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Madia Letizia Stama, Enza Lacivita, Liliya N Kirpotina, Mauro Niso, Roberto Perrone, Igor A Schepetkin, Mark T Quinn, Marcello Leopoldo
Formyl peptide receptor-2 (FPR2) is a G protein-coupled receptor belonging to the N-formyl peptide receptor (FPR) family that plays critical roles in peripheral and brain inflammatory responses. FPR2 has been proposed as a target for the development of drugs that could facilitate the resolution of chronic inflammatory reactions by enhancing endogenous anti-inflammation systems. Starting from the structure of the FPR2 agonists (R)- and (S)-4 and 2, we designed a new series of ureidopropanamide derivatives with the goal of converting functional activity from agonism to antagonism and to develop new FPR2 antagonists...
September 18, 2017: ChemMedChem
Vania Bernardes Genisson, Julie Laborde, Céline Deraeve
The place of prodrugs in the current antitubercular therapeutic arsenal is preponderant, since two of the four first-line antitubercular agents, isoniazid (INH) and pyrazinamide (PZA), need to be activated by Mycobacterium tuberculosis before exerting their activity. In addition, six other prodrugs can be found in the second- and third-line therapeutic regimens, namely ethionamide (ETH), prothionamide (PTH), p-aminosalicylic acid (PAS), thiacetazone (TAC), isoxyl (ISO) and the recently approved delamanid. The emergence of mycobacterial strains resistant to one or several antitubercular agents is one of the main issues of the antitubercular therapy...
September 16, 2017: ChemMedChem
Clemens Richert, Helmut Griesser, Alexander Schwenger
Formulating pharmaceutically active ingredients for drug delivery is a challenge. There is a need for new drug delivery systems that take up therapeutic molecules and release them into biological systems. We propose a novel mode of encapsulation that involves matrices formed through co-assembly of drugs with adamantane hybrids that feature four CG dimers as sticky ends. Such adamantanes are accessible via inexpensive solution-phase syntheses, and the resulting materials show attractive properties for controlled release...
September 15, 2017: ChemMedChem
Kenny Mebrouk, Mathieu Ciancone, Thomas Vives, Sandrine Cammas-Marion, Thierry Benvegnu, Catherine Le Goff-Gaillard, Yannick Arlot-Bonnemains, Marc Fourmigué, Franck Camerel
This work demonstrates that metal-bis(dithiolene) complexes can be efficiently incorporated inside organic nanocarriers and, that under near-infrared (NIR) irradiation, their high photothermal activity can be finely used to release encapsulated drugs on demand. In contrast to gold nanoparticles and other organic NIR dyes, nickel-bis(dithiolene) complexes do not produce singlet oxygen under irradiation, a highly desirable characteristic to preserve the chemical integrity and activity of the loaded drug during the NIR-triggered release from the nanocarriers...
September 13, 2017: ChemMedChem
Dana Jaya Levine, Miguel I Gonzalez, Christina M Legendre, Tomče Runčevski, Julia Oktawiec, Kristen A Colwell, Jeffrey R Long
Calcium coordination solids were synthesized and evaluated for delivery of olsalazine (H₄olz), an anti-inflammatory compound used for treatment of ulcerative colitis. The materials include one-dimensional Ca(H₂olz)·4H₂O chains, two-dimensional Ca(H₂olz)·2H₂O sheets, and a three-dimensional metal-organic framework Ca(H₂olz)·2DMF (DMF = N,N-dimethylformamide). The framework undergoes structural changes in response to solvent, forming a dense Ca(H₂olz) phase when exposed to aqueous HCl. The compounds Ca(H₂olz)·xH₂O (x = 0, 2, 4) were each pressed into pellets and exposed to simulated gastrointestinal fluids to mimic the passage of a pill from the acidic stomach to the pH-neutral intestines...
