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  • Late Stage Functionalization of Drug Like Molecules using Diversinates
    ChemMedChem (IF 3.225) Pub Date : 2018-03-13
    Christian Andreas Kuttruff, Margit Haile, Johannes Kraml, Christofer Siegfried Tautermann

    Late Stage Functionalization (LSF) is a powerful method to quickly generate new analogs of a lead structure without resorting to de novo synthesis. We have leveraged Baran Diversinates to carry out late stage functionalizations on lead structures from internal drug discovery projects and accurately predicted regioselectivities using computational methods. Our functionalization successfully afforded specific regioisomers which were in line with our predictions. To enhance reactivity, reduce reaction time, and increase reaction yields we have developed new functionalization conditions involving Iron(III) catalysis. Finally, we demonstrate how our LSF reactions using Baran Diversinates can lead to new analogs with improved in vitro DMPK parameters.

  • 更新日期:2018-03-14
  • Dithionated Nucleobases as Effective Photodynamic Agents Against Epidermoid Carcinoma Cells
    ChemMedChem (IF 3.225) Pub Date : 2018-03-12
    Marvin Pollum, Minh Lam, Steffen Jockusch, Carlos E. Crespo-Hernández

    Sulfur-substituted nucleobases (i.e. thiobases) are a prospective class of compounds for clinical and cosmetic topical phototherapies. Recent investigations of several thiobases have revealed the ultrafast and efficient population of reactive triplet states upon UVA irradiation and the subsequent generation of singlet oxygen in high yield. In this contribution, we examine the photosensitizing activities of three of the most promising thiobase derivatives discovered to date, 2,4-dithiothymine, 2,4-dithiouracil, and 2,6-dithiopurine. These derivatives are shown to decrease the proliferation of human epidermoid carcinoma cells by up to 63% in vitro, only upon activation with a low dose of UVA radiation (5 J/cm2). The generation of reactive oxygen species plays a minor role in the mode of action, suggesting these dithiobases may be effective within oxygen-deficient environments. Importantly, the photosensitized activity correlates with the magnitude of the triplet lifetime, which should guide the molecular design of next generation photodynamic agents.

  • Fluorinated GluN2B receptor antagonists with a 3-benzazepine scaffold designed for PET studies
    ChemMedChem (IF 3.225) Pub Date : 2018-03-09
    Bernhard Wünsch, Marina Szermerski, Frederik Börgel, Dirk Schepmann, Thomas Betzel, Simon Ametamey, Ahmed Haider

    In order to analyze the NMDA receptor distribution in the central nervous system, fluorinated ligands selectively addressing the ifenprodil binding site of GluN2B subunit containing NMDA receptors were developed. Various strategies to introduce a fluorine atom into the potent GluN2B ligand 2 were pursued including the replacement of the benzylic OH moiety by a F-atom (13) and introduction of fluoroethoxy moieties at different positions (14, 17 18a-c). With respect to GluN2B affinity and selectivity over related receptors, the fluoroethoxy derivatives 14 and 18a represent the most promising ligands. Radiosynthesis of fluoroethoxy derivative [18F]14 was performed by nucleophilic substitution of the phenol 12c with 2-[18F]fluoroethyl tosylate. On rat brain slices the fluorinated PET tracer [18F]14 accumulated in regions with high density of NMDA receptors containing GluN2B subunits. The bound radioactivity could not be replaced by (S)-glutamate. However, the GluN2B ligands eliprodil, Ro 25-6981 and the non-labeled 3-benzazepine 14 were able to abolish the specific binding of [18F]14.

  • A (+)-larixol congener with high affinity and subtype selectivity towards TRPC6
    ChemMedChem (IF 3.225) Pub Date : 2018-03-09
    Stephanie Häfner, Finn Burg, Martina Kannler, Nicole Urban, Peter Mayer, Alexander Dietrich, Dirk Trauner, Johannes Broichhagen, Michael Schaefer

    Natural products have many health benefits and their application can improve the quality of life. Recently, the diterpene (+) larixol and its acetylated congeners demonstrated a selective inhibition of the second messenger-gated cation channel transient receptor potential canonical 6 (TRPC6) over its close isoforms TRPC3 and TRPC7. Building on this knowledge, we expand these findings by chemical diversification of (+)-larixol mostly at position C6. Implementing High-Throughput Ca2+ FLIPR screening assays and electrophysiological patch-clamp recordings, we showcase larixyl N-methylcarbamate, dubbed SH045, as a compound with nanomolar affinity and a 13-fold subtype selectivity over TRPC3 in stably expressing HEK293 cells. Expanding on this finding, TRPC6 inhibition was also achieved in rat pulmonary smooth muscle cells. Furthermore, treatment of isolated perfused lung preparations with SH045 led to a reduction in lung ischaemia reperfusion oedema (LIRE), a life-threatening condition associated with TRPC6 that may occur after organ transplantation. Taken together, and given the cheap, straightforward and scalable preparation of SH045, we report a TRPC6 blocker that holds promise for translational treatment of LIRE.

  • Design, Synthesis, and in vitro Evaluation of Multivalent Drug Linkers for High-Drug-Load Antibody–Drug Conjugates
    ChemMedChem (IF 3.225) Pub Date : 2018-03-08
    Bo Chen, Diego A. Gianolio, James E. Stefano, Charlene M. Manning, Richard C. Gregory, Michelle M. Busch, William H. Brondyk, Robert J. Miller, Pradeep K. Dhal
  • Design of Modular G-quadruplex Ligands
    ChemMedChem (IF 3.225) Pub Date : 2018-03-07
    Ana Rita Duarte, Enrico Cadoni, Ana S. Ressurreição, Rui Moreira, Alexandra Paulo

    Guanine rich nucleic acid sequences able to form four-stranded structures (G-quadruplexes, G4) play key cellular regulatory roles and are considered as promising drug targets for anticancer therapy. Based on the organization of their structural elements, G4 ligands can be divided into three major families: 1) fused hetero-aromatic polycyclic systems; 2) macrocycles and 3) modular aromatic compounds. The design of modular G4 ligands emerged as the answer to achieve not only more drug-like compounds, but also more selective ligands by targeting G4 loops and grooves diversity. The rationale behind the design of a very comprehensive set of ligands, with a particular focus on the structural features required for binding to G4, is discussed and combined with the corresponding biochemical/biological data, to highlight key structure-G4 interaction relationships. Analysis of the data suggests that shape of the ligand is the major factor accounting for the G4 stabilizing effect of ligands. The information here critically reviewed will certainly contribute to the development of new and better G4 ligands with application either as therapeutics or probes.

