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  • Structural Analysis of Small‐Molecule Binding to the BAZ2A and BAZ2B Bromodomains
    ChemMedChem (IF 3.225) Pub Date : 2018-05-17
    Andrea Dalle Vedove; Dimitrios Spiliotopoulos; Vito G. D'Agostino; Jean‐Rémy Marchand; Andrea Unzue; Cristina Nevado; Graziano Lolli; Amedeo Caflisch
    更新日期:2018-06-22
  • Towards novel angiogenesis inhibitors based on the conjugation of organometallic platinum(II) complexes to RGD peptides
    ChemMedChem (IF 3.225) Pub Date : 2018-06-22
    Vicente Marchan; Ana Zamora; Albert Gandioso; Anna Massaguer; Silvia Buenestado; Carme Calvis; Jose Luis Hernández; Francesc Mitjans; Venancio Rodríguez; Jose Ruiz

    A novel conjugate between a cyclometalated platinum(II) complex with dual anti‐angiogenic and antitumor activity and a cyclic peptide containing the RGD sequence (‐Arg‐Gly‐Asp‐) has been synthesized by combining solid‐ and solution‐phase methodologies. Although peptide conjugation rendered a non‐cytotoxic compound in all tested tumor cell lines (+/‐ αVβ3 and αVβ5 integrin receptors), the anti‐angiogenic activity of the Pt‐c(RGDfK) conjugate in HUVEC cells at sub‐cytotoxic concentrations opens the way to the design of a novel class of angiogenesis inhibitors through conjugation of metallodrugs with high anti‐angiogenic activity to cyclic RGD‐containing peptides or peptidomimetic analogues.

    更新日期:2018-06-22
  • Synthesis, Biological Activity, and Mechanism of Action of 2‐Pyrazyl and Pyridylhydrazone Derivatives, New Classes of Antileishmanial Agents
    ChemMedChem (IF 3.225) Pub Date : 2018-05-22
    Elaine S. Coimbra; Luciana M. R. Antinarelli; Mariana de A. Crispi; Thais C. M. Nogueira; Alessandra C. Pinheiro; Marcus V. N. de Souza
    更新日期:2018-06-22
  • Structure‐based Design of a Monosaccharide Ligand Targeting Galectin‐8
    ChemMedChem (IF 3.225) Pub Date : 2018-06-21
    Mohammad Bohari; Xing Yu; Chandan Kishor; Brijesh Patel; Rob-Marc Go; Hadieh Alsadat Eslampanah Seyedi; Yaron Vinik; Irwin Darren Grice; Yehiel Zick; Helen Blanchard

    Galectin‐8 is a β‐galactoside‐recognising protein that has a role in the regulation of bone remodelling and is an emerging new target for tackling diseases with associated bone‐loss. We have designed and synthesised methyl 3‐O‐[1‐carboxyethyl]‐β‐D‐galactopyranoside (compound 6) as a ligand to target the N‐terminal domain of galectin‐8 (galectin‐8N). Our design involved molecular dynamics (MD) simulations that predicted 6 to mimic the interactions made by the galactose ring as well as the carboxylic acid group of 3′‐O‐sialylated lactose (3′‐SiaLac), with galectin‐8N. Isothermal titration calorimetry (ITC) determined that the binding affinity of galectin‐8N for 6 was 37 μM, while no significant affinity was detected for the C‐terminal domain of galectin‐8 (galectin‐8C). The crystal structure of the galectin‐8N‐6 complex validated the predicted binding conformation and revealed the exact protein‐ligand interactions that involve galectin evolutionarily conserved amino acids and also those unique to galectin‐8N for recognition. Overall, we have initiated and demonstrated a rational ligand design campaign to develop a monosaccharide‐based scaffold as a binder of galectin‐8.

    更新日期:2018-06-22
  • Tertiary amine based inhibitors of the astacin protease meprin alpha
    ChemMedChem (IF 3.225) Pub Date : 2018-06-21
    Kathrin Tan; Christian Jäger; Dagmar Schlenzig; Stephan Schilling; Mirko Buchholz; Daniel Ramsbeck

    Metalloproteinases of the astacin family are more and more drawing attention as potential drug targets. However, the knowledge about inhibitors thereof is limited in most cases. Crucial for the development of metalloprotease inhibitors is a high selectivity to avoid side effects through the inhibition of off‐target proteases and the interference with physiological pathways. Here we aimed at the design of novel selective inhibitors for the astacin proteinase meprin α. Based on a recently identified tertiary amine scaffold, a series of compounds was synthesized and evaluated. The compounds exhibit reasonable inhibitory activity with high selectivity over other metalloproteases. Also the isoenzyme meprin β is only slightly inhibited. Hence, the present study revealed a novel class of selective meprin α inhibitors with improved selectivity compared to known compounds.

    更新日期:2018-06-22
  • What has come out from phytomedicines and herbal edibles for the treatment of cancer?
    ChemMedChem (IF 3.225) Pub Date : 2018-06-21
    Srinivasa Reddy Bonam; Seng Wu Yuan; Lakshmi Tunki; Ranjithkumar Chellian; Sampath Kumar Halmuthur M.; Sylviane MULLER; Vijayapandi Pandy

    Several modern treatment strategies have been adopted to combat cancer with the aim of minimizing toxicity. Medicinal plant‐based compounds with the potential to treat cancer have been widely studied in preclinical research and have elicited many innovative ways of leading‐edge clinical research. In parallel, researchers have eagerly tried to reduce the toxicity of current chemotherapeutic agents either by combining them with herbals or in using herbals alone. The focus of this article is to present an update of medicinal plants and their bioactive compounds, or mere changes in the bioactive compounds, and herbal edibles, which display efficacy against diverse cancer cells and in anticancer therapy. It describes the basic mechanism(s) of action of phytochemicals used either alone or in combo therapy with other phytochemicals/herbal edibles. Additionally, it also highlights the remarkable synergistic effects arising between some herbals and chemotherapeutic agents used in oncology. The anticancer phytochemicals used in clinical research are also described and further, we stated our own experience related to semi synthetic derivatives, which are developed based on the phytochemicals. Overall, this compilation aims at facilitating research and development projects on phytopharmaceuticals for successful anticancer drug discovery.

