Kamiyama, Chikara Ohyama, Tohru Yoneyama, Kazuhiro Nouso, Satoshi Kimura, Hiroshi Hinou, Shin-Ichiro Nishimura
Previous studies on the large-scale glycomics of more than 3500 human serum samples revealed that the serum glycoproteins of cancer patients often have more dominant and specific glycoforms, namely, branched tri- and tetra-antennary N-glycans, most cancer patient groups than normal control groups. We herein established an efficient synthetic protocol of glycopeptides having highly complicated N-glycan structures that may be generated by direct tryptic digestion of serum glycoproteins. A preliminary selected reaction monitoring (SRM) assay using the synthetic model glycopeptide 1 , 40 Ser-Val-Gln-Glu-Ile-Gln-Ala-Thr-Phe-Phe-Tyr-Phe-Thr-Pro-Asn-Lys-Thr-Glu-Asp-Thr-Ile-Phe-Leu-Arg63 having an asialo tri-antennary N-glycan at the Asn54 residue as a designated calibration standard allowed for the rapid and absolute quantitation of the tryptic fragment derived from the serum α1-acid glycoprotein carrying a focused N-glycoform of cancer patients and healthy controls in a range between 200 and 1600 fmole μL-1 without any enrichment process for the target glycoprotein...
August 1, 2018: MedChemComm
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