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Arkadii Lin, Dragos Horvath, Valentina Afonina, Gilles Marcou, Reymond Jean-Louis, Alexandre Varnek
This is, to our knowledge, the to-date most comprehensive analysis based on Generative Topographic Mapping (GTM) of the fragment-like chemical space (40M molecules with no more than 17 heavy atoms, both from the theoretically enumerated GDB-17, and real-world PubChem/ChEMBL). The challenge was to prove that a robust map of fragment-like chemical space can actually be built, in spite of a limited (<105) maximal number of compounds ("frame set") usable for fitting the GTM manifold. An evolutionary map building strategy has been updated with a "coverage check" step, discarding manifolds failing to accommodate compounds outside the frame set...
November 20, 2017: ChemMedChem
Truong Thanh Tung, Dao Trong Tuan, Marta Grifell Junyent, Michael Palmgren, Thomas Günther-Pomorski, Anja Thoe Fuglsang, Søren Brøgger Christensen, John Nielsen
The fungal plasma membrane H+-ATPase (Pma1p) is a potential target for the discovery of new antifungal agents. Surprisingly, no structure-activity relationship studies for small molecules targeting Pma1p have been reported. Herein, we disclose a LEGO-inspired fragment assembly strategy for design, synthesis and discovery of benzo[d]thiazoles containing a 3,4-dihydroxyphenyl moiety as potential Pma1p inhibitors. A series of 2-(benzo[d]thiazol-2-ylthio)-1-(3,4-dihydroxyphenyl)ethanones was found to inhibit Pma1p with the most potent IC50 of 8 µM in an in vitro plasma membrane H+-ATPase assay...
November 15, 2017: ChemMedChem
Simone Brogi, Samuele Maramai, Margherita Brindisi, Giulia Chemi, Valentina Porcari, Claudio Corallo, Luigi Gennari, Ettore Novellino, Anna Ramunno, Stefania Butini, Giuseppe Campiani, Sandra Gemma
A computational analysis of the X-ray structure of the low-density lipoprotein receptor-related protein 6 (LRP6) with Dickkopf-1 (DKK1) C-terminal fragment has allowed us to rationally design a small set of decapeptides (1a-e). These compounds behave as agonists of the canonical Wnt pathway in the micromolar range when tested on a dual luciferase Wnt functional assay in glioblastoma cells. Lack of cellular toxicity was assessed for compounds 1c and 1d in human primary osteoblasts isolated from sponge bone tissue (femoral heads or knee of old patients)...
November 13, 2017: ChemMedChem
Domenico Iacopetta, Annaluisa Mariconda, Carmela Saturnino, Anna Caruso, Giuseppe Palma, Jessica Ceramella, Noemi Muià, Mariarita Perri, Maria Stefania Sinicropi, Maria Cristina Caroleo, Pasquale Longo
Cisplatin and other platinum-based drugs are well-known valid anticancer drugs. However, during the chemotherapy, the presence of numerous side effects and the onset of frequent phenomena of resistance pushes forward many research groups to devise new metal-based compounds holding improved anticancer properties and lower undesired effects. Amongst the variety of synthesized compounds, significant anti-proliferative effects were obtained employing organometallic compounds, particularly those based on silver or gold...
November 9, 2017: ChemMedChem
Matthias Wünsch, Johanna Senger, Philipp Schultheisz, Sabrina Schwarzbich, Karin Schmidtkunz, Carmela Michalek, Michaela Klaß, Stefanie Goskowitz, Philipp Borchert, Lucas Praetorius, Wolfgang Sippl, Manfred Jung, Norbert Sewald
As histone deacetylases (HDACs) play an important role in cancer treatment, their selective inhibition has been subject of various studies. The continuous investigations have spawned a large collection of pan- and selective HDAC inhibitors, containing diverse FDA approved representatives. In former studies, a class of alkyne based inhibitors of HDACs was presented. We modified this scaffold in two previously neglected regions and compared cytotoxicity and affinity towards HDAC1, HDAC6 and HDAC8. We could show that (R)-configured propargylamines contribute increased selectivity on HDAC6, while the size of the substituents decreases their affinity...
