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Luca Mologni, Martina Dalla Via, Adriana Chilin, Manlio Palumbo, Giovanni Marzaro
Oncogenic activation of the RET kinase has been found in several neoplastic diseases, like medullary thyroid carcinoma, multiple endocrine neoplasia, papillary thyroid carcinoma and non-small cells lung cancer. Currently approved RET inhibitors were not originally designed to be RET inhibitors and their potency against RET kinase has not been optimized. Hence, novel compounds able to inhibit both wtRET and its mutants (e.g. V804MRET) are needed. Herein we present the development and the preliminary evaluation of a new sub-micromolar wtRET/V804MRET inhibitor (69) endowed with 4-anilinopyridine structure, starting from our previously identified 4-anilinopyrimidine hit compound...
June 22, 2017: ChemMedChem
Filipe Vultos, Célia Fernandes, Filipa Mendes, Fernanda Marques, João Correia, Isabel Santos, Lurdes Gano
A straightforward synthetic route for a new multifunctional DOTA derivative is described. To prove the versatility of this prochelator to prepare radiolabelled hybrid compounds containing two different biological targeting moieties, an antitumoral agent (e.g. DNA intercalating agent) and an Estrogen Receptor ligand (e.g. LXXLL based peptide) were regiospecifically conjugated to the DOTA derivative. The bifunctional probe was radiolabelled with the Auger electron emitter Indium-111 and the radioconjugate demonstrated to induce DNA damage in vitro which along with the nuclear internalization exhibited in breast cancer cells might enhance its therapeutic activity...
June 19, 2017: ChemMedChem
Martin Maxmilian Kaiser, Ondřej Baszczyňski, Dana Hocková, Lenka Poštová-Slavětínská, Martin Dračínský, Dianne T Keough, Luke W Guddat, Zlatko Janeba
Acyclic nucleoside phosphonates (ANPs) are an important class of therapeutic drugs that act as antiviral agents by inhibiting viral DNA polymerases and reverse transcriptases. ANPs containing a 6-oxopurine instead of 6-aminopurine or pyrimidine bases are inhibitors of the purine salvage enzyme, hypoxanthine-guanine-[xanthine]-phosphoribosyltransferase (HG[X]PRT). Such compounds, and their prodrugs, are able to arrest the growth of Plasmodium falciparum (Pf) in cell culture. A new series of ANPs has been synthesized and tested as inhibitors of human HGPRT, PfHGXPRT and Plasmodium vivax (Pv) HGPRT...
June 19, 2017: ChemMedChem
Melanie Göth, Volker Badock, Jörg Weiske, Kevin Pagel, Benno Kuropka
Fragment-based screening presents a promising alternative to high-throughput screening and has gained great attention over the last years. So far, only a few studies discuss mass spectrometry as a screening technology for fragments. Here, we applied native electrospray ionization mass spectrometry (ESI-MS) for screening defined sets of fragments against four different target proteins. Fragments were selected from a primary screen conducted by thermal shift assay (TSA) and represent different binding categories...
June 15, 2017: ChemMedChem
Durairaj Thiyagarajan, Gopal Das, Ramesh Aiyagari
A pyridinium amphiphile-loaded Poly(lactic-co-glycolic acid) (PLGA) nanocarrier (C1-PNC) was developed as an adjuvant in order to break the resistance and restore susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) cells to therapeutic antibiotics. Notably, against a clinical MRSA strain, C1-PNC could render 8 × and 6 × reduction of the minimum biofilm eradication concentration (MBEC90) of gentamicin and ciprofloxacin, respectively. Mechanistic studies on MRSA planktonic cells revealed that in case of gentamicin, C1-PNC promoted enhanced cellular uptake of the antibiotic, while the propensity of C1-PNC to inhibit efflux pump activity could be leveraged to enhance cellular accumulation of ciprofloxacin leading to effective killing of MRSA cells...