    更新日期:2018-06-22
  • NVP‐BHG712: Effects of regioisomers on the affinity and selectivity towards the EPHrin family
    ChemMedChem (IF 3.225) Pub Date : 2018-06-21
    Harald Schwalbe; Alix Tröster; Stephanie Heinzlmeir; Benedict-Tilman Berger; Santosh L. Gande; Krishna Saxena; Sridhar Sreeramulu; Verena Linhard; Amir H. Nasiri; Michael Bolte; Susanne Müller; Bernhard Kuster; Guillaume Médard; Denis Kudlinzki

    Abstract: EPH receptors are transmembrane receptor tyrosine kinases. Their extracellular domains bind specifically to ephrin A/B ligands, and this binding modulates the intracellular kinase activity. EPHs are key players in bidirectional intercellular signaling, controlling cell morphology, adhesion and migration. They are increasingly recognized as cancer drug targets. We analyzed the binding of the Novartis inhibitor NVP‐BHG712 (NVP) to EPHA2 and EPHB4. Unexpectedly, all tested commercially available NVP samples turned out to be a regioisomer (NVPiso) of the inhibitor, initially described in a Novartis patent application. They only differ by the localization of a single methylation on either one of two adjacent nitrogen atoms. The two compounds of identical mass revealed different binding modes. Further, both in vitro and in vivo experiments showed that the isomers differ in their kinase affinity and selectivity.

    更新日期:2018-06-22
  • A minimalist approach to the design of complexity‐enriched bioactive small molecules: discovery of phenanthrenoid mimics as antiproliferative agents.
    ChemMedChem (IF 3.225) Pub Date : 2018-06-21
    Fernando Alonso; María Josefina Quezada; Gabriel Gola; Victoria Richmond; Gabriela Cabrera; Andrea Barquero; Javier Alberto Ramírez

    Over the last decades, much effort has been devoted to the design of the "ideal" library for screening, the most promising strategies being those which draw inspiration from biogenic compounds, as they seek to add biological relevance to such libraries. On the other hand, there is a growing understanding of the role that molecular complexity plays in the discovery of new bioactive small molecules. Nevertheless, the introduction of molecular complexity must be balanced with synthetic accessibility. In this work, we show that both concepts can be efficiently merged ‐in a minimalist way‐ by using very simple guidelines during the design process along with the application of multicomponent reactions as key steps in the synthetic process. Natural phenanthrenoids, a class of plant aromatic metabolites, served as inspiration for the synthesis of a library where complexity‐enhancing features were introduced in few steps using multicomponent reactions. These resulting chemical entities were not only more complex than the parent natural products, but also interrogated an alternative region of the chemical space, which led to an outstanding hit rate in an antiproliferative assay: four out of twenty‐six compounds showed in vitro activity, one of them being more potent than the clinically useful drug 5‐fluorouracil.

    更新日期:2018-06-22
  • Methinylogation approach in chiral pharmacophore design: from alkynyl‐ to allenyl‐carbinol warheads against tumor cells
    ChemMedChem (IF 3.225) Pub Date : 2018-06-20
    Remi Chauvin

    Extension of a structure‐activity relationship study of the antitumor cytotoxicity of lipidic dialkynylcarbinols (DACs) is envisaged by formal methinylogation of one of the ethyndiyl moieties of the DAC warhead into the corresponding allenylalkynylcarbinol (AllAC) counterpart. External AllACs were directly obtained by methynylation of the parent DACs with formaldehyde in either the racemic or scalemic series. Isomers containing external progargyl and propynyl motifs were also prepared. Internal AllACs were obtained as racemic statistical mixtures of stereoisomers in two steps from the key C5‐DAC rac‐TIPS‐C≡C‐CH(OH)‐C≡CH and aldehydes. Kinetic resolution of the (S)‐C5‐DAC in 97% ee and (R)‐C5‐DAC in 99% ee, was achieved by sequential lipase‐mediated acetylation/hydrolysis using the Candida antartica lipase (Novozym 435). The four internal AllAC stereoisomers were prepared by Ma's asymmetric methinylation with (R)‐ or (S)‐diphenylprolinol as chiral auxiliary. Cytotoxicity assays on HCT116 cancer cells showed that the most active (eutomeric) external or internal AllAC exhibits a S configuration, a fatty chain length n = 12, and a 50 % inhibitory concentration IC50 ≈ 1.0 µM.

    更新日期:2018-06-22
  • Differentiating antiproliferative and chemopreventive modes of activity for electron‐deficient aryl isothiocyanates against human MCF‐7 cells
    ChemMedChem (IF 3.225) Pub Date : 2018-06-20
    Ruthellen H Anderson; Cody J Lensing; Benjamin J Forred; Michael W Amolins; Cassandra L Aegerter; Peter F Vitiello; Jared R Mays

    Consumption of Brassica vegetables provides beneficial effects due to organic isothiocyanates (ITCs), a resultant product of the enzymatic hydrolysis of glucosinolate secondary metabolites. The ITC L‐sulforaphane (L‐SFN) is the principle agent in broccoli that demonstrates several modes of anticancer action. While the anticancer properties of ITCs like L‐SFN have been extensively studied and L‐SFN has been the subject of multiple human clinical trials, the scope of this work has largely been limited to those derivatives found in nature. Previous studies have demonstrated that structural changes in an ITC can lead to marked differences in a compound's potency to (1) inhibit growth of cancer cells, and (2) alter cellular transcriptional profiles. This study describes the preparation of a library of non‐natural aryl ITCs and the development of a bifurcated screening approach to evaluate the dose‐ and time‐dependence on antiproliferative and chemopreventive properties against human MCF‐7 breast cancer cells. Antiproliferative effects were evaluated using a commercial MTS cell viability assay. Chemopreventive properties were evaluated using an antioxidant response element (ARE)‐promoted luciferase reporter assay. The results of this study have led to the identification of (1) several key structure‐activity relationships and (2) lead ITCs for continued development.

