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  Subjects -> CHEMISTRY (Total: 838 journals)
    - ANALYTICAL CHEMISTRY (48 journals)
    - CHEMISTRY (587 journals)
    - CRYSTALLOGRAPHY (22 journals)
    - ELECTROCHEMISTRY (26 journals)
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CHEMISTRY (587 journals)                  1 2 3 4 5 6 | Last

2D Materials     Hybrid Journal   (Followers: 5)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 32)
ACS Catalysis     Full-text available via subscription   (Followers: 28)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 15)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 10)
ACS Macro Letters     Full-text available via subscription   (Followers: 20)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 25)
ACS Nano     Full-text available via subscription   (Followers: 203)
ACS Photonics     Full-text available via subscription   (Followers: 6)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 11)
Acta Chemica Iasi     Open Access  
Acta Chimica Sinica     Full-text available via subscription  
Acta Chimica Slovaca     Open Access   (Followers: 6)
Acta Chromatographica     Full-text available via subscription   (Followers: 10)
Acta Facultatis Medicae Naissensis     Open Access   (Followers: 1)
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 5)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 4)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 5)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 11)
Advanced Functional Materials     Hybrid Journal   (Followers: 40)
Advanced Science Focus     Free   (Followers: 1)
Advances in Chemical Engineering and Science     Open Access   (Followers: 23)
Advances in Chemical Science     Open Access   (Followers: 9)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 15)
Advances in Drug Research     Full-text available via subscription   (Followers: 18)
Advances in Enzyme Research     Open Access  
Advances in Fluorine Science     Full-text available via subscription   (Followers: 7)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 13)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 16)
Advances in Nanoparticles     Open Access   (Followers: 12)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 9)
Advances in Polymer Science     Hybrid Journal   (Followers: 39)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 10)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
African Journal of Chemical Education     Open Access   (Followers: 1)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 5)
Afrique Science : Revue Internationale des Sciences et Technologie     Open Access   (Followers: 1)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 1)
Alchemy     Open Access   (Followers: 3)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 5)
AMB Express     Open Access  
Ambix     Hybrid Journal   (Followers: 2)
American Journal of Applied Sciences     Open Access   (Followers: 30)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 86)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 12)
American Journal of Chemistry     Open Access   (Followers: 19)
American Journal of Plant Physiology     Open Access   (Followers: 10)
American Mineralogist     Full-text available via subscription   (Followers: 7)
Analyst     Full-text available via subscription   (Followers: 38)
Angewandte Chemie     Hybrid Journal   (Followers: 20)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 142)
Annales UMCS, Chemia     Open Access   (Followers: 2)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 1)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 2)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 6)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 11)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 11)
Anti-Infective Agents     Hybrid Journal   (Followers: 1)
Antiviral Chemistry and Chemotherapy     Full-text available via subscription  
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 4)
Applied Spectroscopy     Full-text available via subscription   (Followers: 13)
Applied Surface Science     Hybrid Journal   (Followers: 23)
Arabian Journal of Chemistry     Full-text available via subscription   (Followers: 6)
ARKIVOC     Open Access   (Followers: 1)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 4)
Autophagy     Full-text available via subscription   (Followers: 2)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 6)
Biochemistry     Full-text available via subscription   (Followers: 141)
Biochemistry Insights     Open Access   (Followers: 4)
Biochemistry Research International     Open Access   (Followers: 4)
BioChip Journal     Hybrid Journal   (Followers: 1)
Bioinorganic Chemistry and Applications     Open Access   (Followers: 4)
Bioinspired Materials     Open Access  
Biointerface Research in Applied Chemistry     Open Access   (Followers: 1)
Biointerphases     Open Access  
Biomacromolecules     Full-text available via subscription   (Followers: 17)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 6)
Biomedical Chromatography     Hybrid Journal   (Followers: 7)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 2)
BioNanoScience     Partially Free   (Followers: 4)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 30)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 24)
Bioorganic Chemistry     Hybrid Journal   (Followers: 5)
Biopolymers     Hybrid Journal   (Followers: 14)
Biosensors     Open Access   (Followers: 3)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 3)
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 2)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 13)
C - Journal of Carbon Research     Open Access  
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 3)
Canadian Journal of Chemistry     Full-text available via subscription   (Followers: 6)
Canadian Mineralogist     Full-text available via subscription   (Followers: 1)
Carbohydrate Research     Hybrid Journal   (Followers: 11)
Carbon     Hybrid Journal   (Followers: 55)
Catalysis for Sustainable Energy     Open Access   (Followers: 2)

