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Serena Fortunato, Giulia Bononi, Carlotta Granchi, Filippo Minutolo
Many tumors exhibit altered metabolic characteristics relative to normal and healthy tissues. Their metabolic profile highlights a strong prevalence of glycolysis over oxidative phosphorylation, regardless their exposure to different oxygen levels ("Warburg effect"). This condition originates from a set of gene regulations, consisting in the overexpression of some enzymes or transporters involved in the glycolytic pathway. Therefore, these effectors may constitute appealing targets for the implementation of selective therapeutic interventions against cancer...
September 18, 2018: ChemMedChem
Arun K Nandi, A Panja, S Das, A Chakraborty, P Chakraborty, S Pal
Folic acid (FA), vitamin-B9, is a good receptor of drugs triggering cellular uptake via endocytosis. FA is sparingly soluble in water and here a new approach for formation of FA hydrogel at physiological condition is reported using hydrolysis of glucono-δ-lactone in PBS buffer. The gel has fibrillar network morphology arising from intermolecular H-bonding and π-stacking interaction. Thixotropic property of gel is utilized for encapsulation of both hydrophilic (doxorubicin, DOX) and hydrophobic (camptothecin, CPT) drugs...
September 17, 2018: ChemMedChem
Julien Pedron, Clotilde Boudot, Sandra Bourgeade-Delmas, Alix Sournia-Saquet, Lucie Paloque, Maryam Rastegari, Mansour Abdoulaye, Hussein El-Kashef, Colin Bonduelle, Geneviève Pratviel, Susan Wyllie, Alan H Fairlamb, Bertrand Courtioux, Pierre Verhaeghe, Alexis Valentin
An antikinetoplastid pharmacomodulation study at position 3 of the recently described hit molecule 3-bromo-8-nitroquinolin-2(1H)-one was conducted. Twenty-four derivatives were synthesised using the Suzuki-Miyaura cross-coupling reaction and evaluated in vitro on both Leishmania infantum axenic amastigotes and Trypanosoma brucei brucei trypomastigotes. Introduction of a para-carboxyphenyl group at position 3 of the scaffold led to the selective antitrypanosomal hit molecule 3-(4-carboxyphenyl)-8-nitroquinolin-2(1H)-one (21) with a lower reduction potential (-0...
September 17, 2018: ChemMedChem
Patrick Mäder, Georg A Rennar, Alejandra M Peter Ventura, Christoph G Grevelding, Martin Schlitzer
Chemotherapy based on repeated doses of Praziquantel (PZQ) is still the most effective control strategy against schistosomiasis, a neglected tropical disease caused by platyhelminths of the genus Schistosoma spp.. Its long-term use, however, raises serious concerns about drug resistance against PZQ. Therefore, it is generally acknowledged that alternative treatment options are urgently needed. This review intends to summarize data on relinquished drugs as well as recent advances in the area of antischistosomal compounds from a medicinal chemistry point of view...
September 13, 2018: ChemMedChem
Audrey Trommenschlager, Florian Chotard, Benoît Bertrand, Souheila Amor, Philippe Richard, Ali Bettaïeb, Catherine Paul, Jean-Louis Connat, Pierre Le Gendre, Ewen Bodio
Three new gold(I)-coumarin-based trackable therapeutic complexes and two non-trackable analogues have been synthesized and fully characterized. They all display antiproliferative properties on several types of cancer cell lines including colon, breast, and prostate. Two complexes displayed significant anti-inflammatory effect, while one displayed a pro-inflammatory behaviour - highlighting the impact of the position of the fluorophore on the caffeine scaffold. Additionnally, the three coumarin derivatives could be vizualized in vitro by two-photons microscopy...
September 11, 2018: ChemMedChem
Nitzan Ganot, Ori Braitbard, Asaad Gammal, Joseph Tam, Jacob Hochman, Edit Y Tshuva
Due to the toxicity of platinum compounds used in the clinic as anticancer chemotherapies, the safe titanium serves as an attractive alternative. Lately, we introduced a new family of Ti complexes based on readily available phenolato ligands, demonstrating an incredibly high hydrolytic stability, with the lead compound phenolaTi demonstrating a wide cytotoxic activity towards the NCI-60 panel of NIH human cancer cell lines, with an average GI50 of 4.7±2 µM. Herein, we evaluated in vivo: (a) the safety, and (b) the growth inhibitory (efficacy) of this compound...
September 10, 2018: ChemMedChem
Christian Peifer, Dorian Schmidt, Theo Rodat, Linda Heintze, Jantje Weber, Rebecca Horbert, Ulrich Girreser, Tim Raeker, Lara Bußmann, Malte Kriegs, Bernd Hartke
Axitinib is an approved drug targeting tyrosine kinases including the vascular endothelial growth factor receptor 2 (VEGFR2) and is licensed for second-line therapy of renal cell carcinoma. Interestingly, axitinib contains a stilbene-like double bond allowing for E/Z isomerization. In this study, we investigated the photoinduced E/Z isomerization of axitinib to explore if its inhibitory effect can be turned "on" and "off", triggered by light. Compared to the E-isomer, the absorption of the Z-isomer is red-shifted indicating reversible photoswitching properties...