  • Discovery of Benzimidazole Quinolone Hybrids as New Cleaving Agents towards Drug-resistant P. aeruginosa DNA
    ChemMedChem (IF 3.225) Pub Date : 2018-03-07
    Cheng-He Zhou, Ya-Nan Wang, Rammohan R. Yadav Bheemanaboina, Wei-Wei Gao, Jie Kang, Gui-Xin Cai

    A series of benzimidazole quinolone hybrids as new potential antimicrobial agents were designed and synthesized, and their bioactive assay indicated that some prepared compounds exhibited potent antibacterial and antifungal activities. Notably, 2-fluorobenzyl derivative 5b showed remarkable antimicrobial activities against the resistant P. aeruginosa and C. tropicalis isolated from infected patients. The active molecule 5b could not only rapidly kill the tested strains, but also exhibit low toxicity towards Hep-2 cells. It was more difficult than norfloxacin to trigger the development of bacterial resistance against P. aeruginosa. Molecular docking demonstrated that it could effectively bind with topoisomerase IV-DNA complexes, and quantum chemical studies theoretically elucidated the good antimicrobial activity of compound 5b. Preliminary experimental mechanism exploration suggested that derivative 5b could not intercalate into DNA isolated from drug-resistant P. aeruginosa, but it was able to cleave DNA effectively, which might further block DNA replication to exert the powerful bioactivities. In addition, compound 5b was found to be a promising antibacterial agent with membrane disruption ability.

  • Transthyretin Mimetics as Anti-β-Amyloid Agents: A comparison of peptide and protein approaches
    ChemMedChem (IF 3.225) Pub Date : 2018-03-07
    Kayla M Pate, Brandon J Kim, Eric V Shusta, Regina M Murphy

    β-amyloid (Aβ) aggregation is causally linked to neuronal pathology in Alzheimer's disease; therefore, several small molecules, antibodies, and peptides have been tested as anti-Aβ agents. We developed two compounds based on the Aβ-binding domain of transthyretin (TTR), a cyclic peptide cG8 and an engineered protein mTTR, and compared them for therapeutically relevant properties. Both mTTR and cG8 inhibit fibrillogenesis of Aβ, with mTTR inhibiting at a lower concentration than cG8. Both inhibit aggregation of amylin but not of α-synuclein. They both bind more Aβ aggregates than monomer, and neither disaggregates preformed fibrils. cG8 retained more of its activity in the presence of biological materials and was more resistant to proteolysis than mTTR. We examined the effect of mTTR or cG8 on Aβ binding to human neurons. When mTTR was co-incubated with Aβ under oligomer-forming conditions, Aβ morphology was drastically changed and Aβ-cell deposition significantly decreased. In contrast, cG8 did not affect morphology but reduced the amount of Aβ deposited. These results provide guidance for further evolution of TTR-mimetic anti-amyloid agents.

  • Front Cover: Design and Synthesis of A-Ring Simplified Pyripyropene A Analogues as Potent and Selective Synthetic SOAT2 Inhibitors (ChemMedChem 5/2018)
    ChemMedChem (IF 3.225) Pub Date : 2018-03-06
    Masaki Ohtawa, Shiho Arima, Naoki Ichida, Tomiaki Terayama, Hironao Ohno, Takaya Yamazaki, Taichi Ohshiro, Noriko Sato, Satoshi Omura, Hiroshi Tomoda, Tohru Nagamitsu
  • Synthesis and Biological Evaluation of Imidazole-Bearing α-Phosphonocarboxylates as Inhibitors of Rab Geranylgeranyl Transferase (RGGT)
    ChemMedChem (IF 3.225) Pub Date : 2018-03-02
    Łukasz Joachimiak, Aleksandra Marchwicka, Edyta Gendaszewska-Darmach, Katarzyna M. Błażewska
  • Synthesis, Structure-activity Relationship Studies and ADMET Properties of 3-aminocyclohex-2-en-1-ones as Chemokine Receptor 2 (CXCR2) Antagonists
    ChemMedChem (IF 3.225) Pub Date : 2018-02-28
    Weiyang Dai, Wenmin Chen, Bikash Debnath, Wu Yong, Nouri Neamati

    Herein, we describe the synthesis and structure-activity relationship of 3-aminocyclohex-2-en-1-one derivatives as novel CXCR2 antagonists. Thirteen out of 44 derivatives inhibit CXCR2 down-stream signaling in a Tango assay specific for CXCR2 with IC50 values less than 10 µM. In silico ADMET prediction suggests that all active compounds possess drug-like properties. None of these compounds show cytotoxicity, suggesting their potential application in inflammatory mediated diseases. A structure-activity relationship (SAR) map has been generated to gain better understanding of their binding mechanism to guide further optimization of these new CXCR2 antagonists.

  • Discovery of Molidustat (BAY 85-3934): A Small-Molecule Oral HIF-Prolyl Hydroxylase (HIF-PH) Inhibitor for the Treatment of Renal Anemia
    ChemMedChem (IF 3.225) Pub Date : 2018-02-27
    Hartmut Beck, Mario Jeske, Kai Thede, Friederike Stoll, Ingo Flamme, Metin Akbaba, Jens-Kerim Ergüden, Gunter Karig, Jörg Keldenich, Felix Oehme, Hans-Christian Militzer, Ingo V Hartung, Uwe Thuss

    Abstract: Small molecule inhibitors of hypoxia inducible factor prolyl hydroxylases (HIF-PHs) are currently under clinical development as novel treatment option for chronic kidney disease (CKD) associated anemia. Inhibition of HIF-PH mimics hypoxia and leads to increased EPO expression and subsequently increased erythropoiesis. Herein we describe the discovery, synthesis, SAR and proposed binding mode of novel 2,4-diheteroaryl-1,2-dihydro-3H-pyrazol-3-ones as orally bioavailable HIF-PH inhibitors for the treatment of anemia. High-throughput screening of our corporate compound library identified BAY-908 (1) as a promising hit. The lead optimization programme then resulted in the identification of molidustat (BAY 85 3934, 45), a novel small-molecule oral HIF PH inhibitor. Molidustat is currently being investigated in a clinical phase III trial as molidustat sodium (84) for the treatment of anemia in patients with CKD.

  • Chemical features important for activity in a class of inhibitors targeting the Wip1 flap subdomain
    ChemMedChem (IF 3.225) Pub Date : 2018-02-23
    Harichandra D Tagad, Subrata Debnath, Victor Clausse, Mrinmoy Saha, Sharlyn Mazur, Ettore Appella, Daniel H. Appella

    The wild-type p53 induced phosphatase 1, Wip1 (PP2Cδ), is a PP2C family Ser/Thr phosphatase that negatively regulates the function of multiple proteins such as p53, ATM, Chk1, Chk2, Mdm2 and p38 MAPK involved in a DNA damage response. Wip1 dephosphorylates and inactivates its protein targets which are critical for cellular stress responses. Additionally, Wip1 frequently amplified and overexpressed in several human cancer types. Because of its negative role in regulating the function of essential proteins, Wip1 has been identified as a potential therapeutic target in various types of cancers. Based on a recently reported Wip1 inhibitor (G-1), we performed an extensive structure-activity relationship (SAR) analysis. This led us to interesting findings in SAR trends and to the discovery of new chemical analogues with good specificity and bioavailability.