    更新日期:2018-06-22
  • Synthesis and Evaluation of the Anticancer and Trypanocidal Activities of Boronic Tyrphostins
    ChemMedChem (IF 3.225) Pub Date : 2018-06-01
    Noemi de J. Hiller; Nayane A. A. e Silva; Robson X. Faria; André Luís A. Souza; Jackson A. L. C. Resende; André Borges Farias; Nelilma Correia Romeiro; Daniela de Luna Martins
    更新日期:2018-06-20
  • Atomic‐Resolution Structure of a Class C β‐Lactamase and Its Complex with Avibactam
    ChemMedChem (IF 3.225) Pub Date : 2018-05-22
    Cecilia Pozzi; Flavio Di Pisa; Filomena De Luca; Manuela Benvenuti; Jean Denis Docquier; Stefano Mangani
    更新日期:2018-06-20
  • Synthesis and Evaluation of a Series of Bis(pentylpyridinium) Compounds as Antifungal Agents
    ChemMedChem (IF 3.225) Pub Date : 2018-05-20
    Daniel Obando; Yasuko Koda; Namfon Pantarat; Sophie Lev; Xiaoming Zuo; Johanes Bijosono Oei; Fred Widmer; Julianne T. Djordjevic; Tania C. Sorrell; Katrina A. Jolliffe
    更新日期:2018-06-20
  • A Compact and Synthetically Accessible Fluorine‐18 Labelled Cyclooctyne Prosthetic Group for Labelling of Biomolecules by Copper‐free Click Chemistry
    ChemMedChem (IF 3.225) Pub Date : 2018-06-19
    Emily Murrell; Michael S Kovacs; Leonard G Luyt

    A new fluorine‐containing azadibenzocyclooctyne (ADIBO‐F) has been designed using a synthetically accessible pathway. The fluorine‐18 prosthetic group was prepared from its tosylate precursor and isolated in 21‐35% radiochemical yield in 30 minutes. The ADIBO‐F has been incorporated into azide‐functionalized, cancer‐targeting peptides through a strain‐promoted alkyne‐azide cycloaddition with high radiochemical yields and purities. The final products are novel peptide‐based PET imaging agents possessing high affinities to their targets of GHSR‐1a and GRPR with IC50 values of 9.7 and 0.50 nM, respectively. This exhibits a new, rapid labelling option for the incorporation of fluorine‐18 into biomolecules for PET imaging.

    更新日期:2018-06-20
  • Benzofuran and Indole: Promising Scaffolds for Drug Development in Alzheimer's Disease
    ChemMedChem (IF 3.225) Pub Date : 2018-05-09
    Deepti Goyal; Amandeep Kaur; Bhupesh Goyal
    更新日期:2018-06-20
  • 1,2,3‐Triazolium‐based cationic amphipathic peptoid oligomers mimicking antimicrobial helical peptides
    ChemMedChem (IF 3.225) Pub Date : 2018-06-19
    Radhe Shyam; Nicolas Charbonnel; Aurélie Job; Christelle Blavignac; Christiane Forestier; Claude Taillefumier; sophie Faure

    Amphipathic cationic peptoids (N‐substituted glycine oligomers) represent a promising class of antimicrobial peptide mimics. The aim of this study is to explore the potential of the triazolium group as a cationic moiety and helix inducer to develop potent antimicrobial helical peptoids. We report here the first solid‐phase synthesis of peptoid oligomers incorporating 1,2,3‐triazolium‐type side chains, and their evaluation against Escherichia coli, Enterococcus faecalis and Staphylococcus aureus. Several triazolium‐based oligomers, even of short length, selectively kill bacteria over mammalian cells. SEM visualization of S. aureus cells treated with a dodecamer and an hexamer reveals severe cell membrane damages and suggests that the longer oligomer acts by pore formation.

    更新日期:2018-06-20
  • Design and synthesis of pyrophosphate‐targeting vancomycin derivatives for combating vancomycin‐resistant Enterococci
    ChemMedChem (IF 3.225) Pub Date : 2018-06-19
    Dongliang Guan; Feifei Chen; Faridoon Faridoon; Junjie Liu; Jian Li; Lefu Lan; wei huang

    Vancomycin, as the last resort for intractable Gram‐positive bacterial infections, is losing the efficacy with the emergence of vancomycin‐resistant bacteria especially vancomycin‐resistant Enterococci (VRE). To combat this threat, we rationally designed and synthesized 39 novel vancomycin derivatives, via respective or combined modifications with metal‐chelating, lipophilic, and galactose‐attached strategies, for extensive SAR analysis. In a proposed mechanism, the conjugation of dipicolylamine (DPA) on 7th amino acid resorcinol position or C‐terminus endued the vancomycin backbone with the binding activity to pyrophosphate moiety in lipid II while keeping the intrinsic binding affinity to the dipeptide terminus of the bacterial cell wall peptidoglycan precursor. The in vitro antibacterial activities were evaluated and the optimal compounds indicated 16‐1024 fold higher activity against VRE compared with vancomycin. It was also found compound 11b showed the synergistic effect combining two peripheral modification and mechanism especially towards VRE.

    更新日期:2018-06-20
  • Effect of acylation on the antimicrobial activity of temporin B analogues
    ChemMedChem (IF 3.225) Pub Date : 2018-06-19
    Alessandra Romanelli; Concetta Avitabile; Luca Domenico D'Andrea; Elisabetta D'Aversa; Roberta Milani; Roberto Gambari

    New peptides derived from the natural antimicrobial temporin B were obtained. The design, the antimicrobial activity as well as the characterization of the secondary structure of peptides in the presence of bacterial cells is here described. We identified TB_KKG6K (KKLLPIVKNLLKSLL) as the most active analogue against Gram‐positive and Gram‐negative bacteria as compared to natural temporin B (LLPIVGNLLKSLL) and TB_KKG6A (KKLLPIVANLLKSLL). Acylation with hydrophobic moieties led generally to reduced activity, however, acylation at position 6 of TB_KKG6K led to retained submicromolar activity against Staphylococcus epidermidis.