        1 2 3 4 5 6 | Last

Journal Cover   Bioorganic & Medicinal Chemistry
  [30 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0968-0896
   Published by Elsevier Homepage  [2811 journals]
  • PABA/NO lead optimization: Improved targeting of cytotoxicity to
           glutathione S-transferase P1-overexpressing cancer cells
    • Abstract: Publication date: Available online 19 May 2015
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Youseung Kim , Anna E. Maciag , Zhao Cao , Jeffrey R. Deschamps , Joseph E. Saavedra , Larry K. Keefer , Ryan J. Holland
      PABA/NO [O 2-{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino) diazen-1-ium-1,2-diolate] is a nitric oxide (NO)-releasing arylating agent designed to be selectively activated by reaction with glutathione (GSH) on catalysis by glutathione S-transferase P1 (GSTP1), an enzyme frequently overexpressed in cancer cells. PABA/NO has proven active in several cancer models in vitro and in vivo, but its tendency to be metabolized via a variety of pathways, some that generate inactive metabolites and hydrolysis products, limits its potential as a drug. Here we show that a simple replacement of cyano for nitro at the 4 position to give compound 4b (“p-Cyano-PABA/NO”) has the dual effect of slowing the undesired side reactions while enhancing the proportion of NO release and arylating activity on catalysis by GSTP1. Compound 4b showed increased resistance to hydrolysis and uncatalyzed reaction with GSH, along with a more favorable product distribution in the presence of GSTP1. It also showed significant proapoptotic activity. The data suggest p-Cyano-PABA/NO to be a more promising prodrug than PABA/NO, with better selectivity towards cancer cells.
      Graphical abstract image

      PubDate: 2015-05-20T06:26:18Z
       
  • Design and Synthesis of benzothiazole-6-sulfonamides acting as highly
           potent inhibitors of carbonic anhydrase isoforms I, II, IX and XII
    • Abstract: Publication date: Available online 19 May 2015
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Diaa A. Ibrahim , Deena S. Lasheen , Maysoun Y. Zaky , Amany W. Ibrahim , Daniela Vullo , Mariangela Ceruso , Claudiu T. Supuran , Dalal A. Abou El Ella
      A series of novel 2-aminobenzothiazole derivatives bearing sulfonamide at position 6 was designed, synthesized and investigated as inhibitors of four isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), the cytosolic CA I and II, and the tumor-associated isozymes CA IX and XII. Docking and binding energy studies were carried out to reveal details regarding the favorable interactions between the scaffolds of these new inhibitors and the active sites of the investigated CA isoforms. Most of the novel compounds were acting as highly potent inhibitors of the tumor-associated hCA IX and hCA XII with KIs in the nanomolar range. The ubiquitous and dominant rapid cytosolic isozyme hCA II was also inhibited with KIs ranging from 3.5 to 45.4 nM. The favorable interactions between some of the new compounds and the active site of different CA isoforms were delineated by using molecular docking which may be useful for designing compounds with high affinity and selectivity for some CAs with biomedical applications.
      Graphical abstract image