  • Antibody Epitope of human α-Galactosidase A revealed by affinity-mass spectrometry: A basis for reversing immunoreactivity in enzyme replacement therapy of Fabry's Disease
    ChemMedChem (IF 3.225) Pub Date : 2018-02-23
    Michael Przybylski

    Alpha-galactosidase (αGal) is a lysosomal enzyme that hydrolyses the alphagalactosyl moiety from glycosphingo-lipids. Mutations in the αGal genes lead to defect enzyme resulting in substrate accumulation and pathophysiology. The deficiency of αGal, called Fabry's Disease (FD), belongs to the lysosomal storage diseases. Effective treatment of FD has been developed by enzyme replacement therapy (ERT) by infusion of recombinant enzyme to increase enzyme levels and reduce accumulated substrate. Immuno-reactivity and IgG antibody formation are major, therapy-limiting complications of ERT. Here we report the antibody epitope identification of human αGal, αGal(309-332), using a combination of proteolytic excision of the immobilized immune complex and surface plasmon resonance (SPR)- biosensor mass spectrometry. The epitope peptide, αGal(309-332) was synthesized by solid-phase peptide synthesis; its affinity was determined by SPR (KD, 39 x 10-9 M) nearly identical to that of the full length enzyme (KD, 16 x 10-9 M). Proteolytic excision- mass spectrometry is shown to be an efficient tool for epitope identification of immunogenic lysosomal enzymes. Since the full length enzyme and the antibody epitope showed comparable binding affinities, this provides a basis for reversing immunogenicity by (i), treatment of patients with epitope peptide to neutralizing antibodies, or (ii), removal of antibodies by apheresis, thus significantly improving the response to ERT.

  • Novel peroxides as promising anticancer agents with unexpected depressed antimalarial activity
    ChemMedChem (IF 3.225) Pub Date : 2018-02-22
    Paolo Coghi, Ivan A Yaremenko, Parichat Prommana, Peter S Radulov, Mikhail A Syroeshkin, Yu Jun Wu, Jia Ying Gao, Flora M Gordillo-Martinez, Simon Mok, Vincent K.W. Wong, Chairat Uthaipibull, Alexander O Terent'ev

    Twenty six peroxides belonging to bridged 1,2,4,5-tetraoxanes, bridged 1,2,4-trioxolanes (ozonides), and tricyclic monoperoxides were evaluated for the in vitro antimalarial activity against Plasmodium falciparum (3D7) and for their cytotoxic activities against immortalized human normal fibroblast (CCD19Lu), liver (LO2) and lung (BEAS-2B) cell lines as well as human liver (HepG2) and lung (A549) cancer cell lines. Synthetic ozonides were shown to have highest cytotoxicity on HepG2 (IC50 0.19-0.59 µM) and some of these compounds selectively targeted liver cancer (SI for compounds 13a and 14a is 20 and 28 respectively), which in some cases were higher than that of paclitaxel, artemisinin, artesunic acid. In contrast same ozonides have shown only moderate antimalarial activity against the chloroquine sensitive 3D7 strain of P. falciparum (IC50 from 2.76 to 24.2 µM; 12b IC50 2.76 µM, 13a IC50 20.14 µM, 14a IC50 6.32 µM). These results suggest divergent mechanism of action of these derivatives against cancer cells and malaria infected cells. A cyclic voltammetry study of peroxides was performed but most of the compounds do not showed direct correlation in oxidative capacity - activity. Our findings offer a new source of antimalarial and anticancer agents through structural modification of these peroxide compounds.

  • Synthesis and Characterization of the R27S Genetic Variant of Insulin-like Peptide 5
    ChemMedChem (IF 3.225) Pub Date : 2018-02-21
    Alexander Zaykov, Vasily Gelfanov, Fa Liu, Richard Dennis DiMarchi, Richard Dennis DiMarchi

    We report the synthesis and in vitro bioactivity assessment for an insulin-like peptide 5 (INSL5) analog that was recently discovered as a genetic mutation in an Amish population. The mutation was associated with improved metabolic status and receptor-based antagonism was proposed as a potential mechanism for the altered phenotype. We determined the specific peptide analog to be fully potent and of maximal efficacy at the human relaxin family peptide receptor 4 (RXFP-4), suggesting an alternative basis for the observed effect. In preparation of this synthetically challenging hormone, we have introduced several improvements such as implementation of isoacyl chemistry for high-efficiency preparation of INSL5 B-chain and selective intramolecular A6-11 disulfide formation as a first step in sequential disulfide assembly.

  • Claramines : A new class of broad-spectrum antimicrobial agents with bimodal activity
    ChemMedChem (IF 3.225) Pub Date : 2018-02-21
    marine blanchet, diane borselli, anne Rodallec, Franck peiretti, nicolas vidal, jean michel bolla, carole digiorgio, kelly morrison, william wuest, Jean Michel Brunel

    The emergence of multidrug resistant bacteria/pathogens has highlighted the need for the development of new antibiotics. In this manuscript, we report herein our results dealing with the broad spectrum of antibacterial activity against both sensitive and resistant Gram-negative and Gram-positive bacterial strains of an easily prepared water soluble polyaminosterol compound namely claramine A1. We will also demonstrate its peculiar mechanism of action (different from all the well-known classes of antibiotics) towards Gram-negative and Gram-positive bacteria. Finally, due to its low cytotoxicity, this class of molecules could constitute one of the most appropriate response against the questionable emergence of multidrug resistant bacteria and the associated consequence in the name of nosocomial diseases.

  • Front Cover: Helenalin Analogues Targeting NF-κB p65: Thiol Reactivity and Cellular Potency Studies of Varied Electrophiles (ChemMedChem 4/2018)
    ChemMedChem (IF 3.225) Pub Date : 2018-02-20
    John C. Widen, Aaron M. Kempema, Jordan W. Baur, Hannah M. Skopec, Jacob T. Edwards, Tenley J. Brown, Dennis A. Brown, Frederick A. Meece, Daniel A. Harki
  • A Sulfonozanamivir Analogue has Potent Anti-influenza Virus Activity
    ChemMedChem (IF 3.225) Pub Date : 2018-02-17
    Ádám Hadházi, Linghui Li, Benjamin Bailly, Andrea Maggioni, Gael Martin, Larissa Dirr, Jeffrey Dyason, Robin Thomson, George Gao, Anikó Borbás, Thomas Ve, Mauro Pascolutti, Mark von Itzstein

    Influenza virus infection continues to cause significant, often severe, respiratory illness worldwide. A validated target for development of anti-influenza agents is the viral surface protein sialidase. In the current study, we have discovered a highly potent inhibitor of influenza virus sialidase, based on a novel sialosyl sulfonate template. The synthesised 3-guanidino sialosyl α-sulfonate, a sulfonozanamivir analogue, inhibits virus replication in vitro at a nanomolar level, comparable to that of anti-influenza drug zanamivir. Using protein X-ray crystallography we show that the sialosyl α-sulfonate template orients within the sialidase active site in a ¹C₄ chair conformation. The C1-sulfonate moiety forms crucial and strong-binding interactions with the active site's triarginyl cluster, while the 3-guanidino moiety significantly interacts with conserved active site residues. This sulfonozanamivir analogue provides a new direction in anti-influenza virus drug development.