    更新日期:2018-06-20
  • Understanding the rate‐limiting step of glycogenolysis using QM/MM calculations on the human glycogen phosphorylase
    ChemMedChem (IF 3.225) Pub Date : 2018-06-15
    Natercia Bras; Pedro Fernandes; Maria João Ramos

    Liver's glycogen phosphorylase (GP) is a key enzyme to human health, as its increased activity is associated with type 2 diabetes. The GP catalytic mechanism has been explored by quantum mechanics/molecular mechanics methods. Herein, we propose a mechanism that proceeds via three steps: i) it begins with a H transfer from the phosphate group of the pyridoxal 5'‐phosphate (HPO42‐‐PLP) cofactor to the phosphate substrate; ii) then, the glycosidic linkage is cleaved through protonation of the glycosidic oxygen atom by an hydroxyl of the inorganic phosphate group; and iii) an oxygen atom of the phosphate performs a nucleophilic attack on the anomeric carbon of glucose, concomitantly with the return of a proton from phosphate to PO43‐‐PLP, which finally leads to the formation of the glucose‐1‐phosphate product and recovers the initial state of the PLP cofactor. The glycosidic bond cleavage and the nucleophilic attack from the phosphate group to the glycosyl molecule have the highest activation free energies. The structural properties of the hereby characterized transition states could be very useful to structure‐based drug design studies against the liver GP.

    更新日期:2018-06-16
  • Dual‐Responsive Carbon Dot for pH/Redox‐Triggered Fluorescence Imaging with Controllable Photothermal Ablation Therapy of Cancer
    ChemMedChem (IF 3.225) Pub Date : 2018-05-18
    Cheong A. Choi; Jung Eun Lee; Zihnil Adha Islamy Mazrad; Young Kwang Kim; Insik In; Ji Hoon Jeong; Sung Young Park
    更新日期:2018-06-14
  • Bis‐Cyclic Guanidines as a Novel Class of Compounds Potent against Clostridium difficile
    ChemMedChem (IF 3.225) Pub Date : 2018-06-14
    Chunhui Li; Peng Teng; Zhong Peng; Peng Sang; Xingmin Sun; Jianfeng Cai
    更新日期:2018-06-14
  • Design, Synthesis, and Biological Evaluation of Tetrahydro‐β‐carboline Derivatives as Selective Sub‐Nanomolar Gelatinase Inhibitors
    ChemMedChem (IF 3.225) Pub Date : 2018-06-12
    Giuseppe Felice Mangiatordi; Tatiana Guzzo; Eugenio Claudio Rossano; Daniela Trisciuzzi; Domenico Alberga; Giovanni Fasciglione; Massimiliano Coletta; Alessandra Topai; Orazio Nicolotti
    更新日期:2018-06-12
  • Targeting of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Protein with a Technetium‐99m Imaging Probe
    ChemMedChem (IF 3.225) Pub Date : 2018-06-04
    Vera F. C. Ferreira; Bruno L. Oliveira; João D. Santos; João D. G. Correia; Carlos M. Farinha; Filipa Mendes
    更新日期:2018-06-12
  • Modeling the Accumulation of Degradable Polymer Drug Carriers in the Brain
    ChemMedChem (IF 3.225) Pub Date : 2018-05-11
    Celine Bolwerk; Larissa P. M. W. D. Govers; Hanna Knol; Thom F. Oostendorp; Roland Brock
    更新日期:2018-06-12
  • Chiral Cliffs: Investigating the Influence of Chirality on Binding Affinity
    ChemMedChem (IF 3.225) Pub Date : 2018-05-11
    Nadine Schneider; Richard A. Lewis; Nikolas Fechner; Peter Ertl
    更新日期:2018-06-12
  • Design, Synthesis, Biological Activity and Structural Analysis of lactam‐constrained PTPRJ agonist peptides
    ChemMedChem (IF 3.225) Pub Date : 2018-06-11
    Marina Sala; Antonia Spensiero; Maria Carmina Scala; Giacomo Pepe; Anna Bilotta; Francesco Paduano; Sabrina D'Agostino; Delia Lanzillotta; Alessia Bertamino; Ettore Novellino; Francesco Trapasso; Isabel Maria Gomez-Monterrey; Pietro Campiglia

    PTPRJ is a receptor‐like protein tyrosine phosphatase mainly known for its antiproliferative and tumor‐suppressive functions. PTPRJ dephosphorylates several growth factors and their receptors, negatively regulating cell proliferation and migration. We have recently identified a disulfide bridged nonapeptide, named PTPRJ‐19 (H‐[Cys‐His‐His‐Asn‐Leu‐Thr‐His‐Ala‐Cys]‐OH), which activates PTPRJ causing cell growth inhibition and apoptosis of both cancer and endothelial cells. In the present study, we have synthesized seven analogues of PTPRJ‐19 in which the disulfide bridge was replaced by the side‐chain to side‐chain lactam bridge. This replacement led to active analogues.

    更新日期:2018-06-12
  • Development of potent pyrazolopyrimidinone‐based WEE1 inhibitors with limited single‐agent cytotoxicity for cancer therapy
    ChemMedChem (IF 3.225) Pub Date : 2018-06-08
    Christopher J Matheson; Kimberly A Casalvieri; Donald S Backos; Philip Reigan

    WEE1 kinase regulates the G2‐M cell‐cycle checkpoint, a critical mechanism for DNA repair in cancer cells that can confer resistance to DNA‐damaging agents. We previously reported a series of pyrazolopyrimidinones based on AZD1775, a known WEE1 inhibitor, as an initial investigation into the structural requirements for WEE1 inhibition. Our lead inhibitor demonstrated WEE1 inhibition in the same nanomolar range as AZD1775, and potentiated the effects of cisplatin in medulloblastoma cells, but had reduced single‐agent cytotoxicity. These results prompted the development of a more comprehensive series of WEE1 inhibitors. Here, we report a series of pyrazolopyrimidinones and identify a more potent WEE1 inhibitor than AZD1775 and additional compounds that demonstrate that WEE1 inhibition can be achieved with reduced single‐agent cytotoxicity. These studies support that WEE1 inhibition can be uncoupled from the potent cytotoxic effects observed with AZD1775, and this may have important ramifications in the clinical setting where WEE1 inhibitors are used as chemosensitizers for DNA‐targeted chemotherapy.