June 15, 2017: ChemMedChem
Monica Piras, Andrea Testa, Ian N Fleming, Sergio Dall'Angelo, Alexandra Andriu, Sergio Menta, Mattia Mori, Gavin D Brown, Duncan Forster, Kaye J Williams, Matteo Zanda
Non-peptidic RGD-mimic ligands were designed and synthesized by click chemistry between an arginine-azide mimic and an aspartic acid-alkyne mimic. Some of these molecules combine excellent in vitro properties (high αvβ3 affinity, selectivity, drug-like logD, high metabolic stability) with a variety of radiolabeling options (e.g. tritium and [18F]fluorine, plus compatibility with radio-iodination), not requiring the use of chelators or prosthetic groups. The binding mode of the resulting triazole RGD-mimics to αvβ3 or αIIbβ3 receptors was investigated by molecular modeling simulations...
June 13, 2017: ChemMedChem
Nagham Alatrash, Eugenia S Narh, Abhishek Yadav, Mahn-Jong Kim, Thamara Janaratne, James Gabriel, Frederick M MacDonnell
Four mononuclear [(L-L)2 Ru(tatpp)](2+) and two dinuclear [(L-L)2 Ru(tatpp)Ru(L-L)2 ](4+) ruthenium(II) polypyridyl complexes (RPCs) containing the 9,11,20,22-tetraazatetrapyrido[3,2-a:2',3'-c:3'',2''-l:2''',3'''-n]pentacene (tatpp) ligand were synthesized, in which L-L is a chelating diamine ligand such as 2,2'-bipyridine (bpy), 1,10-phenanthroline (phen), 3,4,7,8-tetramethyl-1,10-phenanthroline (Me4 phen) or 4,7-diphenyl-1,10-phenanthroline (Ph2 phen). These Ru-tatpp analogues all undergo reduction reactions with modest reducing agents, such as glutathione (GSH), at pH 7...
June 12, 2017: ChemMedChem
Pengcheng Lv, Tian-Long Yan, Li-Fei Bai, Hai-Liang Zhu, Wei-Ming Zhang
Vascular endothelial growth factor receptor 2 (VEGFR2) has been proven to play a major role in the regulation of tumor angiogenesis. A series of novel glycyrrhetic acid derivatives have been synthesized and evaluated for their VEGFR2 inhibitory activity as well as their antiproliferative properties against four cancer cell lines (MCF-7, Hela, HepG2 and A549). In vitro biological evaluation against four human tumor cell lines indicated that most of the prepared compounds showed antiproliferative activities, and compound 3a exhibited the best inhibitory activity against MCF-7 with the IC50 value of 1...
June 9, 2017: ChemMedChem
Tommaso Felicetti, Rolando Cannalire, Maria Sole Burali, Serena Massari, Giuseppe Manfroni, Maria Letizia Barreca, Oriana Tabarrini, Bryan D Schindler, Stefano Sabatini, Glenn W Kaatz, Violetta Cecchetti
Bacterial resistance to antimicrobial agents has become an increasingly serious health problem in recent years. Among the strategies by which resistance can be achieved, overexpression of efflux pumps such as NorA of S. aureus leads to a sub-lethal concentration of the antibacterial at the active site that in turn may predispose the organism to the development of high-level target-based resistance. With the aim to improve both the chemical stability and the potency of our previously reported 3-phenyl-1,4-benzothiazine NorA inhibitors, we replaced the benzothiazine core with different nuclei...
June 9, 2017: ChemMedChem
Maria Dichiara, Agostino Marrazzo, Orazio Prezzavento, Simona Collina, Antonio Rescifina, Emanuele Amata
Human African trypanosomiasis (HAT), Chagas disease and leishmaniasis, belong to a group of infectious diseases defined as neglected tropical diseases, induced by infection with protozoan parasites named trypanosomatids. Current drugs present several issues and the development of new candidates appears to be needed. The majority of the current therapeutic trypanosomatid targets are represented by enzymes or cell surface receptors. Among these, eukaryotic protein kinases represent a major group of protein targets whose modulation may be beneficial for the treatment of neglected tropical protozoan diseases...