      PubDate: 2015-05-20T06:26:18Z
       
  • Discovery and structural analyses of S-adenosyl-L-homocysteine hydrolase
           inhibitors based on non-adenosine analogs
    • Abstract: Publication date: Available online 19 May 2015
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Akira Nakao , Hiroko Suzuki , Hiroaki Ueno , Hiroshi Iwasaki , Tomofumi Setsuta , Akiko Kashima , Shinji Sunada
      Optimization of a new series of S-adenosyl-L-homocysteine hydrolase (AdoHcyase) inhibitors based on non-adenosine analogs led to very potent compounds 14n, 18a, and 18b with IC50 values of 13 ± 3, 5.0 ± 2.0, and 8.5 ± 3.1 nM, respectively. An X-ray crystal structure of AdoHcyase with NAD+ and 18a showed a novel open form co-crystal structure. 18a in the co-crystals formed intramolecular eight membered ring hydrogen bond formations. A single crystal X-ray structure of 14n also showed an intramolecular eight-membered ring hydrogen bond interaction.
      Graphical abstract image

      PubDate: 2015-05-20T06:26:18Z
       
  • Identification of peptidic substrates for the human kinase Myt1 using
           peptide microarrays
    • Abstract: Publication date: Available online 19 May 2015
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Alexander Rohe , Charlott Platzer , Antonia Masch , Sandra Greiner , Claudia Henze , Christian Ihling , Frank Erdmann , Mike Schutkowski , Wolfgang Sippl , Matthias Schmidt
      Myt1 kinase is a member of the Wee-kinase family involved in G2/M checkpoint regulation of the cell cycle. So far, no peptide substrate suitable for activity-based screening has been reported, hampering systematic development of Myt1 kinase inhibitors. Myt1 inhibitors had to be identified by using either binding assays or activity assays with expensive proteinous substrates. Here, a peptide microarray approach was used to identify peptidic Myt1 substrates. Wee1 kinase was profiled for comparison using the same technology. Myt1 hits from peptide microarray experiments were verified in solution by a fluorescence polarization assay and several peptide substrates derived from cellular proteins were identified. Subsequently, phosphorylation site determination was carried out by MS fragmentation studies and identified substrates were validated by kinase inhibitor profiling.
      Graphical abstract image

      PubDate: 2015-05-20T06:26:18Z
       
  • Aminomethylhydroxylation of alkenes: Exploitation in the synthesis of
           scaffolds for small molecule libraries
    • Abstract: Publication date: 1 June 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
      Author(s): Ignacio Colomer , Ololade Adeniji , George M. Burslem , Philip Craven , Martin Ohsten Rasmussen , Anthony Willaume , Tuomo Kalliokoski , Richard Foster , Stephen P. Marsden , Adam Nelson
      The application of [4+2] cycloadditions between alkenes and an N-benzoyl iminium species, generated in situ under acidic conditions, is described in the synthesis of diverse molecular scaffolds. The key reaction led to the formation of cyclic imidates in good yield and with high regioselectivity. It was demonstrated that the cyclic imidates may be readily converted into 1,3-amino alcohols. Incorporation of orthogonally-reactive functionality, such as aryl and alkyl bromides, into the cycloaddition substrates enabled the synthesis of additional scaffolds. For one scaffold, the synthesis of exemplar screening compounds was undertaken to demonstrate potential value in small molecule library production.
      Graphical abstract image

      PubDate: 2015-05-11T16:37:51Z
       
  • Seven-membered ring scaffolds for drug discovery: Access to functionalised
           azepanes and oxepanes through diazocarbonyl chemistry
    • Abstract: Publication date: 1 June 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
      Author(s): Andrew Nortcliffe , Christopher J. Moody
      Functionalised azepane and oxepane scaffolds were prepared using diazocarbonyl chemistry and elaborated to show their potential use in library synthesis. Key dicarbonyl containing seven-membered rings were functionalised via diastereoselective Luche reduction of the ketone followed by manipulation of the ester and amine groups. Further scaffolds could be accessed by C-alkylation of the dicarbonyl compounds. In addition, an oxepane containing amino acid could be prepared via a diastereoselective enamine reduction.
      Graphical abstract image