  • Novel 5-HT7 antagonists, with an unprecedented selectivity profile
    ChemMedChem (IF 3.225) Pub Date : 2018-02-16
    Ali Ates, Pierre Burssens, Olivier Lorthioir, Patrick Lo Brutto, Gwenael Dehon, Jean Keyaerts, Francis Coloretti, Lallemand Bénédicte, Verbois Valérie, Gillard Michel, Vermeiren Céline

    In the present study, a novel chemical series of serotonin 5-HT7 antagonist is described. The synthesis, structure-activity relationships and selectivity profile are reported. This series includes 5-HT7 antagonists with unprecedented good selectivity for 5-HT7 receptor.

  • Caveat usor: assessing differences between major chemistry databases
    ChemMedChem (IF 3.225) Pub Date : 2018-02-16
    Christopher Southan

    The three databases of PubChem (PC), ChemSpider (CS) and UniChem (UC) capture the majority of open chemical structure records with February 2018 totals of 63, 95 and 154 million, respectively. Collectively, they constitute a massively enabling resource for cheminformatics, chemical biology and drug discovery. As meta-portals, they subsume and link-out to the major proportion of public bioactivity data extracted from the literature and screening center assay results. They thus not only present three different entry points but the many subsumed independent resources present yet a fourth in the form of standalone databases. Because this presents a complex picture it is important for users to have at least some appreciation of differential content to enable utility judgments for the tasks at hand. This turns out to be challenging. By comparing the three resources in detail, this review assesses their differences, some of which are non-obvious. This includes the fact that coverage is significantly different between the 477, 556 and 37 contributing sources, respectively. This not only presents the "who-has-what" question but also the reason "why" any particular inclusion is considered valuable is rarely made explicit. Also confusing is that sources nominally in common (i.e. having the same submitter name) can have significantly different structure counts, not only in each of the three but also from their stand-alone instantiations. Assessing a series of examples indicates that differences in loading dates and structural standardisation are the main cause of this inter-portal discordance.

  • Stacking Interactions of Heterocyclic Drug Fragments with Protein Amide Backbones
    ChemMedChem (IF 3.225) Pub Date : 2018-02-16
    Andrea N. Bootsma, Steven Edge Wheeler

    Stacking interactions can be important enthalpic contributors to drug binding. Among the less well-studied stacking interactions are those occurring between an arene and the π-face of an amide group. Given the ubiquity of heterocycles in drugs, combined with the abundance of amides in the protein backbone, optimizing these non-covalent interactions can provide a potential route to enhanced drug binding. Previously, Diederich et al. (ChemMedChem 2013, 8, 397-404) studied stacked dimers of a model amide with a set of 18 heterocycles, showing that computed interaction energies correlate with the dipole moments of the heterocycles and providing guidelines for the optimization of these interactions. We have considered stacked dimers of the same model amide with a larger set of 28 heterocycles common in pharmaceuticals using more robust ab initio methods. While the overall trends in these new data corroborate many of the results of Diederich et al., these data provide a more refined view of the nature of amide stacking interactions. We present a robust scoring function for amide stacking interaction energies based on the molecular dipole moment and strength of the electric field above the arene.

  • Design, synthesis and biological evaluation of novel bivalent ligands targeting Dopamine D2-like receptors and µ opioid receptor
    ChemMedChem (IF 3.225) Pub Date : 2018-02-16
    Mingcheng Qian, Lakshmi Vasudevan, Jelle Huysentruyt, Martijn D. P. Risseeuw, Christophe Stove, Patrick M. L. Vanderheyden, Kathleen Van Craenenbroeck, Serge Van Calenbergh

    Nowadays, there is mounting evidence that intermolecular receptor-receptor interactions may result in altered receptor recognition, pharmacology and signaling. Heterobivalent ligands have been proven useful molecular probes for confirming and targeting heteromeric receptors. This paper describes the design and synthesis of novel heterobivalent ligands for dopamine D2-like receptors (D2-likeR) and the µ opioid receptor (µOR) and their evaluation using radioactive ligand binding and functional assays.

  • Simultaneous Multiple MS Binding Assays for the Dopamine, Norepinephrine, and Serotonin Transporters
    ChemMedChem (IF 3.225) Pub Date : 2018-02-16
    Patrick Neiens, Angela De Simone, Georg Höfner, Klaus T. Wanner
  • Development of a Focused Library of Triazole-Linked Privileged-Structure-Based Conjugates Leading to the Discovery of Novel Phenotypic Hits against Protozoan Parasitic Infections
    ChemMedChem (IF 3.225) Pub Date : 2018-02-16
    Elisa Uliassi, Lorna Piazzi, Federica Belluti, Andrea Mazzanti, Marcel Kaiser, Reto Brun, Carolina B. Moraes, Lucio H. Freitas-Junior, Sheraz Gul, Maria Kuzikov, Bernhard Ellinger, Chiara Borsari, Maria Paola Costi, Maria Laura Bolognesi
  • Discovery of Rogaratinib (BAY 1163877): a pan-FGFR Inhibitor
    ChemMedChem (IF 3.225) Pub Date : 2018-02-16
    Marie-Pierre Collin, Mario Lobell, Walter Hübsch, Dirk Brohm, Hartmut Schirok, Rolf Jautelat, Klemens Lustig, Ulf Bömer, Verena Vöhringer, Mélanie Héroult, Sylvia Grünewald, Holger Hess-Stumpp
  • Synthesis, characterization and biodistribution of a novel dinuclear gadolinium complex with improved properties as blood pool MRI agent
    ChemMedChem (IF 3.225) Pub Date : 2018-02-14
    Francesca La Cava, Alberto Fringuello Mingo, Luigi Miragoli, Enzo Terreno, Enrico Cappelletti, Luciano Lattuada, Luisa Poggi, Sonia Colombo Serra

    A dinuclear gadolinium(III) chelate containing two moieties of diethylenetriaminepentaacetic acid (DTPA), covalently conjugated to an analogue of deoxycholic acid has been synthesized and widely characterized. A full relaxometric analysis was carried out, consisting of (i) the acquisition of nuclear magnetic resonance dispersion (NMRD) profiles in different media; (ii) the study of binding affinity to serum albumin; (iii) the measurement of 17O transverse relaxation rate vs temperature and (iv) a transmetallation assay. Biodistribution MRI in vivo studies at 1 T and blood pharmacokinetic were carried out in comparison with Gd-DTPA (Magnevist®) and gadocoletic acid trisodium salt (B22956/1), two well-known Gd-complexes both sharing the same chelating cage and the same deoxycholic residue of the herein investigated Gd-complex ((GdDTPA)2-Chol). A good affinity to the plasma protein and, in particular, the availability of more than one binding site, allows the complex to reach a fairly high relaxivity value in plasma (approx. 20 mM-1s-1, 20 MHz, 310 K) as well as to show unexpectedly strongly enhanced properties of blood pooling, with an elimination half time in rats about 7 times longer than B22956/1.