November 9, 2017: ChemMedChem
Giulio Poli, Romano Di Fabio, Luca Ferrante, Vincenzo Summa, Maurizio Botta
Since the time of its identification, the natural compound largazole rapidly caught the attention of the medicinal chemistry community for its impressive potency as histone deacetylases (HDACs) inhibitor and its strong antiproliferative activity against a broad panel of cancer cell lines. The design of largazole analogues is an expanding field of study, due to their remarkable potential as novel anticancer therapeutics. At present, a large ensemble of largazole analogues has been reported in literature, thus allowing the identification of important structure-activity relationships (SAR) that can guide the design of novel compounds with improved HDAC inhibitory profile, anticancer activity and pharmacokinetic properties...
November 8, 2017: ChemMedChem
Salvatore Sortino, Federica Sodano, Elena Gazzano, Aurore Fraix, Barbara Rolando, Loretta Lazzarato, Marina Russo, Marco Blangetti, Chiara Riganti, Roberta Fruttero, Alberto Gasco
The design, synthesis, spectroscopic and photochemical properties and biological evaluation of a novel, molecular hybrid that is able to deliver nitric oxide (NO) into the mitochondria are reported. This molecular conjugate unites a tailored o-CF3-p-nitroaniline chromophore, for photo-regulated NO release, and a Rhodamine moiety, for mitochondria targeting, in the same molecular skeleton via an alkyl spacer. A combination of steady-state and time-resolved spectroscopic and photochemical experiments demonstrate that the two chromogenic units preserve their individual photophysical and photochemical properties in the conjugate quite well...
November 7, 2017: ChemMedChem
Yoshimasa Tanaka, Yuki Sakai, Satoshi Mizuta, Asuka Kumagai, Mohamed S O Tagod, Hiroaki Senju, Tatsufumi Nakamura, Craig T Morita
Immunotherapy using immune checkpoint inhibitors and CAR-T cells has revolutionized treatment for patients with malignant tumors. However, measuring tumor cell cytotoxicity mediated by immune effector cells in clinical laboratories has been difficult due to the requirement for radioactive substances. In this study, a series of novel terpyridine derivative proligands were synthesized and a non-radioactive cellular cytotoxicity assay using the newly synthesized compounds was developed for use in preclinical and clinical studies for cancer immunotherapy...
November 7, 2017: ChemMedChem
Arun K Ghosh, W Sean Fyvie, Margherita Brindisi, Melinda Steffey, Johnson Agniswamy, Yuan-Fang Wang, Manabu Aoki, Masayuki Amano, Irene T Weber, Hiroaki Mitsuya
The structure-based design, synthesis, and biological evaluation of a series of nonpeptidic HIV-1 protease inhibitors with rationally designed P2' ligands are described. The inhibitors are designed to enhance backbone binding interactions, particularly at the S2'-subsite. Synthesis of inhibitors was carried out efficiently. The stereochemistry of alcohol functionalities of the P2'-ligands was set by asymmetric reduction of the corresponding ketone using (R,R)- or (S,S)-Noyori's catalysts. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity...
November 6, 2017: ChemMedChem
Lucyantie Mazalan, Andrew Bell, Laura Sbaffi, Peter Willett
The screening effectiveness of a chemical similarity search depends on a range of factors, including the bioactivity of interest, the types of similarity coefficient and fingerprint that comprise the similarity measure, and the nature of the reference structure that is being searched against a database. This study introduces the use of cross-classified multilevel modelling as a way to investigate the relative importance of these four factors when carrying out similarity searches on the ChEMBL database. Two principal conclusions can be drawn from the analyses: that the fingerprint plays a more important role than the similarity coefficient in determining the effectiveness of a similarity search, and that comparative studies of similarity measures should involve many more reference structures than has been the case in much previous work...
