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ChemMedChem

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https://www.readbyqxmd.com/read/28426179/novel-selective-and-developable-dopamine-d3-antagonists-with-modified-amino-region
#1
Fabrizio Micheli
This minireview describes the presentation made at the XXIV National Meeting in Medicinal Chemistry held in Perugia (Italy) in 2016, September 11-14. It relates to the discovery of novel templates of the so called "amino" region of the Dopamine D3 antagonists. Moving from the early scaffolds which were modified in the amine portion, the review describes the variations which led to the discovery of new systems which were published in 2016 allowing the identification of molecules endowed of great selectivity over DA D2 receptor and hERG channel...
April 20, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28425177/design-and-synthesis-of-c3-substituted-%C3%AE-carboline-based-histone-deacetylase-inhibitors-with-potent-antitumor-activities
#2
Yong Ling, Jiao Feng, Lin Luo, Jing Guo, Yanfu Peng, Tingting Wang, Xiang Ge, Qibing Xu, Xinyang Wang, Hong Dai, Yanan Zhang
A series of hydroxamic acid histone deacetylase (HDAC) inhibitors in which the β-carboline motif has been incorporated were designed and synthesized. The effect of substitution at the C3 amide on HDAC inhibition and antiproliferative activities was investigated. Most of these compounds were found to display significant HDAC inhibitory effects and good antiproliferative activity, with IC50 values in the low-micromolar range. In particular, the HDAC inhibition IC50 value of N-(2-(dimethylamino)ethyl)-N-(4-(hydroxylcarbamoyl)benzyl)-1-(4-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxamide (9 h) is five-fold lower than that of suberoylanilide hydroxamic acid (SAHA, vorinostat)...
April 20, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28423228/targeting-dna-pk-for-cancer-therapy
#3
Céline Cano, Suzannah J Harnor
The catalytic activity of DNA-dependent protein kinase (DNA-PK) is critical to its ability to repair lethal DNA-double strand breaks (DSBs). This includes repair of DSB lesions resulting from oxidative stress, oncogene-induced transcription, or following therapeutic treatment of cancer cells. Armed with this knowledge, many attempts have been made to identify small molecule inhibitors of DNA-PK activity as an approach to induce tumour chemo- and radio-sensitisation. This review examines the structures of known reversible and irreversible inhibitors, including those based upon chromen-4-one, arylmorpholine, and benzaldehyde scaffolds...
April 19, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28422428/identification-of-novel-transthyretin-fibril-formation-inhibitors-using-structure-based-virtual-screening
#4
Gabriella Ortore, Adriano Martinelli
Transthyretin (TTR) is the primary carrier for thyroxine (T4) in cerebrospinal fluid and a secondary carrier in blood. TTR is a stable homotetramer, but certain factors, genetic or environmental, could promote its degradation to form amyloid fibrils. A docking study in the wild-type TTR crystal structures was planned; our aim was to design new ligands able to inhibit TTR fibril formation. The computational protocol was thought to overcome the multiple binding modes of the ligands induced by the specularity of the TTR binding site and by the pseudosymmetry of the site pockets, which generally weaken such structure-based studies...
April 19, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28417557/a-multitarget-approach-toward-the-development-of-a-new-series-of-8-substituted-purines-for-photoprotection-and-prevention-of-ultra-violet-uv-related-damages
#5
Ernestine Nicaise Djuidje, Valeria Dissette, Alessia Bino, Simonetta Benetti, Jan Balzarini, Sandra Liekens, Stefano Manfredini, Silvia Vertuani, Anna Baldisserotto
In environmental abundance, UV is the most important modifiable risk factor for skin cancer and many other skin diseases such as early photo-aging. Among solar radiation, ultraviolet (UV) is mainly responsible for inducing skin problems. In search of novel photoprotective purines, a new series of 8-substituted purines were synthesized from commercially available 6-hydroxy-4,5-diaminopyrimidine hemisulfate or 4,5-diaminopyrimidine. All the title compounds were investigated for their UV-filter, antioxidant, antifugal and antiproliferative activities...