June 7, 2017: ChemMedChem
Joerg Kallen, Aude Izaac, Celine Be, Luca Arista, David Orain, Klemens Kaupmann, Christine Guntermann, Klemens Hoegenauer, Samuel Hintermann
RORγt is a key transcription factor for the production of pro-inflammatory Th17 cytokines which are implicated in the pathogenesis of autoimmune diseases. We have recently reported a new series of inverse agonists based on an imidazopyridine core with good physicochemical properties and excellent selectivity. Here we report eight new X-ray structures for different classes of natural and synthetic compounds including examples selected from the patent literature. An analysis of their respective binding modes reveals insights into the molecular mechanisms leading to agonism, antagonism or inverse agonism...
June 7, 2017: ChemMedChem
Valentina Straniero, Ermanno Valoti, Carlo Zanotto, Letizia Straniero, Andrea Casiraghi, Stefano Duga, Antonia Radaelli, Carlo de Giuli Morghen
A wide variety of drug-resistant microorganism are continuously emerging, restricting the therapy of common bacterial infections. Originally potent antimicrobial agents are now no longer helpful, due to their weak or null activity towards these antibiotic-resistant bacteria. In addition, none of the recently approved antibiotics affects innovative targets, resulting in a requirement of novel drugs, with innovative antibacterial mechanisms of action. The essential cell division protein FtsZ (Filamentous temperature sensitive Z) emerged as a possible target, thanks to its ubiquitous expression and its homology to eukaryotic -tubulin...
June 6, 2017: ChemMedChem
Leonardo Pisani, Marco Catto, Annalisa De Palma, Roberta Farina, Saverio Cellamare, Cosiamo Damiano Altomare
Acetylcholinesterase (AChE) inhibitors are still the majority of the marketed drugs for Alzheimer's disease (AD). The structural arrangement of the enzyme, featuring a narrow gorge that separates the catalytic from a peripheral anionic subsite (CAS and PAS, respectively), inspired the development of bivalent ligands able to bind and block the catalytic activity of CAS as well as the role of PAS in beta amyloid (Aβ) fibrillogenesis. Aiming at discovering novel AChE dual binders with improved druglikeness, homo- and heterodimers containing 2H-chromen-2-one building blocks were developed...
June 1, 2017: ChemMedChem
Elisabetta Teodori, Silvia Dei, Gianluca Bartolucci, Maria Grazia Perrone, Dina Manetti, Maria Novella Romanelli, Marialessandra Contino, Nicola Antonio Colabufo
A series of derivatives were synthesized and studied with the aim to investigate the structure-activity relationships of the two P-glycoprotein (P-gp) modulators elacridar and tariquidar. Then different aryl substituted amides were inserted and to explore the effects of varying the amide function, the corresponding isosteric ester derivatives and some alkylamine analogues were synthesized. The new compounds were studied to evaluate their P-gp interaction profile and selectivity towards the two other ABC transporters, Multidrug-Resistance-associated Protein-1 (MRP-1) and Breast Cancer Resistance Protein (BCRP)...
June 1, 2017: ChemMedChem
Robert Kuhnert, Menyhárt-Botond Sárosi, Sven George, Peter Lönnecke, Bettina Hofmann, Dieter Steinhilber, Blagoje Murganic, Sanja Mijatovic, Danijela Maksimovic-Ivanic, Evamarie Hey-Hawkins
The progression of cancer is accelerated by increased proliferation, angiogenesis, and inflammation. These processes are mediated by leukotrienes. Several cancer cell lines overexpress 5-lipoxygenase, an enzyme that converts arachidonic acid into leukotrienes. An early inhibitor of the 5-lipoxygenase pathway is Rev-5901, which, however, lacks in in vivo efficacy, as it is rapidly metabolized. We investigated the introduction of carboranes as highly hydrophobic and metabolically stable pharmacophores into lipoxygenase inhibitors...