      PubDate: 2015-05-11T16:37:51Z
       
  • Synthesis and functionalization of bicyclic N,O-acetal scaffolds from
           furfural
    • Abstract: Publication date: 1 June 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
      Author(s): Ferdi van der Pijl , Floris L. van Delft , Floris P.J.T. Rutjes
      We have synthesized biologically relevant 6-aza-8-oxa[3.2.1]bicyclooctane scaffolds in a five-step procedure starting from furfural. Besides showing that these scaffolds are amenable to decoration via standard functional group interconversions, we also describe investigations for further functionalization via Lewis acid-mediated N,O-acetal opening, followed by nucleophilic trapping of the resulting intermediate cation. By using different nucleophiles, we have successfully prepared a modest library of 2,6-trans-disubstituted pyrans in good yields and in a highly diastereoselective manner.
      Graphical abstract image

      PubDate: 2015-05-11T16:37:51Z
       
  • Design and synthesis of 1,1-disubstituted-1-silacycloalkane-based compound
           libraries
    • Abstract: Publication date: 1 June 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
      Author(s): Raquel Ortega , Jorge Sanchez-Quesada , Christoph Lorenz , Grzegorg Dolega , Anna Karawajczyk , Miguel Sanz , Graham Showell , Fabrizio Giordanetto
      The introduction of silicon in biologically-relevant molecules represents an interesting medicinal chemistry tactic. Its use is mainly confined to the fine-tuning of specific molecular properties and organosilicon compounds are underrepresented in typical screening libraries. As part of the European Lead Factory efforts to generate novel, drug discovery-relevant chemical matter, the design and synthesis of 1,1-disubstituted-1-silacycloalkane-based compound libraries is described.
      Graphical abstract image

      PubDate: 2015-05-11T16:37:51Z
       
  • MCR synthesis of a tetracyclic tetrazole scaffold
    • Abstract: Publication date: 1 June 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
      Author(s): Pravin Patil , Kareem Khoury , Eberhardt Herdtweck , Alexander Dömling
      Scaffold diversity is key in the ongoing exercise of discovery of novel bioactive compounds using high throughput screening (HTS). Based on the Ugi tetrazole synthesis we have designed novel bi- and tri-cyclic scaffolds featuring interesting pharmacophore properties. The compounds of the scaffold (B) are synthesizable in large diversity and numbers in two steps using (hetero)phenylethylamines, HN3, oxo components and iscyanoacetaldehyde(dimethylacetale). The chemistry is amenable to parallel synthesis and is used to enhance and fill the screening decks of the European Lead factory (ELF). Here, we are reporting full experimental details, scope and limitations of the reaction, cheminformatic analysis and the 3D structures of selected compounds.
      Graphical abstract image

      PubDate: 2015-05-11T16:37:51Z
       
  • Synthesis of 1,4,5 trisubstituted γ-lactams via a 3-component cascade
           reaction
    • Abstract: Publication date: 1 June 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
      Author(s): Michael Åxman Petersen , Michael A. Mortensen , A. Emil Cohrt , Rico Petersen , Peng Wu , Nicolas Fleury-Brégeot , Rémy Morgentin , Claude Lardy , Thomas E. Nielsen , Mads H. Clausen
      A three component one-pot cascade reaction was developed for the synthesis of 1,4,5-trisubstituted γ-lactams. The resulting scaffold can be modified independently at three positions, two of which are conveniently accessed by changing the components of the one-pot reaction. The phases of building block generation, scaffold synthesis and subsequent appendage modification were adapted to library production, which resulted in a screening library of 500 compounds.
      Graphical abstract image