April 18, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28417566/cannabinoid-type-1-receptor-cb1-bioligand-with-therapeutic-potential-for-withdrawal-syndrome-in-chemical-dependents-cannabis-sativa
#6
Lorane Hage Melim, Jaderson V Ferreira, Gisele A Chaves, Bianca L B Marino, Kessia P A Sousa, Lucilene R Souza, Maiara F B Brito, Hueldem R C Teixeira, Carlos H T P Silva, Cleydson B R Santos
Cannabis sativa withdrawal syndrome is characterized mainly by psychological symptoms. Using computational tools, the aim was to propose drug candidates based on natural ligands of the cannabinoid type 1 receptor (CB1), where only the molecule ZINC1730183 showed a positive prediction for the human CB1 receptor and easy synthetic prediction of accessibility. Therefore, this molecule proves to be a favorable proposal, suggesting the continuation of this research as a pharmacotherapeutic alternative to the withdrawal syndrome of C...
April 17, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28403559/integrin-receptor-targeting-rgdk-tagged-nanocarrier-anticancer-efficacy-of-loaded-curcumin
#7
Prasanta Kumar Das, Krishnendu Das, Sahithi Nimushakavi, Arabinda Chaudhuri
Herein we report the design and development of α5β1 integrin receptor specific RGDK-lipopeptide associated non-covalently dispersed single walled carbon nanotube (SWNT) that selectively deliver anti-cancer curcumin to tumor cells. Arg-Gly-Asp-Lys (RGDK) tetrapeptide tagged amphiphiles were synthesized that efficiently dispersed SWNT with >80% suspension stability index in cell culture media. MTT & LDH based cell viability assays in tumor (melanoma, B16F10) and non-cancerous (mouse fibroblast cells, NIH3T3) revealed non-cytotoxic nature of RGDK-lipopeptide-SWNT conjugates...
April 12, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28403522/structure-activity-relationship-studies-spr-affinity-characterization-and-conformational-analysisof-peptides-mimicking-the-hnk-1-carbohydrate-epitope
#8
Paolo Rovero, Matthaia Ieronymaki, Francesca Nuti, Diego Brancaccio, Giada Rossi, Feliciana Real-Fernández, Yihong Cao, Olivier Monasson, Maud Larregola, Elisa Peroni, Jacques Uziel, Giuseppina Sabatino, Ettore Novellino, Alfonso Carotenuto, Anna Maria Papini
The design of molecules mimicking biologically relevant glycans is a significant goal for understanding important biological processesand may lead to new therapeutic and diagnostic agents. We focused our attention on the trisaccharide human natural killer cell-1 (HNK-1), considered the antigenic determinant ofmyelin-associated glycoprotein and the target of clinically relevant auto-antibodies in autoimmune neurological disorders such as IgM monoclonal gammopathy and demyelinating polyneuropathy.We describe a structure-activity relationship study based on surface plasmon resonance binding affinities aiming at the optimization of a peptide mimicking the HNK-1 minimal epitope...
April 12, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28395128/probing-mercaptobenzamides-as-hiv-inactivators-via-nucleocapsid-protein-7
#9
Mrinmoy Saha, Michael T Scerba, Nathaniel I Shank, Tracy L Hartman, Caitlin A Buchholz, Robert W Buckheit, Stewart R Durell, Daniel H Appella
Human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein 7 (NCp7), a zinc finger protein, plays critical roles in viral replication and maturation and represents an attractive target for drug development. However, development of drug-like molecules that inhibit NCp7 has been a significant challenge. In this report, a series of novel 2-mercaptobenzamide prodrugs have been investigated for anti-HIV activity in the context of NCp7 inactivation. The molecules are synthesized from the corresponding thiosalicylic acids, and they are all crystalline solids and stable at room temperature...
April 10, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28378923/biological-evaluation-of-dipyrromethanes-in-cancer-cell-lines-antiproliferative-and-pro-apoptotic-properties
#10
Radek Jorda, Susana M M Lopes, Eva Řezníčková, Vladimír Kryštof, Teresa M V D Pinho E Melo
Functionalized dipyrromethanes were synthesized by hetero-Diels-Alder reactions of nitroso- and azoalkenes and screened for their in vitro activity as anticancer agents. The studied dipyrromethanes were tested against leukemia and lymphoma cell lines, and showed GI50 values in the mid-micromolar range. The pro-apoptotic activities of two candidates, (E)-1-(2'-ethoxycarbonylhydrazono-1'-benzyl-1H-tetrazol-5-yl)-5,5'-diethyldipyrromethane and (E)-1-(2'-p-nitrophenyl-2'-hydroxyiminoethyl)-5-phenyldipyrromethane, and their effects on the cell cycle are described...