    更新日期:2018-06-09
  • Development of novel inhibitors for histone methyltransferase SET7/9 based on cyproheptadine
    ChemMedChem (IF 3.225) Pub Date : 2018-06-07
    Tomoya Hirano; Takashi Fujiwara; Hideaki Niwa; Michitake Hirano; Kasumi Ohira; Yusuke Okazaki; Shin Sato; Takashi Umehara; Yuki Maemoto; Akihiro Ito; Minoru Yoshida; Hiroyuki Kagechika

    The histone methyltransferase SET7/9 methylates not only histone but also non‐histone proteins as substrates, and therefore SET7/9 inhibitors are considered candidates for treatment of diseases. Previously, our group identified cyproheptadine, which is used clinically as a serotonin receptor antagonist or histamine receptor (H1) antagonist, as a novel scaffold of SET7/9 inhibitor. In this work, we focused on dibenzosuberene as a substructure of cyproheptadine, and synthesized derivatives with various functional groups. Among them, compound bearing a 2‐hydroxy group showed the most potent activity. On the other hand, a 3‐hydroxy group or other hydrophilic functional groups such as acetamide decreased the activity. Structural analysis clarified a rationale for the improved potency only by tightly restricted location and type of hydrophilic group. In addition, a SET7/9 loop, which was only partially visible in the complex with cyproheptadine, became more clearly visible in that with 2‐hydroxycyproheptadine. These results are expected to be helpful for further structure‐based development of SET7/9 inhibitors.

    更新日期:2018-06-08
  • Expanding the SAR of Nontoxic Antiplasmodial Indolyl‐3‐ethanone Ethers and Thioethers
    ChemMedChem (IF 3.225) Pub Date : 2018-05-13
    Mayibongwe J. Lunga; Ruramai L. Chisango; Carli Weyers; Michelle Isaacs; Dale Taylor; Adrienne L. Edkins; Setshaba D. Khanye; Heinrich C. Hoppe; Clinton G. L. Veale
    更新日期:2018-06-07
  • Deciphering specificity determinants for FR900359‐derived Gαq inhibitors based on computational and structure‐activity studies
    ChemMedChem (IF 3.225) Pub Date : 2018-06-06
    Diana Imhof; Raphael Reher; Toni Kühl; Suvi Annala; Tobias Benkel; Desiree Kaufmann; Britta Nubbemeyer; Justin P. Odhiambo; Pascal Heimer; Charlotte A. Bäuml; Stefan Kehraus; Max Crüsemann; Evi Kostenis; Daniel Tietze; Gabriele M. König

    Direct targeting of intracellular Gα subunits of G protein‐coupled receptors by chemical tools represents a challenging task in both, current pharmacological studies and developing novel therapeutic approaches. Here we analyzed novel FR900359‐based analogs from natural sources, synthetic cyclic peptides as well as all so‐far known Gαq inhibitors in a comprehensive study to devise a strategy for the elucidation of characteristics that determine interaction with and inhibition of Gq in the specific FR/YM binding pocket. Using 2D NMR spectroscopy and molecular docking we have identified unique features in the macrocyclic structures responsible for binding to the target protein correlating with inhibitory activity. While all novel compounds were devoid of effects on Gi and Gs proteins, no inhibitor surpassed biological activity of FR. This raises the question of whether depsipeptides such as FR already represent valuable chemical tools for specific inhibition of Gq and, at the same time, are suitable natural lead structures for the development of novel compounds to target Gα subunits other than Gq.

    更新日期:2018-06-07
  • Targeted Delivery of DNA‐Au Nanoparticles across the Blood–Brain Barrier Using Focused Ultrasound
    ChemMedChem (IF 3.225) Pub Date : 2018-05-09
    Tiffany G. Chan; Sophie V. Morse; Matthew J. Copping; James J. Choi; Ramon Vilar
    更新日期:2018-06-06
  • Targeting Serotonin 2A and Adrenergic α1 Receptors for Ocular Antihypertensive Agents: Discovery of 3,4‐Dihydropyrazino[1,2‐b]indazol‐1(2H)‐one Derivatives
    ChemMedChem (IF 3.225) Pub Date : 2018-06-06
    Guido Furlotti; Maria Alessandra Alisi; Nicola Cazzolla; Beatrice Garrone; Gabriele Magarò; Giorgina Mangano; Marco Vitiello; Francesca Ceccacci; Tecla Gasperi; Angela La Bella; Francesca Leonelli; Maria Antonietta Loreto; Emanuela Masini; Rinaldo Marini Bettolo; Martina Miceli; Luisa Maria Migneco

    Glaucoma affects millions of people worldwide, causing optic nerve damage and blindness. The elevation of the intraocular pressure (IOP) is the main risk factor associated with this pathology, and nowadays, the key therapeutic target of the existing pharmacological treatments. We studied, as potential ocular hypotensive agents, compounds acting on two receptors (serotonin 2A, 5‐HT2A, and adrenergic α1) linked to the regulation of the humour aqueous dynamic. In this article we describe the design, synthesis, and pharmacological profiling of a series of novel bicyclic and tricyclic 2N‐alkyl‐indazole‐amide derivatives. The work brought to the identification of compound 28, a 3,4‐dihydropyrazino[1,2‐b]indazol‐1(2H)‐one derivative, with potent 5‐HT2A antagonism, >100 fold selectivity over other serotonin subtype receptors and high affinity for the α1 receptor. Moreover, when administered locally, 28 showed superior ocular hypotensive action in vivo, compared to the clinically used reference compound timolol.

    更新日期:2018-06-06
  • Structure‐Activity Relationship Studies on (R)‐PFI‐2 Analogs as Inhibitors of Histone Lysine Methyltransferase SETD7
    ChemMedChem (IF 3.225) Pub Date : 2018-06-05
    Danny C Lenstra; Eddy Damen; Ruben G. G. Leenders; Richard H. Blaauw; Floris P. J. T. Rutjes; Anita Wegert; Jasmin Mecinovic

    SETD7 is a histone H3K4 lysine methyltransferase involved in human gene regulation. Aberrant expression of SETD7 has been associated with various diseases, including cancer, therefore SETD7 is considered as a target for the development of new epigenetic drugs. To date, few selective small molecule inhibitors have been reported that target SETD7, the most potent being (R)‐PFI‐2. Here we report structure‐activity relationship studies on (R)‐PFI‐2 and its analogs. A library of 29 structural analogs of (R)‐PFI‐2 was synthesized and evaluated for inhibition of recombinantly expressed human SETD7. The key interaction was found to be a salt‐bridge formed between (R)‐PFI‐2's NH2+ and SETD7's Asp256.