November 6, 2017: ChemMedChem
Daniel P Flaherty, Michael T Harris, Chad E Schroeder, Haaris Khan, Elizabeth Kahney, Amber Hackler, Stephen Patrick, Warren S Weiner, Jeffrey Aube, Elizabeth R Sharlow, James C Morris, Jennifer E Golden
Kinetoplastid-based infections are neglected diseases that represent a significant human health issue. Chemotherapeutic options are limited due to toxicity, parasite susceptibility, and poor patient compliance. In response, we studied a molecular target-directed approach involving intervention of hexokinase activity - a pivotal enzyme in parasite metabolism. A benzamidobenzoic acid hit with modest biochemical inhibition of Trypanosoma brucei hexokinase 1 (TbHK1, IC₅₀ = 9.1 μM), low mammalian cytotoxicity (IMR90, EC₅₀ > 25 μM), and no appreciable activity on whole BSF parasites was optimized to afford a probe with improved TbHK1 potency and, significantly, efficacy against whole BSF parasites (TbHK1, IC₅₀ = 0...
November 4, 2017: ChemMedChem
Daniel Horak, Uliana Kostiv, Vitalii Patsula, Agnieszka Noculak, Artur Podhorodecki, David Vetvicka, Pavla Pouckova, Zdenka Sedlakova
Monodisperse NaYF4:Yb3+/Er3+ nanospheres 20 nm in diameter that serve as a near-infrared (NIR)-to-visible light converter and activator of a photosensitizer were synthesized by high-temperature co-precipitation of lanthanide chlorides in a high-boiling organic solvent (octadec-1-ene). The nanoparticles were coated with a thin shell (ca. 3 nm) of homogenous silica via the hydrolysis and condensation of tetramethyl orthosilicate. The NaYF4:Yb3+/Er3+@SiO2 particles were further functionalized by methacrylate-terminated groups via 3-(trimethoxysilyl)propyl methacrylate...
November 3, 2017: ChemMedChem
Britta Bauer, Anna-Lena Göderz, Heidi Braumüller, Jörg Martin Neudörfl, Martin Röcken, Thomas Wieder, Hans-Günther Schmalz
Autoimmune diseases are characterized by dendritic cell (DC)-driven activation of pro-inflammatory T cell responses. Therapeutic options for these severe diseases comprise small molecules such as dimethyl fumarate, or "gasotransmitters" such as CO. Herein we describe the synthesis of bifunctional enzyme-triggered CO-releasing molecules (ET-CORMs) that allow the simultaneous intracellular release of both CO and methyl fumarate. Using bone-marrow-derived DCs the impressive therapeutic potential of these methyl fumarate-derived compounds (FumET-CORMs) is demonstrated by strong inhibition of lipopolysaccharide-induced pro-inflammatory signaling pathways and blockade of downstream interleukin-12 or -23 production...
November 2, 2017: ChemMedChem
Guohao Wang, Shi Gao, Rui Tian, Jasmine Miller-Kleinhenz, Zainen Qin, Tianji Liu, Lu Li, Fan Zhang, Qingjie Ma, Lei Zhu
The delivery of therapeutic cancer agents via nanomaterials has attracted great attention recently. Although encouraging, tumor treatment response remains unsatisfactory. To address this concern, we constructed a new micellar nanocomplex by conjugating hyaluronic acid (HA) with iron oxide nanoparticle (IONP). When an external magnetic field is applied to the tumor area, HA-IONP will specifically accumulate in the tumor due to the strong IONP magnetism. In addition, HA can bind to CD44 that is overexpressed on tumor cells...
October 30, 2017: ChemMedChem
Pavel A Petukhov, Hazem Abdelkarim, Raghupathi Neelarapu, Antonett Madriaga, Irida Kastrati, Yue-Ting Wang, Aditya S Vaidya, Taha Y Taha, Gregory R J Thatcher, Jonna Frasor
Histone deacetylases (HDACs) are promising drug targets for a variety of therapeutic applications. Here we describe the design, synthesis, biological evaluation in cellular models of cancer, and preliminary drug metabolism and pharmacokinetic studies (DMPK) of a series of secondary and tertiary amine-based HDAC inhibitors. Introduction of an amino group with one or two surface binding groups (SBGs) yielded a successful strategy to develop novel and potent HDAC inhibitors. Secondary amines 2 were found to be generally more potent than the corresponding tertiary amines 3...