June 1, 2017: ChemMedChem
Bernhard Wünsch, Artur Kokornaczyk, Dirk Schepmann, Junichiro Yamaguchi, Kenichiro Itami, Erik Laurini, Maurizio Fermeglia, Sabrina Pricl
Spirocyclic thiophene derivatives represent promising sigma-1 ligands with high sigma-1 affinity and selectivity over the sigma-2 subtype. In order to increase ligand efficiency, the thiophene ring was replaced bioisosterically by a thiazole ring and the pyran ring was opened. Late-stage diversification by regioselective C-H arylation of thiazoles 9a-c resulted in a set of 53 compounds with high diversity. This set of compounds was analyzed with respect to sigma-1 affinity, sigma-1/sigma-2 selectivity, lipophilicity (logD7...
May 24, 2017: ChemMedChem
Wesam E Mehanna, Tiangong Lu, Bikash Debnath, Deena S Lasheen, Rabah A T Serya, Khaled A Abouzid, Nouri Neamati
Herein, we describe the synthesis and biological evaluation of a series of novel benzothiazoles based on a diaryl urea scaffold previously reported in some allosteric CXCR2 inhibitors. From a library of 41 new compounds, 17 showed significant inhibition of CXCR2 with IC50 less than 10 M and selectivity over CXCR4. Our ADMET simulations suggest favorable drug-like properties for the active compounds. Importantly, we developed a predictive model that can distinguish active from inactive compounds and will serve as a valuable tool to guide the design of optimized compounds to be evaluated in preclinical models...
May 23, 2017: ChemMedChem
Frieda Anna Sorgenfrei, Simone Fulle, Benjamin Merget
Extensive kinase profiling data, covering more than half of the human kinome, are nowadays available and allow construction of activity prediction models of high practical use. Proteochemometric (PCM) approaches utilize compound and protein descriptors, which enables the extrapolation of bioactivity values also to so far unexplored kinases. In this study, the potential of PCM to make large-scale predictions on the entire kinome is explored, considering the applicability on novel compounds and kinases, including clinically relevant mutants...
May 23, 2017: ChemMedChem
Hezhen Wang, Bader Huwaimel, Kshitij Verma, James Miller, Todd Germain, Nihar Kinarivala, Dimitri Pappas, Paul Brookes, Paul Charles Trippier
Mitochondrial complex II (CII) is an emerging target for numerous human diseases. Sixteen analogues of the CII inhibitor natural product atpenin A5 were prepared to evaluate the structure-activity relationship of the C-5 pyridine side chain. The side chain ketone moiety was determined to be pharmacophoric, engendering a bioactive conformation. Analogue 16c displayed CII IC50 = 64 nM, retained selectivity for CII over mitochondrial complex I (>156-fold) and possessed a ligand-lipophilicity efficiency of 5...
May 18, 2017: ChemMedChem
Francesca Aiello, Gabriele Carullo, Francesca Giordano, Elena Spina, Alessandra Nigro, Antonio Garofalo, Sabrina Tassini, Gabriele Costantino, Paolo Vincetti, Agostino Bruno, Marco Radi
Together with estrogen receptors ERα and ERβ, the G protein-coupled estrogen receptor (GPER) mediates important pathophysiological signaling pathways induced by estrogens and is currently regarded as a promising target for ER-negative (ER-) and triple-negative (TN) breast cancer. Only a few selective GPER modulators have been reported to date, and their use in cancer cell lines has often led to contradictory results. Herein we report the application of virtual screening and cell-based studies for the identification of new chemical scaffolds with a specific antiproliferative effect against GPER-expressing breast cancer cell lines...
May 18, 2017: ChemMedChem
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