      PubDate: 2015-05-11T16:37:51Z
       
  • Synthesis of a hexahydropyrrolo indole (HPI) compound library
    • Abstract: Publication date: 1 June 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
      Author(s): Sabrina Nickel , Philipp Nickel , Marco Hellmert , Silvia Ernst , Robert Jewell , Christopher A. Pearce , Geraint Jones , Daniel Hamza , Markus Kaiser
      Scaffolds of natural products represent promising starting points for the development of focused compound libraries. Here, we describe the development of a synthetic route to a compound library based on the hexahydropyrrolo indole (HPI) scaffold, the denoting structural motif of the HPI natural product family. To this end, a two-step approach consisting of a batch synthesis of an advanced functionalizable HPI intermediate followed by the establishment of reaction conditions that allow derivatization of this scaffold at three different positions is described. Subsequently, the optimized methods were applied to the synthesis of a 276-member library.
      Graphical abstract image

      PubDate: 2015-05-11T16:37:51Z
       
  • Design, synthesis and decoration of molecular scaffolds for exploitation
           in the production of alkaloid-like libraries
    • Abstract: Publication date: 1 June 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
      Author(s): Philip Craven , Anthony Aimon , Mark Dow , Nicolas Fleury-Bregeot , Rachel Guilleux , Remy Morgentin , Didier Roche , Tuomo Kalliokoski , Richard Foster , Stephen P. Marsden , Adam Nelson
      The design, synthesis and decoration of six small molecule libraries is described. Each library was inspired by structures embedded in the framework of specific alkaloid natural products. The development of optimised syntheses of the required molecular scaffolds is described, in which reactions including Pd-catalysed aminoarylation and diplolar cycloadditions have been exploited as key steps. The synthesis of selected exemplar screening compounds is also described. In five cases, libraries were subsequently nominated for production on the basis of the scope and limitations of the validation work, as well as predicted molecular properties. In total, the research has led to the successful synthesis of >2500 novel alkaloid-like compounds for addition to the screening collection (the Joint European Compound Library, JECL) of the European Lead Factory.
      Graphical abstract image

      PubDate: 2015-05-11T16:37:51Z
       
  • Lead-oriented synthesis: Investigation of organolithium-mediated routes to
           3-D scaffolds and 3-D shape analysis of a virtual lead-like library
    • Abstract: Publication date: 1 June 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
      Author(s): Monique Lüthy , Mary C. Wheldon , Chehasnah Haji-Cheteh , Masakazu Atobe , Paul S. Bond , Peter O’Brien , Roderick E. Hubbard , Ian J.S. Fairlamb
      Synthetic routes to six 3-D scaffolds containing piperazine, pyrrolidine and piperidine cores have been developed. The synthetic methodology focused on the use of N-Boc α-lithiation-trapping chemistry. Notably, suitably protected and/or functionalised medicinal chemistry building blocks were synthesised via concise, connective methodology. This represents a rare example of lead-oriented synthesis. A virtual library of 190 compounds was then enumerated from the six scaffolds. Of these, 92 compounds (48%) fit the lead-like criteria of: (i) −1⩽ A log P ⩽3; (ii) 14⩽number of heavy atoms⩽26; (iii) total polar surface area⩾50Å2. The 3-D shapes of the 190 compounds were analysed using a triangular plot of normalised principal moments of inertia (PMI). From this, 46 compounds were identified which had lead-like properties and possessed 3-D shapes in under-represented areas of pharmaceutical space. Thus, the PMI analysis of the 190 member virtual library showed that whilst scaffolds which may appear on paper to be 3-D in shape, only 24% of the compounds actually had 3-D structures in the more interesting areas of 3-D drug space.
      Graphical abstract image

      PubDate: 2015-05-11T16:37:51Z
       
  • Studies towards the synthesis of indolizin-5(3H)-one derivatives and
           related 6,5-azabicyclic scaffolds by ring-closing metathesis
    • Abstract: Publication date: 1 June 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
      Author(s): Michelle S. Frei , Matthew K. Bilyard , Thomas A. Alanine , Warren R.J.D. Galloway , Jamie E. Stokes , David R. Spring
      Herein, we report on work towards the development of a new strategy for the synthesis of rare and biologically interesting indolizin-5(3H)-ones, which is based around the use of ring-closing metathesis to construct the carbocyclic ring system. This study has provided insights into the general stability of indolizin-5(3H)-ones and their tendency to exist as the tautomeric indolizin-5-ols. Furthermore, this approach has allowed access to other novel structurally related compounds based around unusual 6,5-azabicyclic scaffolds, which are also difficult to generate using typical methods. The azabicyclic compounds synthesized in this study reside in attractive regions of heterocyclic chemical space that are underexploited in current drug and agrochemical discovery efforts.
      Graphical abstract image