    更新日期:2018-06-05
  • Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure Degradation Relationships
    ChemMedChem (IF 3.225) Pub Date : 2018-06-05
    George M Burslem; Philipp Ottis; Saul Jaime-Figueroa; Alicia Morgan; Philipp Cromm; Momar Toure; Craig Crews

    The Immunomodulatory Drugs (IMiDs) Thalidomide, Pomalidomide and Lenalidomide have been approved for the treatment of multiple myeloma for many years. Recently, their usage as E3 ligase recruiting elements for small molecule induced protein degradation has led to a resurgence in interest in ImiD synthesis and functionalization. Traditional ImiD synthesis follows a step‐wise route employing multiple purification steps. Herein, we describe a novel one‐pot synthesis without purification giving rapid access to a multitude of IMiD analogues. Binding studies with the IMiD target protein Cereblon (CRBN) reveals a narrow SAR with only a few compounds showing sub‐micromolar binding affinity in the range of Pomalidomide and Lenalidomide. However, anti‐proliferative activity as well as Aiolos degradation could be identified for two ImiD analogues. This study provides useful insight into the structure degradation relationships for molecules of this type as well as a rapid and robust method for IMiD synthesis.

    更新日期:2018-06-05
  • Cyclic Hexapeptide Mimics of the LEDGF Integrase Recognition Loop in Complex with HIV‐1 Integrase
    ChemMedChem (IF 3.225) Pub Date : 2018-06-04
    Susan Northfield; Jerome Wielens; Stephen Headey; Billy Williams-Noonan; Mark Mulcair; Martin Scanlon; Michael Parker; Philip Thompson; David Chalmers

    The p75 splice variant of lens epithelium‐derived growth factor (LEDGF) is a 75 kDa protein that is recruited by the human immunodeficiency virus (HIV) to tether the pre‐integration complex to the host chromatin and promote integration of proviral DNA into the host genome. We have designed a series of small cyclic peptides that are structural mimics of the LEDGF binding domain, which interact with integrase as potential binding inhibitors. Here we present the X‐ray crystal structures, NMR studies, SPR analysis and conformational studies of four cyclic peptides bound to the HIV‐1 integrase core domain. Although the X‐ray studies show that the peptides closely mimic the LEDGF binding loop, the measured affinities of the peptides are in the low mM range. Computational analysis using conformational searching and free energy calculations suggest that the low affinity of the peptides is due to mismatch between the low‐energy solution and bound conformations.

    更新日期:2018-06-04
  • Recent advances in the development of indazole based anti‐cancer agents
    ChemMedChem (IF 3.225) Pub Date : 2018-06-04
    Shaoshun Li; Jinyun Dong; Qijing Zhang; Zengtao Wang; Guang Huang

    Cancer is one of the leading causes of human mortality globally, and thus intensive efforts have been made to seek new active drugs with improved anti‐cancer efficiency. Indazole‐containing derivatives endow with a broad range of biological properties including anti‐inflammatory, anti‐microbial, anti‐HIV, anti‐hypertensive and anti‐cancer activities. In recent years, the development of anti‐cancer drugs have given rise to a wide range of indazole derivatives, and some of which exhibit outstanding activity against different tumors. The aim of this review is to outline the recent developments concerning the anti‐cancer activity of indazole derivatives as well as summarize the design strategies and structure‐activity relationships of these compounds.

    更新日期:2018-06-04
  • A DNA‐Encoded Library of Chemical Compounds Based on Common Scaffolding Structures Reveals the Impact of Ligand Geometry on Protein Recognition
    ChemMedChem (IF 3.225) Pub Date : 2018-06-01
    Nicholas Favalli; Stefan Biendl; Marco Hartmann; Jacopo Piazzi; Filippo Sladojevich; Susanne Gräslund; Peter J. Brown; Katja Näreoja; Herwig Schüler; Jörg Scheuermann; Raphael Franzini; Dario Neri
    更新日期:2018-06-01
  • Identification of Broad‐Spectrum Dengue/Zika Virus Replication Inhibitors by Functionalization of Quinoline and 2,6‐Diaminopurine Scaffolds
    ChemMedChem (IF 3.225) Pub Date : 2018-05-09
    Suzanne J. F. Kaptein; Paolo Vincetti; Emmanuele Crespan; Jorge I. Armijos Rivera; Gabriele Costantino; Giovanni Maga; Johan Neyts; Marco Radi
    更新日期:2018-06-01
  • PET imaging of T cells: Target identification and feasibility assessment
    ChemMedChem (IF 3.225) Pub Date : 2018-06-01
    Yves P. Auberson; Emmanuelle Briard; Bettina Rudolph; Klemen Kaupmann; Paul Smith; Berndt Oberhauser

    Imaging T cells using positron emission tomography (PET) would be highly useful for diagnosis and monitoring in immunology and oncology patients. There are however no obvious targets that can be used to develop imaging agents for this purpose. We evaluated several potential target proteins with selective expression in T cells, and for which lead molecules were available: PKC , Lck, ZAP70 and Itk. Ultimately, we focused on Itk (interleukin‐2‐inducible T cell kinase) and identified a tool molecule with properties suitable for in vivo imaging of T cells, (5aR)‐5,5‐difluoro‐5a‐methyl‐N‐(1‐((S)‐3‐(methylsulfonyl)‐phenyl)(tetrahydro‐2H‐pyran‐4‐yl)methyl)‐1H‐pyrazol‐4‐yl)‐1,4,4a,5,5a,6‐hexahydro‐cyclopropa[f]‐indazole‐3‐carboxamide (23). While not having the optimal profile for clinical use, this molecule indicates that it might be possible to develop Itk‐selective PET ligands for imaging the distribution of T cells in patients.