  • Application of Mono- or Disaccharides in Drug Targeting and Efficacy
    ChemMedChem (IF 3.225) Pub Date : 2018-02-13
    SiSi Yuan, MaoLin Li, Jiansheng Chen, Li zhou, Wen Zhou

    Carbohydrates and their conjugates play important roles in many life processes including fertilization, differentiation, development, immune response, and infection. Their activities were largely dependent on the properties of terminal mono- or disaccharides. Galactose, mannose, fucose, glucose, sialic acid, etc. are commonly used as powerful scaffolds installed on drug molecules for targeting specific tissues including brain, liver and cancers, and as epitopes for enhancing the targeting of various vaccination. Herein this highlight will focus on the influence of their structural variations, including the changing of sugar type, substituent groups and their positions, length of linkage and so forth, on the drugs targeting or their efficacy, particular attention will be paid to the targeting property of mono-and disaccharides applied in drug design and discovery.

  • Insights into the Target Interaction of Naturally Occurring Muraymycin Nucleoside Antibiotics
    ChemMedChem (IF 3.225) Pub Date : 2018-02-13
    Stefan Koppermann, Zheng Cui, Patrick D. Fischer, Xiachang Wang, Jannine Ludwig, Jon S. Thorson, Steven G. Van Lanen, Christian Ducho

    Muraymycins are a subclass of antimicrobially active uridine-derived natural products. Biological data on several muraymycin analogues have already been reported, including some inhibitory in vitro activities towards their target protein, the bacterial membrane enzyme MraY. However, a structure-activity relationship (SAR) study on naturally occurring muraymycins based on such in vitro data has been missing so far. In this work, we report a detailed SAR investigation on representatives of the four muraymycin subgroups A-D using a fluorescence-based in vitro MraY assay. For some muraymycins, inhibition of MraY with IC50 values in the low pM range was observed. These inhibitory potencies were compared with antibacterial activities and were correlated to modelling data derived from a previously reported X-ray crystal structure of MraY in complex with a muraymycin inhibitor. Overall, these results will pave the way for the development of muraymycin analogues with optimized properties as antibacterial drug candidates.

  • Design of Highly Potent, Dual Acting and Central Nervous System Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants
    ChemMedChem (IF 3.225) Pub Date : 2018-02-13
    Arun K Ghosh, Kalapala Venkateswara Rao, Prasanth R. Nyalapatla, Satish Kovela, Margherita Brindisi, Heather L. Osswald, Bhavanam Sekhara Reddy, Johnson Agniswamy, Yuan-Fang Wang, Manabu Aoki, Shin-ichiro Hattori, Irene T. Weber, Hiroaki Mitsuya

    We report here the design, synthesis, X-ray-structural, and biological studies of an exceptionally potent HIV-1 protease inhibitor 5. In this inhibitor, we incorporated an unprecedented structure-based designed 6-5-5-ring fused crown-like tetrahydropyranofuran as the P2-ligand, a cyclopropylaminobenzothiazole as the P2'-ligand and 3,5-difluorophenylmethyl as the P1-ligand. The resulting inhibitor 5, exhibited exceptional HIV-1 inhibitory and antiviral potency at picomolar level. Furthermore, it displayed antiviral IC50 values in picomolar range against a wide panel of highly multidrug-resistant HIV-1 variants. The inhibitor shows an extremely high genetic barrier against the emergence of drug-resistant variants. It also showed extremely potent dimerization inhibitory activity and penetrated CNS favourably. We have determined a high resolution X-ray structure of inhibitor 5-bound HIV-1 complex which provided molecular insight into the unprecedented activity profiles.

  • Glucagon-like Peptide-1 (GLP-1)-Based Therapeutics: Current Status and Future Opportunities Beyond Type 2 Diabetes
    ChemMedChem (IF 3.225) Pub Date : 2018-02-11
    Jia Ying Cheang, Peter Michael Moyle

    Glucagon-like peptide-1 (GLP-1) is secreted by intestinal L-cells following food intake, and plays an important role in glucose homeostasis due to its stimulation of glucose-dependent insulin secretion. Further, GLP-1 is also associated with protective effects on pancreatic β-cells and the cardiovascular system, reduced appetite, and weight loss, making GLP-1 derivatives an exciting treatment for type 2 diabetes and obesity. Despite these benefits, wild-type GLP-1 exhibits a short circulation time, due to its poor metabolic stability and rapid renal clearance, and needs to be administered by injection, making it a poor therapeutic agent. Many strategies have been employed to improve the circulation time of GLP-1 (e.g. mutations, unnatural amino acids, depot formulations, use of exendin-4 sequences and fusions with high molecular weight proteins or polymers), with its therapeutic utility further improved by adding agonist activity for gastric inhibitory peptide and glucagon receptors. This minireview focuses on strategies that have been used to improve the pharmacokinetics of GLP-1 and provides an overview of GLP-1 based therapeutics in the pipeline.

  • Probing ligand structure-activity relationships in pregnane X receptor (PXR): efavirenz and 8-hydroxyefavirenz exhibit divergence in activation
    ChemMedChem (IF 3.225) Pub Date : 2018-02-11
    Bhargavi Narayanan, Julie Lade, Carley J.S. Heck, Kevin D. Dietz, Herschel V. Wade, Namandje N. Bumpus

    Efavirenz (EFV), an antiretroviral that interacts clinically with co-administered drugs via activation of the pregnane X receptor (PXR), is extensively metabolized by the cytochromes P450. We tested whether its primary metabolite, 8-hydroxyEFV (8-OHEFV) can activate PXR and potentially contribute to PXR-mediated drug-drug interactions attributed to EFV. Luciferase reporter assays revealed that despite only differing from EFV by an oxygen atom, 8-OHEFV did not activate PXR. Corroborating this, treatment with EFV for 72 h elevated the mRNA abundance of the PXR target gene, Cyp3a11, an approximate 28-fold in primary hepatocytes isolated from PXR-humanized mice while treatment with 8-OHEFV did not result in a change in Cyp3a11 mRNA levels. FRET-based competitive binding assays and isothermal calorimetry demonstrated that even with the lack of ability to activate PXR, 8-OHEFV displays an affinity for PXR (IC50 12.1 µM; KD 7.9 µM) nearly identical to that of EFV (IC50 18.7 µM; KD 12.5 µM). The use of 16 EFV analogs suggest that other discreet changes to the EFV structure beyond the 8-position are well-tolerated. Molecular docking simulations implicate an 8-OHEFV binding mode that may underlie its divergence in PXR activation from EFV.