September 12, 2017: ChemMedChem
Hisashi Doi, Tatsuya Kida, Kosuke Nishino, Masatoshi Nakatsuji, Shiho Sakamoto, Shota Shimizu, Yoshiaki Teraoka, Yasuhisa Tamura, Yosky Kataoka, Takashi Inui
With the objective of improving the poor water solubility of the potent antitumor compound SN-38, 10-O-substituted SN-38 derivatives were developed by the introduction of fluoroalkyl, fluorobenzoyl, or bromobenzoyl groups. The 10-O-fluoropropyl-substituted compound 2 (RLC140050) was found to be 17-fold more soluble than SN-38 in phosphate buffered saline, and it exhibited a level of biological activity ~50% that of SN-38 in a cytotoxicity assay using the prostate cancer cell line PC-3. Five other derivatives did not show solubility improvement to the same extent, but their activities in cytotoxicity assays were almost the same as that of SN-38...
September 11, 2017: ChemMedChem
Melanie Chypre, Maria-Bernadette Madel, Olivier Chaloin, Chlaudine Blin-Wakkach, Christophe Morice, Christopher G Mueller
Receptor Activator of NF-κB (RANK), a member of the TNF-receptor superfamily, plays an important role in bone resorption and stimulates immune and epithelial cell activation. Denosumab, a human monoclonal antibody blocking RANK ligand (RANKL), is approved for the treatment of osteoporosis and bone metastasis. However, a small molecule inhibiting RANK-RANKL interaction would be beneficial to reduce costs and to facilitate treatments with orally available therapeutic agents. Here, we report the discovery of the first non-peptidic inhibitors of RANK-RANKL interactions...
September 8, 2017: ChemMedChem
Ryoko Koga, Mohamed O Radwan, Tomohiko Ejima, Yosuke Kanemaru, Hiroshi Tateishi, Taha F S Ali, Halil Ibrahim Ciftci, Yuri Shibata, Yuu Taguchi, Jun-Ichiro Inoue, Masami Otsuka, Mikako Fujita
Despite various inhibitors targeting the zinc center(s) of enzymes, drugs that target zinc fingers have not been examined in detail. We already developed a dithiol compound named SN-1 having an inhibitory effect on function of zinc finger transcription factors, but its mechanism has not been elucidated yet. For establishment of a general principle of new drugs, the detail of the action of SN-1 against a zinc finger protein was examined. As a zinc finger-containing protein, we focused on TRAF6 related to cancer and inflammation...
September 8, 2017: ChemMedChem
Mubarak A AlAmri, Hachemi Kadri, Binar A Dhiani, Shumail Mahmood, Abdulrahman Elzwawi, Youcef Mehellou
Since the discovery of WNK mutations causing an inherited form of hypertension in humans, there has been an increasing interest in targeting WNK-signaling as a novel strategy for modulating blood pressure. This notion is now supported by numerous mouse models with impaired WNK-signaling that exhibit reduced blood pressure. Biochemical analyses of the different protein components making up this signaling pathway have identified a number of plausible molecular targets that are amenable to targeting by small molecules...
September 7, 2017: ChemMedChem
Allan S Wagman, Ryan Cirz, Glenn McEnroe, James Aggen, Martin S Linsell, Adam A Goldblum, Sara Lopez, Marcela Gomez, George Miller, Lloyd J Simons, Thomas R Belliotti, Christina R Harris, Toni-Jo Poel, Michael J Melnick, Ricky D Gaston, Heinz E Moser
Conformationally-constrained tetracyclic fluoroquinolones (FQs) were synthesized and profiled for their microbiological spectrum. The installation of a 7-membered ring between the pyrrolidine substituents and the C8-position on the FQ core scaffold resulted in a remarkable enhancement of microbiological potency on both Gram-positive and Gram-negative bacteria. Focused optimization of 7-membered ring composition, stereochemistry, and amine placement led to the discovery of the two lead compounds that were selected for further progression...