September 10, 2018: ChemMedChem
Magdalena Slusarczyk, Valentina Ferrari, Michaela Serpi, Blanka Gonczy, Jan Balzarini, Christopher McGuigan
We herein report on the application of phosphorodiamidate technology to both pyrimidine and purine nucleosides with anticancer activity. Sixteen symmetrical phosphorodiamidates esterified with natural amino acids such as L-alanine and glycine were synthesized. All the compounds were evaluated for their cytotoxic activity in a wide panel of solid and leukemic tumour cell lines. In addition, a carboxypeptidase Y assay was performed on a representative phosphorodiamidate in order to reveal the putative bioactivation pathway for the reported phosphorodiamidate-type prodrugs...
September 10, 2018: ChemMedChem
Charles Rice, Anh K Lam, Melissa A Foxley, Erika L Moen, Jennifer Pusavat, Cassandra L Wouters
Staphylococcus epidermidis is one of the most prevalent prokaryotic species on human skin and mucosal membranes that constitute the commensal flora. S. epidermidis has become one of the most common causes of primary bacteremia. Infections are difficult to diagnose because the pathogen has natural niches on human skin and the ability to adhere to inanimate surfaces via biofilms. Alarmingly, S. epidermidis has acquired resistance to many antibiotics, which presents a danger to human health. Most clinical isolates of S...
September 7, 2018: ChemMedChem
Fliur Macaev, Veaceslav Boldescu, Natalia Sucman, Sidra Hassan, Jamshed Iqbal, Mariana Neamțu, Joanna Lecka, Jean Sevigny, Denis Prodius
Cytotoxicity against cancerous and normal cells, inhibition of ectonucleotidase, and redox properties of a new group of imidazole-based organic salts and ionic liquids have been explored. The tetrachloroferrate salt of a 1-methylimidazole derivative of salicylic aldehyde has been shown to have most prominent inhibitory activity against ectonucleotidase, as well as a higher cytotoxicity against HeLa cells than that of the reference compound carboplatin, while having lower cytotoxicity towards BHK-21 cells. The studied compounds have shown a moderate level of antioxidant activity with better results for the salicylic aldehyde derivatives than for the spiropyrans...
September 7, 2018: ChemMedChem
Arun K Ghosh, Margherita Brindisi, Anindya Sarkar
The Curtius rearrangement is the thermal decomposition of an acyl azide derived from carboxylic acid to produce an isocyanate as the initial product. The isocyanate can undergo further reactions to provide amines and their derivatives. Due to its tolerance for a large variety of functional groups and complete retention of stereochemistry during rearrangement, the Curtius rearrangement has been utilized in the synthesis of a wide variety of medicinal agents with amines and amine-derived functional groups such as ureas and urethanes The current review outlines various applications of the Curtius rearrangement in drug discovery and medicinal chemistry...
September 5, 2018: ChemMedChem
Andreas Hans Göller, Arndt Robert Finkelmann, Daria Goldmann, Gisbert Schneider
The metabolism of xenobiotics by humans and other organisms is a complex process involving numerous enzymes that catalyze phase I (functionalization) and phase II (conjugation) reactions. We here introduce MetScore, a machine learning model that can predict both phase I and phase II reaction sites of drugs. We developed cheminformatics workflows to filter and process reactions to obtain suitable phase I and phase II data sets for model training. Employing a recently developed molecular representation based on quantum chemical partial charges, we constructed random forest machine learning models for phase I and phase II reactions...
September 5, 2018: ChemMedChem
Satoshi Mizuta, Juliann Nzembi Makau, Ayako Kitagawa, Kanami Kitamura, Hiroki Otaki, Kodai Nishi, Ken Watanabe
To explore potential biological activities of trifluoromethyl heterocycles, we recently developed a synthetic approach to assess a series of α-trifluoromethyl-α,β-unsaturated lactones and trifluoromethyl pyrazolinones. The compounds were tested for their antimicrobial activity, and we found that some compounds had anti-influenza viral activity. The β-aryl-α-trifluoromethyl α,β-unsaturated lactone derivatives 5g, 7b and the trifluoromethyl pyrazolinone 12c possessed promising inhibitory activity against influenza virus type A, strain A/WSN/33 (H1N1)...
September 5, 2018: ChemMedChem
Prasanthi Medarametla, Viviana Gatta, Tommi Kajander, Tuomo Laitinen, Päivi Tammela, Antti Poso
In the era of increased antibiotic resistance, targeting enzymes involved in bacterial communication (quorum sensing) represents a new strategy to fight bacterial infections. LsrK is a kinase responsible for the phosphorylation of autoinducer-2, a signal molecule involved in quorum sensing. Inhibiting LsrK would lead to quorum sensing inactivation and interfere with the pathogenesis. In this study, we built the first LsrK 3D model and performed virtual screening of a locally available database. Selected compounds were tested against LsrK and the analogue search conducted based on the positive hits led to the identification of low micromolar LsrK inhibitors...