      PubDate: 2015-05-11T16:37:51Z
       
  • Branching cascades provide access to two amino-oxazoline compound
           libraries
    • Abstract: Publication date: 1 June 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
      Author(s): Annamalai Murali , Federico Medda , Matthias Winkler , Fabrizio Giordanetto , Kamal Kumar
      An efficient synthetic access to two amino-oxazoline compound libraries was developed employing the branching cascades approach. A common precursor, that is, chromonylidene β-ketoester was transformed into two different ring-systems, that is, the pyridine and the benzopyrane substituted hydroxyphenones. In further two steps, the ketone moiety in two ring-systems was transformed into an amino-oxazoline ring. The functional groups on the two amino-oxazoline scaffolds were exploited further to generate, a compound collection of ca. 600 amino-oxazolines which are being exposed to various biological screenings within the European Lead Factory consortium.
      Graphical abstract image

      PubDate: 2015-05-11T16:37:51Z
       
  • Cyclopentitol as a scaffold for a natural product-like compound library
           for drug discovery
    • Abstract: Publication date: 1 June 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
      Author(s): Jalindar D. Padwal , Dmitri V. Filippov , Bharat D. Narhe , Sjoerd Aertssen , Remmelt Jan Beuving , Jorg C.J. Benningshof , Gijsbert A. van der Marel , Herman S. Overkleeft , Mario van der Stelt
      A concise and efficient synthesis of cyclopentitols as a scaffold for a two-dimensional compound library for drug discovery is described. Starting from d-mannose, the key steps are Wittig olefination and ring-closing metathesis (RCM) followed by a [3,3]-sigmatropic Overmann rearrangement to form an sp3-rich, natural product-like scaffold from which a focused compound library with different functionalities is prepared.
      Graphical abstract image

      PubDate: 2015-05-11T16:37:51Z
       
  • Synthesis of hexahydropyrrolo[2,1-a]isoquinoline compound libraries
           through a Pictet–Spengler cyclization/metal-catalyzed cross
           coupling/amidation sequence
    • Abstract: Publication date: 1 June 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
      Author(s): Rico Petersen , A. Emil Cohrt , Michael Åxman Petersen , Peng Wu , Mads H. Clausen , Thomas E. Nielsen
      Molecular libraries of natural product-like and structurally diverse compounds are attractive in early drug discovery campaigns. In here, we present synthetic methodology for library production of hexahydropyrrolo[2,1-a]isoquinoline (HPIQ) compounds. Two advanced HPIQ intermediates, both incorporating two handles for diversification, were synthesized through an oxidative cleavage/Pictet–Spengler reaction sequence in high overall yields. A subsequent metal-catalyzed cross coupling/amidation protocol was developed and its utility in library synthesis was validated by construction of a 20-membered natural product-like molecular library in good overall yields.
      Graphical abstract image

      PubDate: 2015-05-11T16:37:51Z
       
  • Combining two-directional synthesis and tandem reactions. Part 21:
           Exploitation of a dimeric macrocycle for chain terminus differentiation
           and synthesis of an sp3-rich library
    • Abstract: Publication date: 1 June 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
      Author(s): Thomas E. Storr , Sarah J. Cully , Michael J. Rawling , William Lewis , Daniel Hamza , Geraint Jones , Robert A. Stockman
      The application of a tandem condensation/cyclisation/[3+2]-cycloaddition/elimination reaction gives an sp3-rich tricyclic pyrazoline scaffold with two ethyl esters in a single step from a simple linear starting material. The successive hydrolysis and cyclisation (with Boc anhydride) of these 3-dimensional architectures, generates unprecedented 16-membered macrocyclic bisanhydrides (characterised by XRD). Selective amidations could then be achieved by ring opening with a primary amine followed by HATU-promoted amide coupling to yield an sp3-rich natural product-like library.
      Graphical abstract image