September 7, 2017: ChemMedChem
Xinyu Hu, Yongmei Wang, Liangliang Zhang, Man Xu, Jianfa Zhang, Wei Dong
Salecan is a water-soluble extracellular β-glucan and has excellent physicochemical and biological properties for hydrogel preparation. In this study, a new pH/magnetic field dual-responsive hydrogel was prepared by the graft copolymerization of salecan with 4-pentenoic acid (PA) and N-hydroxyethylacrylamide (HEAA) in the presence of Fe3 O4 @SiO2 nanoparticles for doxorubicin hydrochloride (DOX) release. Integration of Fe3 O4 @SiO2 nanoparticles in salecan-g-poly(PA-co-HEAA) copolymers afforded magnetic sensitivity to the original material...
August 31, 2017: ChemMedChem
Tracey Pirali, Elisa Ciraolo, Silvio Aprile, Alberto Massarotti, Alex Berndt, Alessia Griglio, Marta Serafini, Valentina Mercalli, Clarissa Landoni, Carlo Cosimo Campa, Jean Piero Margaria, Rangel L Silva, Giorgio Grosa, Giovanni Sorba, Roger Williams, Emilio Hirsch, Gian Cesare Tron
Activation of the phosphoinositide 3-kinase (PI3K) pathway is a key signaling event in cancer, inflammation, and other proliferative diseases. PI3K inhibitors are already approved for some specific clinical indications, but their systemic on-target toxicity limits their larger use. In particular, whereas toxicity is tolerable in acute treatment of life-threatening diseases, this is less acceptable in chronic conditions. In the past, the strategy to overcome this drawback was to block selected isoforms mainly expressed in leukocytes, but redundancy within the PI3K family members challenges the effectiveness of this approach...
August 31, 2017: ChemMedChem
Hedi Rahnel, Kaido Viht, Darja Lavogina, Olga Mazina, Tõiv Haljasorg, Erki Enkvist, Asko Uri
The pleiotropic nature, role in many cellular processes, and constitutive activity of protein kinase CK2 exemplify its importance in a number of diseases, e.g. thrombosis and cancer. Compounds developed in this paper represent a novel class of biologically active scaffold that may be developed into promising drug candidates, but also applied to study the yet still unspecified pathways regulated by CK2. Biligand inhibitors of CK2 were constructed by conjugating 4-(2-amino-1,3-thiazol-5-yl)benzoic acid and carboxylate-rich peptoids...
August 24, 2017: ChemMedChem
Violetta Cecchetti, Benedetto Natalini
A Special Year of Italian Medchem: Guest Editors Violetta Cecchetti and Benedetto Natalini of the University of Perugia look back at the XXIV National Meeting in Medicinal Chemistry (NMMC 2016) held in Perugia, Italy. It was this at special conference where ChemMedChem also held its 10(th) Anniversary Celebration. In this editorial, they provide highlights of last year's events, including some key presentations now collected in this Special Issue.
August 23, 2017: ChemMedChem
Anna K Laskowska, Anna K Puszko, Piotr Sosnowski, Krzysztof Różycki, Piotr Kosson, Joanna Matalińska, Marek Durlik, Aleksandra Misicka
According to the World Health Organization, mortality rate among patients with pancreatic cancer will increase in the upcoming years. Gemcitabine is the first choice for treatment of pancreatic malignancy, but rising resistance to this drug decreases the final outcome. Studies on new therapies targeting metabolic pathways, growth factors inhibitors and tumour stroma or tumour stem cells, are currently underway in many laboratories. Here, we report the bioactive properties (cytotoxicity and haemolytic activity) of synthetic peptidomimetics containing opioid tripeptide fragment (Tyr-X1-X2-; where X1 is D-Ala or D-Thr, and X2 is Phe or Trp) hybridized with trans-1-cinnamylpiperazine...