    更新日期:2018-06-01
  • 更新日期:2018-05-31
  • Fragment‐Based Phenotypic Lead Discovery: Cell‐Based Assay to Target Leishmaniasis
    ChemMedChem (IF 3.225) Pub Date : 2018-05-02
    Yann Ayotte; François Bilodeau; Albert Descoteaux; Steven R. LaPlante
    更新日期:2018-05-31
  • Design, Synthesis, and in vitro Biological Evaluation of 3,5‐Dimethylisoxazole Derivatives as BRD4 Inhibitors
    ChemMedChem (IF 3.225) Pub Date : 2018-05-29
    Xiangyang Li; Jian Zhang; Leilei Zhao; Yifei Yang; Huibin Zhang; Jinpei Zhou
    更新日期:2018-05-29
  • 更新日期:2018-05-29
  • Identification of Potentially Potent Heme Oxygenase 1 Inhibitors through 3D‐QSAR Coupled to Scaffold‐Hopping Analysis
    ChemMedChem (IF 3.225) Pub Date : 2018-04-25
    Giuseppe Floresta; Emanuele Amata; Maria Dichiara; Agostino Marrazzo; Loredana Salerno; Giuseppe Romeo; Orazio Prezzavento; Valeria Pittalà; Antonio Rescifina
    更新日期:2018-05-29
  • Designing Anticancer Peptides by Constructive Machine Learning
    ChemMedChem (IF 3.225) Pub Date : 2018-04-21
    Francesca Grisoni; Claudia S. Neuhaus; Gisela Gabernet; Alex T. Müller; Jan A. Hiss; Gisbert Schneider
    更新日期:2018-05-29
  • Development of an Efficient Dual‐Action GST‐Inhibiting Anticancer Platinum(IV) Prodrug
    ChemMedChem (IF 3.225) Pub Date : 2018-04-10
    Keefe Guang Zhi Lee; Maria V. Babak; Andrea Weiss; Paul J. Dyson; Patrycja Nowak‐Sliwinska; Diego Montagner; Wee Han Ang
    更新日期:2018-05-29
  • Synthesis, crystallization studies and in vitro characterization of novel cinnamic acid derivatives as SmHDAC8 inhibitors for the treatment of Schistosomiasis
    ChemMedChem (IF 3.225) Pub Date : 2018-05-27
    Theresa Bayer; Alokta Chakrabarti; Julien Lancelot; Tajith B. Shaik; Kristin Hausmann; Jelena Melesina; Karin Schmidtkunz; Martin Marek; Frank Erdmann; Matthias Schmidt; Dina Robaa; Christophe Romier; Raymond J. Pierce; Manfred Jung; Wolfgang Sippl

    Schistosomiasis is a neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy relies on mass treatment with only one drug, praziquantel. Based on the 3‐chlorobenzothiophene‐2‐hydroxamic acid J1075, a series of hydroxamic acids with different scaffolds was prepared as potential inhibitors of Schistosoma mansoni histone deacetylase 8 (SmHDAC8). The crystal structures of SmHDAC8 with four inhibitors provided insights into the binding mode and orientation of molecules in the binding pocket as well as the orientation of its flexible amino acid residues. The compounds were evaluated in screenings for inhibitory activity against schistosome and human HDACs. The most promising compounds were further investigated for their activity toward the major human HDAC isotypes. The most potent inhibitors were additionally screened for lethality against the schistosome larval stage using a fluorescence‐based assay. Two of the compounds showed significant, dose‐dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture.

    更新日期:2018-05-29
  • Synthesis and pharmacological evaluation of enantiomerically pure GluN2B selective NMDA receptor antagonists
    ChemMedChem (IF 3.225) Pub Date : 2018-05-27
    Bernhard Wünsch; Frederik Börgel; Marina Szermerski; Julian A. Schreiber; Louisa Temme; Nathalie Strutz-Seebohm; Kirstin Lehmkuhl; Dirk Schepmann; Simon M. Ametamey; Guiscard Seebohm; Thomas J. Schmidt

    In order to determine the eutomers of potent GluN2B selective NMDA receptor antagonists with 3‐benzazepine scaffold, benzyl ethers (S)‐2 and (R)‐2 were separated by chiral HPLC. Hydrogenolysis and subsequent methylation of the enantiomerically pure benzyl ethers (S)‐2 and (R)‐2 provided the enantiomeric phenols (S)‐3 and (R)‐3 and methyl ethers (S)‐4 and (R)‐4. All enantiomers were obtained with high enantiomeric purity (ee ≥ 99.7 %). The absolute configuration was determined by CD‐spectroscopy. (R)‐configured enantiomers turned out to be the eutomers in receptor binding studies and two‐electrode voltage clamp experiments. The most promising ligand of this series of compounds is the (R)‐configured phenol (R)‐3 displaying high GluN2B affinity (Ki = 30 nM), high inhibition of ion flux (IC50 = 61 nM) and high cytoprotective activity (IC50 = 93 ± 39 nM). Whereas the eudismic ratio in the receptor binding assay is 25, the eudismic ratio in the electrophysiological experiment is 3.

    更新日期:2018-05-29
  • A new class of 1‐aryl‐5,6‐dihydropyrrolo[2,1‐a]isoquinoline derivatives as reversers of P‐glycoprotein‐mediated multidrug resistance in tumor cells
    ChemMedChem (IF 3.225) Pub Date : 2018-05-26
    Cosimo Damiano Altomare; Alisa A. Nevskaya; Maria D. Matveeva; Tatiana N. Borisova; Mauro Niso; Nicola Antonio Colabufo; Angelina Boccarelli; Rosa Purgatorio; Modesto de Candia; Saverio Cellamare; Leonid G. Voskressensky

    A number of aza‐heterocyclic compounds, which share with members of the lamellarin alkaloids' family the 5,6‐dihydropyrrolo[2,1‐a]isoquinoline (DHPIQ) scaffold, were synthesized and evaluated for their ability to reverse in vitro multidrug resistance (MDR) in cancer cells, through inhibition of P‐glycoprotein (P‐gp) and/or multidrug‐resistance‐associated protein‐1 (MRP‐1). Most of the investigated DHPIQs proved to be selective P‐gp modulators, and the most potent ones, which are 2‐carbaldehydes (3 and 4) or a thiosemicarbazone derivative (10), attained submicromolar inhibition potencies (average IC50s of 0.24, 0.19 and 0.24 µM, respectively). Schiff bases prepared by condensation of some 1‐aryl‐DHPIQ aldehydes with p‐aminophenol also proved to be of some interest, compound 15 displaying IC50 of 1.01 µM. In drug combination assays in multidrug‐resistant cells, some DHPIQ compounds, at non‐toxic doses, significantly increased the cytotoxicity of doxorubicin in a concentration‐dependent manner. Structure‐activity relationship studies and investigation of the chemical stability of the Schiff bases provided physicochemical information useful for molecular optimization of lamellarin‐like cytotoxic drugs active toward chemoresistant tumors as well as non‐toxic reversers of P‐gp‐mediated MDR in tumor cells.