      PubDate: 2015-05-11T16:37:51Z
       
  • Editorial board
    • Abstract: Publication date: 1 June 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11




      PubDate: 2015-05-11T16:37:51Z
       
  • Innovative approaches to the design and synthesis of small molecule
           libraries
    • Abstract: Publication date: 1 June 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
      Author(s): Adam Nelson , Didier Roche



      PubDate: 2015-05-11T16:37:51Z
       
  • Stereoselective synthesis of a natural product inspired
           tetrahydroindolo[2,3-a]-quinolizine compound library
    • Abstract: Publication date: 1 June 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
      Author(s): Muthukumar G. Sankar , Luca Mantilli , James Bull , Fabrizio Giordanetto , Jonathan O. Bauer , Carsten Strohmann , Herbert Waldmann , Kamal Kumar
      A natural product-inspired synthesis of a compound collection embodying the tetrahydroindolo[2,3-a]quinolizine scaffold was established with a five step synthesis route. An imino-Diels–Alder reaction between Danishefsky’s diene and the iminoesters derived from tryptamines was used as a key reaction. Reductive amination of the ketone function and amide synthesis with the carboxylic acid derived from the ethyl ester, were used to decorate the core scaffold. Thus a compound library of 530 tetrahydroindolo[2,3-a]quinolizines was generated and submitted to European lead factory consortium for various biological screenings.
      Graphical abstract image

      PubDate: 2015-05-11T16:37:51Z
       
  • Graphical contents list
    • Abstract: Publication date: 1 June 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11




      PubDate: 2015-05-11T16:37:51Z
       
  • Antileishmanial pharmacomodulation in 8-nitroquinolin-2(1H)-one series
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Charline Kieffer , Anita Cohen , Pierre Verhaeghe , Lucie Paloque , Sébastien Hutter , Caroline Castera-Ducros , Michèle Laget , Sylvain Rault , Alexis Valentin , Pascal Rathelot , Nadine Azas , Patrice Vanelle
      An antileishmanial pharmacomodulation at position 4 of 8-nitroquinolin-2(1H)-one was conducted by using the Sonogashira and Suzuki–Miyaura coupling reactions. A series of 25 derivatives was tested in vitro on the promastigote stage of Leishmania donovani along with an in vitro cytotoxicity evaluation on the human HepG2 cell line. Only the derivatives bearing a phenyl moiety at position 4 of the quinoline ring displayed interesting biologic profile, when the phenyl moiety was substituted at the para position by a Br or Cl atom, or by a CF3 group. Among them, molecules 17 and 19 were the most selective and were then tested in vitro on the intracellular amastigote stage of both L. donovani and Leishmania infantum, in parallel with complementary in vitro cytotoxicity assays on the macrophage cell lines THP-1 and J774A.1. Molecule 19 showed no activity on the amastigote stages of the parasites and some cytotoxicity on the J774A.1 cell line while molecule 17, less cytotoxic than 19, showed anti-amastigote activity in L. infantum, being 3 times less active than miltefosine but more active and selective than pentamidine. Nevertheless, hit-molecule 17 did not appear as selective as the parent compound.
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      PubDate: 2015-05-06T13:33:05Z
       