April 5, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28374567/a-time-resolved-fret-cell-based-binding-assay-for-the-apelin-receptor
#11
Christel Valencia, Céline Dujet, Jean-François Margathe, Xavier Iturrioz, Thomas Roux, Eric Trinquet, Pascal Villa, Marcel Hibert, Elodie Dupuis, Catherine Llorens-Cortes, Dominique Bonnet
Analogues of apelin-13 carrying diverse spacers and an ad hoc DY647-derived fluorophore were designed and synthesized by chemoselective acylation of α-hydrazinopeptides. The resulting probes retain very high affinity and efficacy for both the wild-type and SNAP-tagged apelin receptor (ApelinR). They give a time-resolved FRET (TR-FRET) signal with rare-earth lanthanides used as donor fluorophores grafted onto the SNAP-tagged receptor. This specific signal allowed the validation of a binding assay with a high signal-to-noise ratio...
April 4, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28371477/rafoxanide-and-closantel-inhibit-spak-and-osr1-kinases-by-binding-to-a-highly-conserved-allosteric-site-on-their-c-terminal-domains
#12
Mubarak A Alamri, Hachemi Kadri, Luke J Alderwick, Nigel S Simpkins, Youcef Mehellou
SPAK and OSR1 are two protein kinases that emerged as attractive targets in the discovery of novel antihypertensive agents due to their role in regulating electrolyte balance in vivo. In this work, we report on the identification of an allosteric pocket on their highly conserved C-terminal domains, which influences their kinase activity. Also, we show that some known WNK-signaling inhibitors bind to this allosteric site. Using in silico screening, we identified Rafoxanide, an anti-parasitic agent, as a novel allosteric inhibitor of SPAK and OSR1...
March 31, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28371340/molecular-hybridization-tool-in-development-of-furoxan-based-no-donor-prodrugs
#13
Leonid Fershtat, Nina N Makhova
The molecular hybridization of different compounds with known pharmacological activity comes into particular prominence for the design of potential drugs with improved pharmacokinetic profile. Especially great attention in last decade is focused on the synthesis of hybrid structures comprising an NO-donor framework since NO is a ubiquitous and crucial regulator for cellular metabolism, affecting various physiological and pathophysiological processes. 1,2,5-Oxadiazole 2-oxides (furoxans) which are capable to exogenous NO release at the presence of thiol cofactors constitute an important class of perspective NO-donors...
March 31, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28371485/target-deconvolution-efforts-on-wnt-pathway-screen-reveal-dual-modulation-of-oxidative-phosphorylation-and-serca2
#14
Matias Casas-Selves, Andrew Zhang, James E Dowling, Stefan Hallen, Aarti Kawatkar, Nicholas J Pace, Christopher Denz, Timothy Pontz, Farzin Garahdaghi, Qing Cao, Alan Sabirsh, Kumar Thakur, Nichole O'Connell, Jun Hu, Ivan Cornella-Taracido, Eranthie Weerapana, Michael Zinda, Robert A Goodnow
Wnt signaling is critical for development, cell proliferation and differentiation, and mutations in this pathway resulting in constitutive signaling have been implicated in various cancers. A pathway screen using a Wnt-dependent reporter identified a chemical series based on a 1,2,3-thiadiazole-5-carboxamide (TDZ) core with sub-M potency. We report here a comprehensive mechanism of action deconvolution study towards identifying the efficacy target(s) and biological implication of this chemical series involving bottom-up quantitative chemoproteomics, cell biology, and biochemical methods...
March 29, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28371191/structure-based-target-specific-screening-leads-to-small-molecule-camkii-inhibitors
#15
David Xu, Liwei Li, Donghui Zhou, Degang Liu, Andy Hudmon, Samy O Meroueh
Target-specific scoring methods are more commonly used to identify small-molecule inhibitors among compounds docked to a target of interest. Top candidates that emerge from these methods have rarely been tested for activity and specificity across a family of proteins. In this study we docked a chemical library into CaMKIIδ, a member of the Ca(2+) /calmodulin (CaM)-dependent protein kinase (CaMK) family, and re-scored the resulting protein-compound structures using Support Vector Machine SPecific (SVMSP), a target-specific method that we developed previously...