August 18, 2017: ChemMedChem
Sushil N Benke, Hirekodathakallu V Thulasiram, Hosahudya N Gopi
Herein we report the potent antimicrobial activity of α,γ-hybrid lipopeptides composed of 1:1 alternating α- and γ-amino acids. Along with their potent antimicrobial activity against various Gram-positive and Gram-negative bacteria, these hybrid lipopeptides were found to be less hemolytic. Studies into the mechanism of action revealed that these short cationic lipopeptides bind and disrupt the bacterial cell membrane. Time-kill kinetics analyses revealed that the potent α,γ-hybrid lipopeptides completely inhibit bacterial growth in less than 20 minutes...
August 18, 2017: ChemMedChem
Paramita Mukherjee, Martin Pettersson, Jason K Dutra, Longfei Xie, Christopher W Am Ende
The synthesis of a new trifluoromethyl oxetane was developed using a Corey-Chaykovsky epoxidation/ring-expansion reaction of trifluoromethyl ketones. The reaction was shown to proceed under mild conditions and displays a broad substrate scope. The trifluoromethyl oxetane was also evaluated as a tert-butyl isostere in the context of the γ-secretase modulator (GSM) program. We demonstrate that the trifluoromethyl oxetane-containing GSM has decreased lipophilicity, improved lipophilic efficiency (LipE) and metabolic stability relative to the corresponding tert-butyl GSM analogue, thus highlighting several benefits of trifluoromethyl oxetane as a more polar tert-butyl isostere...
August 16, 2017: ChemMedChem
Christian Brengel, Andreas Thomann, Alexander Schifrin, Giuseppe Allegretta, Ahmed A M Kamal, Joerg Haupenthal, Isabell Schnorr, Sang Hyun Cho, Scott Gary Franzblau, Martin Empting, Jens Eberhard, Rolf W Hartmann
The development of novel antimycobacterial agents against Mycobacterium tuberculosis (Mtb) is urgently required due to the appearance of multi-drug resistance (MDR) combined with a complicated long-term treatment. CYP121 was shown to be a promising novel target for inhibition of mycobacterial growth. In this study, we describe the rational discovery of new CYP121 inhibitors by a systematic screening based on biophysical and microbiological methods. Best hits originating from only one structural class gave first information about molecular motifs required for binding and activity...
August 16, 2017: ChemMedChem
Katharina Stenzel, Ming Jang Chua, Sandra Duffy, Yevgeniya Antonova-Koch, Stephan Meister, Alexandra Hamacher, Matthias U Kassack, Elizabeth Winzeler, Vicky M Avery, Thomas Kurz, Katherine T Andrews, Finn K Hansen
In this work we aimed to develop parasite-selective histone deacetylase inhibitors (HDAC) inhibitors with activity against the disease-causing asexual blood stages of Plasmodium as well as causal prophylactic and/or transmission blocking properties. We report the design, synthesis, and biological testing of a series of 13 terephthalic acid-based HDAC inhibitors. All compounds showed low cytotoxicity against human embryonic kidney (HEK293) cells (IC50 : 8->51 μm), with 11 also having sub-micromolar in vitro activity against drug-sensitive (3D7) and multidrug-resistant (Dd2) asexual blood-stage P...
August 15, 2017: ChemMedChem
Antonio Peón, Adrián Robles, Beatriz Blanco, Marino Convertino, Paul Thompson, Alastair R Hawkins, Amedeo Caflisch, Concepción González-Bello
A multidisciplinary approach was used to identify and optimize a quinazolinedione-based ligand that would decrease the flexibility of the substrate-covering loop (catalytic loop) of the type II dehydroquinase from Helicobacter pylori. This enzyme, which is essential for the survival of this bacterium, is involved in the biosynthesis of aromatic amino acids. A computer-aided fragment-based protocol (ALTA) was first used to identify the aromatic fragments able to block the interface pocket that separates two neighboring enzyme subunits and is located at the active site entrance...
August 9, 2017: ChemMedChem
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