October 27, 2017: ChemMedChem
Lily Arrue, Lars Ratjen
The photochemical control of structure and reactivity bears great potential for chemistry, biology, and life sciences. A key feature of photochemistry is the spatiotemporal control over secondary events. Well-established applications of photochemistry in medicine are photodynamic therapy (PDT) and photopharmacology (PP). However, although both are highly localizable through the application of light, they lack cell- and tissue-specificity. The combination of nanomaterial-based drug delivery and targeting has the potential to overcome limitations for many established therapy concepts...
October 26, 2017: ChemMedChem
Christopher R M Asquith, Tuomo Laitinen, James M Bennett, Paulo H Godoi, Michael P East, Graham J Tizzard, Lee M Graves, Gary L Johnson, Ronna E Dornsife, Carrow I Wells, Jonathan M Elkins, Timothy M Willson, William Zuercher
4-Anilinoquinolines were identified as potent and narrow spectrum inhibitors of the cyclin G associated kinase (GAK), an important regulator of viral and bacterial entry into host cells. Optimization of the 4-anilino group and the 6,7-quinoline substituents produced GAK inhibitors with nanomolar activity, over 50,000-fold selectivity relative to other members of the numb-associated kinase (NAK) sub-family, and a compound (49) with a narrow spectrum kinome profile. These compounds may be useful tools to explore the therapeutic potential of GAK in prevention of a broad range of infectious and systemic diseases...
October 26, 2017: ChemMedChem
Stephanie A Schallenhammer, Stephanie M Duggan, Kelly R Morrison, Brian S Bentley, William M Wuest, Kevin P C Minbiole
Benzalkonium chloride (BAC) and cetyl pyridinium chloride (CPC) are two of the most common household antiseptics, but show weaker efficacy against Gram-negative bacteria as well as against methicillin-resistant Staphylococcus aureus (MRSA) strains, relative to other S. aureus strains. We prepared 28 novel quaternary ammonium compounds (QACs) that represent a hybrid of these two structures, using 1- to 2-step synthetic sequences. The biscationic (bisQAC) species prepared show uniformly potent activity against six bacterial strains tested, with nine novel antiseptics displaying single-digit micromolar activity across the board...
October 25, 2017: ChemMedChem
Teodora Ivanova, Kornelia Hardes, Stephanie Kallis, Sven O Dahms, Manuel E Than, Sebastian Künzel, Eva Böttcher-Friebertshäuser, Iris Lindberg, Guan-Sheng Jiao, Ralf Bartenschlager, Torsten Steinmetzer
The proprotein convertase furin is a potential target for drug design, especially for the inhibition of furin-dependent virus replication. All effective synthetic furin inhibitors identified thus far are multibasic compounds; the highest potency was found for our previously developed inhibitor 4-(guanidinomethyl)-phenylacetyl-Arg-Tle-Arg-4-amidinobenzylamide (MI-1148). A first study in mice revealed a narrow therapeutic range for this tetrabasic compound, while significantly reduced toxicity was observed for some tribasic analogs...
October 23, 2017: ChemMedChem
Dulce Consuelo Guzmán-Ocampo, Rodrigo Aguayo-Ortiz, Lucia Cano-González, Alicia Hernández-Campos, Rafael Castillo, Laura Dominguez
Regulation of microtubule assembly by antimitotic agents is a potential therapeutic strategy for the treatment of cancer, parasite infections, and neurodegenerative diseases. One of these agents is Nocodazole (NZ), which inhibits microtubule polymerization by binding to β-tubulin. NZ was recently co-crystallized in Gallus gallus tubulin, displaying novel information of the interaction features for ligand recognition and stability. In this work, we employed state of the art computational approaches to evaluate the protonation effects of titratable residues and the presence of water molecules in the binding of NZ...
October 23, 2017: ChemMedChem
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