March 29, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28346821/structure-activity-relationships-on-cynnamoyl-derivatives-as-inhibitors-of-p300-histone-acetyltransferase
#16
Valentina Noemi Madia, Rosaria Benedetti, Maria Letizia Barreca, Liza Ngo, Luca Pescatori, Antonella Messore, Giovanni Pupo, Francesco Saccoliti, Sergio Valente, Antonello Mai, Luigi Scipione, Yujun George Zheng, Cristina Tintori, Maurizio Botta, Violetta Cecchetti, Lucia Altucci, Roberto Di Santo, Roberta Costi
Human p300 is a polyhedric transcriptional coactivator, playing a crucial role by acetylating histones on specific lysine residues. A great deal of evidences shows that p300 is involved in several diseases as leukemia, tumors and viral infection. Its involvement in pleiotropic biological roles and connections to diseases provide the rationale as to how its modulation could represent an amenable drug target. Several p300 inhibitors (HATi) have been described so far, but all suffer from low potency, lack of specificity or low cell-permeability, highlighting the need to find more effective inhibitors...
March 27, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28342294/benzylphenylpyrrolizinones-with-anti-amyloid-and-scavenging-effects-potentially-useful-in-alzheimer-s-disease-treatment
#17
Jean-Pierre Gabriel Jourdan, Marc Since, Laîla El Kihel, Cédric Lecoutey, Sophie Corvaisier, Rémi Legay, Jana Sopkova-de Oliveira Santos, Thierry Cresteil, Aurélie Malzert-Fréon, Christophe Rochais, Patrick Dallemagne
This article describes the drug design steps developed to try to increase the scavenging and Aβ aggregation inhibition activities of a previously described series of benzylidenephenyl-pyrrolizinones. Among the novel synthesized derivatives, some benzylphenylpyrrolizinones exhibited interesting results in regard to those activities and first druggability parameters which confer to these compounds a potential therapeutic interest in Alzheimer's disease.
March 25, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28334511/elongated-and-shortened-peptidomimetic-inhibitors-of-the-proprotein-convertase-furin
#18
Kornelia Hardes, Teodora Ivanova, Bastian Thaa, Gerald M McInerney, Tove Irene Klokk, Kirsten Sandvig, Sebastian Künzel, Iris Lindberg, Torsten Steinmetzer
Novel elongated and shortened derivatives of the peptidomimetic furin inhibitor phenylacteyl-Arg-Val-Arg-4-amidinobenzylamide were synthesized. The most potent compounds, e.g., Nα(carbamidoyl)Arg-Arg-Val-Arg-4-amidinobenzylamide (Ki = 6.2 pM), contain additional basic residues at the N-terminus and inhibit furin in the low picomolar range. Furthermore, to decrease the molecular weight of this inhibitor type, compounds lacking the P5-moiety were prepared. The best inhibitors of this series, 5-(guanidino)-valeroyl-Val-Arg-4-amidinobenzylamide and its P3 tert...
March 23, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28334506/molecular-features-of-the-yap-inhibitor-verteporfin-synthesis-of-hexasubstituted-dipyrrins-as-potential-inhibitors-of-yap-taz-the-downstream-effectors-of-the-hippo-pathway
#19
Floriane Gibault, Fabrice Bailly, Matthieu Corvaisier, Mathilde Coevoet, Guillemette Huet, Patricia Melnyk, Philippe Cotelle
Porphyrin derivatives, in particular verteporfin (VP), a photosensitizer initially designed for cancer therapy, have been identified as inhibitors of the YAP-TEAD interaction and transcriptional activity. Herein we report the efficient convergent synthesis of the dipyrrin half of protoporphyrin IX dimethyl ester (PPIX-DME), in which the sensitive vinyl group was created at the final stage by a dehydroiodination reaction. Two other dipyrrin derivatives were synthesized, including dipyrrin 19 [(Z)-2-((3,5-dimethyl-4-vinyl-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-4-vinyl-1H-pyrrole], containing two vinyl groups...
March 23, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28333400/an-improved-model-of-the-trypanosoma-brucei-ctp-synthetase-glutaminase-domain-acivicin-complex
#20
Juliana Oliveira de Souza, Alice Dawson, William N Hunter
The natural product acivicin inhibits the glutaminase activity of cytidine triphosphate (CTP) synthetase and is a potent lead compound for drug discovery in the area of neglected tropical diseases, specifically trypanosomaisis. A 2.1-Å-resolution crystal structure of the acivicin adduct with the glutaminase domain from Trypanosoma brucei CTP synthetase has been deposited in the RCSB Protein Data Bank (PDB) and provides a template for structure-based approaches to design new inhibitors. However, our assessment of that data identified deficiencies in the model...
March 23, 2017: ChemMedChem
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