  • Preparation of new tetradentate copper chelators as potential anti-Alzheimer agents
    ChemMedChem (IF 3.225) Pub Date : 2018-02-08
    Anne Robert, Weixin ZHANG, Daya HUANG, Meijie HUANG, Ju HUANG, Dean WANG, Michel NGUYEN, Laure VENDIER, Serge MAZÈRES, Bernard MEUNIER, Yan LIU, LIU Xingguo

    The non-controlled redox activity of metal ions, especially copper, in the brain of patients with Alzheimer's disease (AD) should be considered at the origin of the intense oxidative damage on neurons in AD brain. In order to obtain low molecular weight copper chelators acting as tetradentate ligands, we designed new compounds based on an 8-aminoquinoline motif with a lateral chain attached at the position 2 of the aromatic ring. Some of these new ligands, named TDMQ for TetraDentate MonoQuinolines, are specific for copper chelation. Full characterization of these ligands are reported in the present article, as well as their affinities for Cu(II), and their capacities to inhibit oxidative stress induced by copper-amyloids activated by a reductant. Such metal ligands can be considered as potential anti-AD agents, are able to regulate the homeostasis of copper in brains.

  • Front Cover: Harnessing the Maltodextrin Transport Mechanism for Targeted Bacterial Imaging: Structural Requirements for Improved in vivo Stability in Tracer Design (ChemMedChem 3/2018)
    ChemMedChem (IF 3.225) Pub Date : 2018-02-08
    Alexander Axer, Sven Hermann, Gerald Kehr, David Clases, Uwe Karst, Lena Fischer-Riepe, Johannes Roth, Manfred Fobker, Michael Schäfers, Ryan Gilmour, Andreas Faust
  • Structure-Activity Relationship Studies of Vitamin D3 Analogues Containing an Ether or Thioether Linker as Hedgehog Pathway Inhibitors
    ChemMedChem (IF 3.225) Pub Date : 2018-02-06
    Jiachen Wen, Matthew Kyle Hadden

    The Hedgehog (Hh) signaling pathway is critical for embryonic patterning and postembryonic tissue regeneration. Constitutive pathway activation has also been linked to human malignancies such as basal cell carcinoma (BCC) and medulloblastoma; therefore, multiple small molecule scaffolds that inhibit Hh signaling are in development. Previously, Grundmann's alcohol, also known as the "northern region" of vitamin D3 (VD3), has been identified as a moderate Hh pathway inhibitor. In this study, isomers of Grundmann's alcohol with different orientations of the C-4 hydroxyl and C-3α proton were investigated to determine the optimal configuration for this hexahydroindane scaffold with respect to Hh inhibition. A series of analogues containing Grundmann's alcohol linked to a substituted phenyl or benzyl ring through an ether or thioether linker were synthesized and evaluated for their anti-Hh activity. Of these, analogue 17 demonstrated potent anti-Hh activity in Hh-dependent BCC cells and did not activate canonical vitamin D receptor signaling, demonstrating its selective nature for the Hh signaling pathway.

  • Screening of a novel fragment library with functional complexity against Mycobacterium tuberculosis InhA
    ChemMedChem (IF 3.225) Pub Date : 2018-02-05
    Federica Prati, Fabio Zuccotto, Daniel Fletcher, Maire A Convery, Raquel Fernandez-Menendez, Robert Bates, Lourdes Encinas, Jingkun Zeng, Chun-wa Chung, Paco De Dios Anton, Alfonso Mendoza-Losana, Claire Mackenzie, Simon R. Green, Margaret Huggett, David Barros, Paul Graham Wyatt, Peter C Ray

    Our findings reported herein, provide support for the benefits of including functional group complexity (FGC) within fragments when screening against protein targets such as Mycobacterium tuberculosis InhA. We show that InhA fragment actives with FGC maintained their binding pose during elaboration. Furthermore, weak fragment hits with functional group handles also allowed for facile fragment elaboration to afford novel and potent InhA inhibitors with good ligand efficiency metrics for optimization.

  • CHIPMUNK: A virtual synthesizable small molecule library for medicinal chemistry exploitable for protein-protein interaction modulators.
    ChemMedChem (IF 3.225) Pub Date : 2018-02-01
    Lina Humbeck, Sebastian Weigang, Till Schäfer, Petra Mutzel, Oliver Koch

    A common issue during drug design and development is the discovery of novel scaffolds for protein targets. On the one hand the chemical space of purchasable compounds is rather limited and on the other hand artificially generated molecules suffer from a grave lack of accessibility in practice. Therefore, we generated a novel virtual library of small molecules which are synthesizable from purchasable educts, called CHIPMUNK (CHemically feasible In silico Public Molecular UNiverse Knowledge base). Altogether CHIPMUNK covers over 95 million compounds and encompasses regions of the chemical space that are not covered by existing databases. The coverage of CHIPMUNK exceeds the chemical space spanned by the rule of five to foster the exploration of novel and difficult target classes. The analysis of the generated property space reveals that CHIPMUNK is well suited for the design of protein-protein interaction inhibitors (PPIIs). Furthermore, a recently developed structural clustering algorithm (StruClus) for big data was utilized to partition the sub-libraries into meaningful subsets and assist scientists to process the large amount of data. These clustered subsets also contain the target space based on ChEMBL data which was included during clustering.

  • Mapping of the Available Chemical Space versus the Chemical Universe of Lead-Like Compounds
    ChemMedChem (IF 3.225) Pub Date : 2018-01-29
    Arkadii Lin, Dragos Horvath, Valentina Afonina, Gilles Marcou, Jean-Louis Reymond, Alexandre Varnek
  • AquaMMapS: An Alternative Tool to Monitor the Role of Water Molecules During Protein–Ligand Association
    ChemMedChem (IF 3.225) Pub Date : 2018-01-25
    Alberto Cuzzolin, Giuseppe Deganutti, Veronica Salmaso, Mattia Sturlese, Stefano Moro
  • Harnessing the Maltodextrin Transport Mechanism for Targeted Bacterial Imaging: Structural Requirements for Improved in vivo Stability in Tracer Design
    ChemMedChem (IF 3.225) Pub Date : 2018-01-16
    Alexander Axer, Sven Hermann, Gerald Kehr, David Clases, Uwe Karst, Lena Fischer-Riepe, Johannes Roth, Manfred Fobker, Michael Schäfers, Ryan Gilmour, Andreas Faust
  • Rationalizing Promiscuity Cliffs
    ChemMedChem (IF 3.225) Pub Date : 2017-11-06
    Dilyana Dimova, Jürgen Bajorath
  • Cross-Classified Multilevel Modelling of the Effectiveness of Similarity-Based Virtual Screening
    ChemMedChem (IF 3.225) Pub Date : 2017-11-06
    Lucyantie Mazalan, Andrew Bell, Laura Sbaffi, Peter Willett
  • Matched Molecular Pair Analysis on Large Melting Point Datasets: A Big Data Perspective
    ChemMedChem (IF 3.225) Pub Date : 2017-08-23
    Michael Withnall, Hongming Chen, Igor V. Tetko
  • Kinome-Wide Profiling Prediction of Small Molecules
    ChemMedChem (IF 3.225) Pub Date : 2017-06-26
    Frieda A. Sorgenfrei, Simone Fulle, Benjamin Merget
  • Inhibitors against Fungal Cell Wall Remodeling Enzymes
    ChemMedChem (IF 3.225) Pub Date : 2017-12-12
    Ignacio Delso, Jessika Valero-Gonzalez, Fernando Gomollón-Bel, Jorge Castro-López, Wenxia Fang, Iva Navratilova, Daan M. F. van Aalten, Tomás Tejero, Pedro Merino, Ramon Hurtado-Guerrero
  • Anticancer Properties of Halogenated Pyrrolo[3,2-d]pyrimidines with Decreased Toxicity via N5 Substitution
    ChemMedChem (IF 3.225) Pub Date : 2017-12-18
    Brian M. Cawrse, Rena S. Lapidus, Brandon Cooper, Eun Yong Choi, Katherine L. Seley-Radtke
  • 1,3,5-Triazino-Peptide Derivatives: Synthesis, Characterization and Preliminary Antileishmanial Activity
    ChemMedChem (IF 3.225) Pub Date : 2018-02-01
    Sherine N Khattab, Hosam H Khalil, Adnan A Bekhit, Mohamed M Abd El-Rahman, Beatriz G de la Torre, Ayman El-Faham, Fernando Albericio