    更新日期:2018-05-27
  • 更新日期:2018-05-24
  • Fully Automated Production and Characterization of 64Cu and Proof‐of‐Principle Small‐Animal PET Imaging Using 64Cu‐Labelled CA XII Targeting 6A10 Fab
    ChemMedChem (IF 3.225) Pub Date : 2018-04-18
    Luise Fiedler; Markus Kellner; Rosel Oos; Guido Böning; Sibylle Ziegler; Peter Bartenstein; Reinhard Zeidler; Franz Josef Gildehaus; Simon Lindner
    更新日期:2018-05-24
  • Synthesis and Biological Evaluation of Indole‐2‐carbohydrazide Derivatives as Anticancer Agents with Anti‐angiogenic and Antiproliferative Activities
    ChemMedChem (IF 3.225) Pub Date : 2018-04-10
    Jianqiang Zhang; Tongyang Liu; Mei Chen; Feifei Liu; Xingyuan Liu; Jihong Zhang; Jun Lin; Yi Jin
    更新日期:2018-05-24
  • 更新日期:2018-05-24
  • Synthesis and Biological Evaluation of 4‐Sulfamoylphenyl/Sulfocoumarin Carboxamides as Selective Inhibitors of Carbonic Anhydrase Isoforms hCA II, IX, and XII
    ChemMedChem (IF 3.225) Pub Date : 2018-04-19
    Srinivas Angapelly; Andrea Angeli; Arbaj Jabbar Khan; P. V. Sri Ramya; Claudiu T. Supuran; Mohammed Arifuddin
    更新日期:2018-05-22
  • Antichagasic, Leishmanicidal, and Trichomonacidal Activity of 2‐Benzyl‐5‐nitroindazole‐Derived Amines
    ChemMedChem (IF 3.225) Pub Date : 2018-04-06
    Cristina Fonseca‐Berzal; Alexandra Ibáñez‐Escribano; Nerea Vela; José Cumella; Juan José Nogal‐Ruiz; José Antonio Escario; Patrícia Bernardino da Silva; Marcos Meuser Batista; Maria de Nazaré C. Soeiro; Sergio Sifontes‐Rodríguez; Alfredo Meneses‐Marcel; Alicia Gómez‐Barrio; Vicente J. Arán
    更新日期:2018-05-22
  • Virtual Fragment Screening Identification of a Quinoline‐5,8‐dicarboxylic Acid Derivative as a Selective JMJD3 Inhibitor
    ChemMedChem (IF 3.225) Pub Date : 2018-04-06
    Assunta Giordano; Federica del Gaudio; Catrine Johansson; Raffaele Riccio; Udo Oppermann; Simone Di Micco
    更新日期:2018-05-22
  • Alkynylnicotinamide‐Based Compounds as ABL1 Inhibitors with Potent Activities against Drug‐Resistant CML Harboring ABL1(T315I) Mutant Kinase
    ChemMedChem (IF 3.225) Pub Date : 2018-04-02
    Elizabeth A. Larocque; N. Naganna; Clement Opoku‐Temeng; Alyssa M. Lambrecht; Herman O. Sintim
    更新日期:2018-05-22
  • 更新日期:2018-05-18
  • Cytotoxic Activity and Structure–Activity Relationship of Triazole‐Containing Bis(Aryl Ether) Macrocycles
    ChemMedChem (IF 3.225) Pub Date : 2018-05-17
    Eduardo Hernández‐Vázquez; Alejandra Chávez‐Riveros; Adriana Romo‐Pérez; María Teresa Ramírez‐Apán; Alma D. Chávez‐Blanco; Rocío Morales‐Bárcenas; Alfonso Dueñas‐González; Luis D. Miranda
    更新日期:2018-05-17
  • Dichlorophenylacrylonitriles as AhR Ligands displaying selective breast cancer cytotoxicity in vitro
    ChemMedChem (IF 3.225) Pub Date : 2018-05-17
    Jennifer R Baker; Jayne Gilbert; Stefan Paula; Xiao Zhu; Jennette A Sakoff; Adam McCluskey

    Knoevenagel condensation of 3,4‐dichloro‐ and 2,6‐dichloro‐ phenylacetonitriles gave a library of dichlorophenylacrylonitriles. Our leads 5 and 6 displayed 0.56±0.03 and 0.127±0.04 μM growth inhibition (GI₅₀) and 260‐fold selectivity for the MCF‐7 breast cancer cell line. A 2,6‐dichlorophenyl moiety saw a 10‐fold potency loss; additional nitrogen moieties (‐NO₂) enhanced activity (26 and 27), with the corresponding ‐NH₂ analogues (29 and 30) more potent. Despite this, both 29 (2.8±0.03 μM) and 30 (2.8±0.03 μM) were 10‐fold less cytotoxic than 6. A bromine moiety effected a 3‐fold enhancement in solubility with 18 relative to 5 at 211 μg mL‐1. Modelling led synthesis saw the introduction of 4‐aminophenyl substituent gave 35 and 38, 0.030±0.014 and 0.034±0.01 μM potent, respectively. Other analogues, e.g. 35 and 36, were sub‐micromolar potent against our cell line panel (HT29, colon; U87 and SJ‐G2, glioblastoma; A2780, ovarian; H460, lung; A431, skin; Du145, prostate; BE2‐C neuroblastoma; MIA, pancreas and SMA murine glioblastoma) except 35 against U87. A more extensive evaluation of 38 ((Z)‐N‐(4‐(2‐cyano‐2‐(3,4‐dichlorophenyl)vinyl)phenyl)acetamide), in a panel of drug resistant breast carcinoma cell lines showed 10‐206 nM potency against MDAMB468, T47D, ZR‐75‐1, SKBR3 and BT474. MOE docking scores showed a good correlation between predicted binding efficiencies and observed MCF‐7 cytotoxicity. This supports the use of this model in developing breast cancer specific drugs.

    更新日期:2018-05-17
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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