September 4, 2018: ChemMedChem
Anna Katharina Herta Hirsch, Varsha R Jumde, Milon Mondal, Robin M Gierse, M Yagiz Unver, Francesca Magari, Roos C W van Lier, Andreas Heine, Gerhard Klebe
Acylhydrazone-based dynamic combinatorial chemistry (DCC) is a powerful strategy for the rapid identification of novel hits. Even though acylhydrazones are important structural motifs in medicinal chemistry, their further progression in development may be hampered by major instability and toxicity issues under physiological conditions. It is therefore of paramount importance to identify stable replacements for acylhydrazone linkers. Here, we present the first report on the design and synthesis of stable bioisosteres of acylhydrazone-based inhibitors of the aspartic protease endothiapepsin as a follow-up to a DCC study...
September 3, 2018: ChemMedChem
Tony LE Gall, Gilles Lemercier, Sylviane Chevreux, Katrin-Stephanie Tucking, Julian Ravel, Franck Thetiot, Ulrich Jonas, Holger Schonherr, Tristan Montier
As a growing public health concern, the worldwide spread of antimicrobial resistance urges the development of new therapies. Antibacterial photodynamic therapy (a-PDT) may be an alternative to conventional antibiotherapy. Here, we report the synthesis and characterization of seven original reactive oxygen species (ROS) producing ruthenium(II) polypyridyl complexes. These are part of a collection of seventeen derivatives varying in terms of the nature of the substituent(s), molecular symmetry, electrical charge, and counter-ions...
August 29, 2018: ChemMedChem
Wei Zhao, Aihua Li, Aitang Zhang, Yiwei Zheng, Jingquan Liu
In this review, we focus on recent advances in the synthesis of polymer-functionalized transition-metal-based nanomaterials and follow this up by discussing their applications in bioimaging diagnosis and cancer therapy. Transition-metal-based nanomaterials show great potential in cancer therapy owing to their intensive near-IR absorption, excellent photothermal conversion efficiency, strong X-ray attenuation, and magnetic properties. Functional polymers are usually introduced by a one-step or multistep method to further endow these nanomaterials with great biocompatibility and physiological stability...
August 28, 2018: ChemMedChem
Gregorio Cullia, Lucia Tamborini, Paola Conti, Carlo De Micheli, Andrea Pinto
Trypanosoma brucei (T. brucei) is the agent of Human African Trypanosomiasis (HAT), a neglected disease that threats the life of 65 million people in sub Saharan Africa every year. Unfortunately, available therapy is unsatisfactory, mainly due to safety issues and developing resistances. Significant efforts over the last decades have been made in the discovery of new potential agents from the World Health Organization and public-private partnership organizations such as the Drugs for Neglected Diseases Initiative (DNDi)...
August 27, 2018: ChemMedChem
Christian Steinebach, Agnieszka Ambrożak, Stefan Dosa, Shaunna L Beedie, Jonathan D Strope, Gregor Schnakenburg, William D Figg, Michael Gütschow
The introduction of fluorine into bioactive molecules is a matter of importance in medicinal chemistry. In this study, representatives of various chemical entities of fluoroaromatic compounds were synthesized. Depending on the reaction conditions, either tetrafluorophthalimides or ammonium tetrafluorophthalamates are accessible from tetrafluorophthalic anhydride and primary amines. Tetrafluorophthalamic acids undergo thermal decarboxylation to yield tetrafluorobenzamides. These could be successfully converted upon treatment with primary amines, in the course of an aromatic nucleophilic substitution, to 2,3,5-trifluorobenzamides with respective amino substituents at the 4-position...
August 22, 2018: ChemMedChem
Samuel Ristovski, Monika Uzelac, Jakob Kljun, Tanja Lipec, Matija Uršič, Špela Zemljič Jokhadar, Monika Cecilija Žužek, Tomaž Trobec, Robert Frangež, Kristina Sepcic, Iztok Turel
A small library of 17 organoruthenium compounds with the general formula [RuII(fcl)(chel)(L)]n+ (fcl, face capping ligand; chel, chelating bidentate ligand; L, monodentate ligand) was screened for inhibitory activity against cholinesterases and glutathione-S-transferases of human and animal origins. Compounds were selected to include different chelating ligands (i.e., N,N-, N,O-, O,O-, S,O-) and monodentate ligands that can modulate the aquation rate of the metal species. Compounds with a labile ruthenium chloride bond that provided rapid aquation inhibited both sets of enzymes in reversible competitive modes and at pharmaceutically relevant concentrations...
August 20, 2018: ChemMedChem
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