    A library of short di- to tetra-peptides with a s-triazine moiety at the N-terminal and the C-terminal in the form of either ethyl ester or amide were prepared in solution and in solid-phase. The two remaining positions of the s-triazine moiety were substituted by dimethoxy, dimorpholino, or dipiperidino groups. All the peptide derivatives synthesized were analyzed by HPLC and fully characterized by IR, NMR (1H-NMR and 13C-NMR), elemental analysis, andmass spectra analysis (MALDI TOF/TOF). A preliminary study of the antileishmanial activity of the 1,3,5-triazino-peptide derivatives revealed that four dipeptide amide derivatives showed better antipromastigote or antiamastigote activity than that of the reference standard drug miltefosine with no significance acute toxicity.

  • In Vitro Photodynamic Activity of N-Methylated and N-Oxidised Tripyridyl Porphyrins with Long Alkyl Chains and Their Inhibitory Activity in Sphingolipid Metabolism
    ChemMedChem (IF 3.225) Pub Date : 2018-01-30
    Mateo Jelovica, Petra Grbčić, Martina Mušković, Mirela Sedić, Sandra Kraljević Pavelić, Martin Lončarić, Nela Malatesti
  • Comparative pharmacological study of common NMDA receptor open channel blockers regarding their affinity and functional activity towards GluN2A- and GluN2B-NMDA receptors
    ChemMedChem (IF 3.225) Pub Date : 2018-01-27
    Bernhard Wünsch, Louisa Temme, Dirk Schepmann, Julian A Schreiber, Bastian Frehland

    Since only a few studies investigated the affinity and functional activity of NMDA receptor open channel blockers under same assay conditions, a comparative study of common open channel blockers is of major interest. The pharmacological activity of MK-801, phencyclidine, dexoxadrol, etoxadrol, (S)- and (R)-ketamine, dextromethorphan, memantine and amantadine was analyzed under same uniform assay conditions. The affinity towards the PCP and ifenprodil binding sites was recorded in radioligand binding assays. GluN2A and GluN2B subtype specific cytoprotective activity was determined in LDH assays. The data were correlated with published IC50 values obtained in two-electrode voltage clamp experiments. A high correlation was found between PCP affinity, ion flux inhibition and cytoprotective activity. The channel blockers were classified into four groups showing high, moderate, low and very low potency. Some of the open channel blockers display unexpected subtype selectivity. The comparative study allows the characterization of open channel blockers from their receptor ligand interaction via inhibition of ion flux up to overall cytoprotective activity. The subtype preference of some open channel blockers will stimulate the development of novel subtype selective open channel blockers with reduced side effect potential.

  • Design, Synthesis and Biological Evaluation of New Pyrazoline-Based Hydroxamic Acid Derivatives as Aminopeptidase N (APN) Inhibitors
    ChemMedChem (IF 3.225) Pub Date : 2018-01-27
    Jiangying Cao, Jie Zang, Chunhua Ma, Xiaoguang Li, Jinning Hou, Jin Li, Yongxue Huang, Wenfang Xu, Binghe Wang, Yingjie Zhang

    Aminopeptidase N (APN) has been recognized as a target for anticancer treatment due to its overexpression on diverse malignant tumor cells and association with cancer invasion, metastasis and angiogenesis. Herein, we described the synthesis, biological evaluation and structure-activity relationship study of two new series of pyrazoline analogs as APN inhibitors. Among these compounds, compound 13e showed the best APN inhibition with an IC50 value of 0.16 ± 0.02 μM, which was over one order of magnitude lower than that of bestatin (IC50 = 9.4 ± 0.5 μM). Moreover, compound 13e inhibited proliferation of diverse carcinoma cells and showed potent anti-angiogenesis activity. At the same concentration, compound 13e presented significantly higher anti-angiogenesis activity than bestatin in the human umbilical vein endothelial cells (HUVECs) capillary tube formation assay. Moreover, the putative binding mode of 13e in the active site of APN was also discussed.

  • Front Cover: [Carboxyl-11C]Labelling of Four High-Affinity cPLA2α Inhibitors and Their Evaluation as Radioligands in Mice by Positron Emission Tomography (ChemMedChem 2/2018)
    ChemMedChem (IF 3.225) Pub Date : 2018-01-26
    Martin J. Fisher, Lindsay McMurray, Shuiyu Lu, Cheryl L. Morse, Jeih-San Liow, Sami S. Zoghbi, Aneta Kowalski, George L. Tye, Robert B. Innis, Franklin I. Aigbirhio, Victor W. Pike
  • 更新日期:2018-01-24
  • Screening of drug library identifies inhibitors of cell intoxication by CNF1
    ChemMedChem (IF 3.225) Pub Date : 2018-01-23
    Nassim Mahtal, Clémence Brewee, Sylvain Pichard, Orane Visvikis, Jean-Christophe Cintrat, Julien Barbier, Emmanuel Lemichez, Daniel Gillet

    The Cytotoxic Necrotizing Factor 1 (CNF1) is a toxin produced by pathogenic strains of Escherichia coli responsible for extra-intestinal infections. CNF1 deamidates Rac1, thereby triggering its permanent activation, and worsening inflammatory reactions. Activated Rac1 is prone to proteasomal degradation. There is no targeted therapy against CNF1, despite its clinical relevance. In this work, we developed a fluorescent, cell-based immunoassay to screen for inhibitors of CNF1-induced Rac1 degradation among 1,120 mostly approved drugs. Eleven compounds prevented CNF1-induced Rac1 degradation and five showed also a protective effect on CNF1-induced multinucleation. At last, lasalocid, monensin, bepridil and amodiaquine protect cells from both diphtheria toxin and CNF1 challenges. These data highlight potential drug repositioning to fight several bacterial toxi-infections and Rac1-based diseases.

  • Phenyl boronic acids development led to validated leads active in clinical strains overexpressing KPC-2: a step against bacterial resistance.
    ChemMedChem (IF 3.225) Pub Date : 2018-01-22
    Giuseppe Celenza, Mattia Vicario, Pierangelo Bellio, Linciano Pasquale, Mariagrazia Perilli, Antonio Oliver, Jesus Blazquez, Laura Cendron, Donatella Tondi

    The emergence and dissemination of multi drug resistant (MDR) pathogens resistant to near all available antibiotics poses a significant threat in clinical therapy. Among them, Klebsiella pneumoniae clinical isolates overexpressing KPC-2 carbapenemase are the most worrisome, extending bacterial resistance to last resort carbapenems. In this study we investigate the molecular recognition requirements in KPC-2 active site by small phenyl boronic acid derivatives. Four new phenyl boronic acid derivatives were designed and tested vs KPC-2. For the most active, despite their simple chemical structures, nanomolar affinity was achieved. New derivatives restored susceptibility to meropenem in clinical strains overexpressing KPC-2. Moreover no cytotoxicity was detected in cell viability assays, further validating the designed leads. Two crystallographic binary complexes of best inhibitors binding KPC-2 were obtained at high resolution. Kinetic descriptions of slow binding, time dependent inhibition and interactions geometries in KPC-2 were fully investigated. This study will ultimately lead toward optimization and development of more effective KPC-2 inhibitors.

  • Helenalin Analogues Targeting NF-κB p65: Thiol Reactivity and Cellular Potency Studies of Varied Electrophiles
    ChemMedChem (IF 3.225) Pub Date : 2018-01-19
    John C. Widen, Aaron M. Kempema, Jordan W. Baur, Hannah M. Skopec, Jacob T. Edwards, Tenley J. Brown, Dennis A. Brown, Frederick A. Meece, Daniel A. Harki
  • Targeting BCL2 Gene Promoter G-quadruplex with a New Class of Furopyridazinone-Based Molecules
    ChemMedChem (IF 3.225) Pub Date : 2018-01-18
    Jussara Amato, Alessia Pagano, Domenica Capasso, Sonia Di Gaetano, Mariateresa Giustiniano, Ettore Novellino, Antonio Randazzo, Bruno Pagano

    Targeting of G-quadruplex-forming DNA in BCL2 gene promoter to inhibit the expression of anti-apoptotic Bcl-2 protein represents an attractive opportunity in cancer treatment. So far, efforts made in the discovery of molecules able to target BCL2 G-quadruplex mainly succeeded in the identification of ligands with poor drug-like properties. Here, a small series of furo[2,3-d]pyridazin-4(5H)-one derivatives were evaluated as a new class of drug-like G-quadruplex-targeting compounds. Biophysical studies showed that two derivatives could effectively bind to BCL2 G-quadruplex with good selectivity. Moreover, one of such ligands appreciably inhibited BCL2 gene transcription, with a substantial reduction of protein expression level, and showed significant cytotoxicity on the human T lymphoblastoid cell line Jurkat.

  • Hollow Mesoporous Silica@Metal−Organic Framework and Its Applications for pH-Responsive Doxorubicin Drug Delivery
    ChemMedChem (IF 3.225) Pub Date : 2018-01-16
    Xiaomin Jia, Zhiyuan Yang, Yujun Wang, Ya Chen, Haitao Yuan, Heyin Chen, Xiaoxiang Xu, Xueqing Gao, Zuozhong Liang, Yu Sun, Jian-Rong Li, Haoquan Zheng, Rui Cao

    Metal−organic frameworks (MOFs), a new type of porous crystalline materials, have great potential in biomedical applications, such as drug delivery. However, the efficacy of drug delivery is limited by the low loading of drugs. We have synthesized hollow mesoporous silica (HMS)@MOF capsule that can be used as pH-responsive drug delivery system for anti-cancer drug doxorubicin (DOX). DOX is loaded into the inner cavity of HMS.Then, zeolitic imidazolate framework-8 (ZIF-8) nanoparticles are coated on the outer surface of DOX loaded HMS. The obtained material is a capsule (denoted as DOX/HMS@ZIF), where DOX is encapsulated. The DOX/HMS@ZIF can be used as an efficient pH-responsive drug delivery system. The DOX is not released at physiological condition (pH 7.4) and released at low pH (4−6) from DOX/HMS@ZIF. The DOX/HMS@ZIF capsule shows a much higher cytotoxicity than free DOX and alters the delivery pathway for DOX in cancer cells, while the drug-free HMS@ZIF shows excellent biocompatibility. This opens new opportunities to construct a safe and efficient delivery system for targeted molecules using pH-responsive release for a wide range of applications.

  • Specific Non-Covalent Interactions Determine Optimal Structure of a Buried Ligand Moiety: QM/MM and Pure QM Modeling of Complexes of the Small-Molecule CD4 Mimetics and HIV1 Gp120
    ChemMedChem (IF 3.225) Pub Date : 2018-01-16
    Francesca Moraca, David Rinaldo, Amos Brittain Smith, Cameron Abrams

    The small molecule CD4 mimetics (smCD4mc) are a class of highly potent HIV-1 entry inhibitors characterized by a unique SAR. They share a halogenated phenyl ring (region 1) that deeply inserts into an otherwise water-filled cavity at the CD4 binding site on the gp120 surface, so-called F43 cavity. Conservative modifications to region 1 away from this halogenated phenyl motif have all lead to loss of activity, despite they are predicted to bind equally well via standard empirical computational approaches making difficult to further optimize this region of the compounds to increase binding to gp120. Here, we employed quantum mechanical methods to understand the roots of the interactions between region 1 and the F43 cavity. We clearly demonstrate the presence of halogen bond/σ-hole and dispersion interactions between region 1 and the F43 cavity residues F376-N377 that are not captured by standard molecular mechanics approaches and the role played by the smCD4mc in the F43 cavity desolvation. These findings rationalize why the halogenated region 1 has proven so difficult to move beyond in smCD4mc optimization, in agreement with experimental evidence.

  • 3D-e-Chem: Structural Cheminformatics Workflows for Computer-Aided Drug Discovery
    ChemMedChem (IF 3.225) Pub Date : 2018-01-16
    Albert J Kooistra, Marton Vass, Ross McGuire, Rob Leurs, Iwan JP de Esch, Gerrit Vriend, Stefan Verhoeven, Chris de Graaf

    eScience technologies are needed to process the information available in many heterogeneous types of protein-ligand interaction data and to capture these data into models that enable the design of efficacious and safe medicines. Here we present scientific KNIME tools and workflows that enable the integration of chemical, pharmacological, and structural information for: i) structure-based bioactivity data mapping, ii) structure-based identification of scaffold replacement strategies for ligand design, iii) ligand-based target prediction, iv) protein sequence-based binding site identification and ligand repurposing, and v) structure-based pharmacophore comparison for ligand repurposing across protein families. The modular setup of the workflows and the use of well-established standards allows the re-use of these protocols and facilitates the design of customized computer-aided drug discovery workflows.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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