  • Design, synthesis and biological evaluation of new hybrid anticonvulsants
           derived from N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide and
           2-(2,5-dioxopyrrolidin-1-yl)butanamide derivatives
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Krzysztof Kamiński , Anna Rapacz , Jarogniew J. Łuszczki , Gniewomir Latacz , Jolanta Obniska , Katarzyna Kieć-Kononowicz , Barbara Filipek
      The purpose of this study was to synthesize the library of 33 new N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamides, 2-(3-methyl-2,5-dioxopyrrolidin-1-yl)propanamides, and 2-(2,5-dioxopyrrolidin-1-yl)butanamides as potential new hybrid anticonvulsant agents. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. The coupling reaction of the 2-(2,5-dioxopyrrolidin-1-yl)propanoic acid, 2-(3-methyl-2,5-dioxopyrrolidin-1-yl)propanoic acid, or 2-(2,5-dioxopyrrolidin-1-yl)butanoic acid with the appropriately substituted benzylamines in the presence of the coupling reagent, N,N-carbonyldiimidazole (CDI) generated the final compounds 4–36. Spectral data acquired via 1H NMR, 13C NMR, and LC–MS confirmed the chemical structures of the newly prepared compounds. The initial anticonvulsant screening was performed in mice intraperitoneally (ip), using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests. The rotarod test determined the acute neurological toxicity (NT). The results of preliminary pharmacological screening revealed that 25 compounds showed protection in half or more of the animals tested in the MES and/or scPTZ seizure models at the fixed dose of 100mg/kg. The broad spectra of activity across the preclinical seizure models displayed compounds 4, 7, 8, 13, 15–18, 24, and 26. The quantitative pharmacological studies in mice demonstrated the highest protection for compounds 4 (ED50 MES=67.65mg/kg, ED50 scPTZ=42.83mg/kg); 8 (ED50 MES=54.90mg/kg, ED50 scPTZ=50.29mg/kg); and 20 (ED50 scPTZ=47.39mg/kg). These compounds were distinctly more potent and provided better safety profiles in the rotarod test compared to valproic acid or ethosuximide, which were used as model AEDs. Compound 8 underwent only a slight metabolic change by the human liver microsomes (HLMs), and also did not affect the activity of human cytochrome P450 isoform, CYP3A4, in the in vitro assays.
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      PubDate: 2015-05-06T13:33:05Z
       
  • Promising antiproliferative platinum(II) complexes based on imidazole
           moiety: synthesis, evaluation in HCT-116 cancer cell line and interaction
           with Ctr-1 Met-rich domain
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Nicola Ferri , Giorgio Facchetti , Sara Pellegrino , Chiara Ricci , Giuseppe Curigliano , Elena Pini , Isabella Rimoldi
      A series of imidazole based platinum(II) complexes were synthesised and evaluated for their cytotoxicity in HCT-116 cancer cell line, known for being partially resistant to cisplatin but sensitive to oxaliplatin. Lipophilicity was modulated by introducing differently long saturated and unsaturated chains at the N1 of the imidazole moiety. Pt-I displayed the higher cytotoxic effect achieving a IC50 =38.0±14.1μM, comparable to the oxaliplatin value. The interaction between the imidazole platinum(II) complexes and the octapeptide called Mets7, the methionine-rich motif mimicking the N-terminal domain of the yCtr-1, was evaluated in order to have a major insight of the uptake and the eventual resistance mechanisms for the so-synthesised novel platinum compounds.
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      PubDate: 2015-05-06T13:33:05Z
       
  • Synthesis of a new series of dithiocarbamates with effective human
           carbonic anhydrase inhibitory activity and antiglaucoma action
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Murat Bozdag , Fabrizio Carta , Daniela Vullo , Atilla Akdemir , Semra Isik , Cecilia Lanzi , Andrea Scozzafava , Emanuela Masini , Claudiu T. Supuran
      A new series of dithiocarbamates (DTCs) was prepared from primary/secondary amines incorporating amino/hydroxyl-alkyl, mono- and bicyclic aliphatic ring systems based on the quinuclidine, piperidine, hydroxy-/carboxy-/amino-substituted piperidine, morpholine and piperazine scaffolds, and carbon disulfide. The compounds were investigated for the inhibition of four mammalian α-carbonic anhydrases (CAs, EC 4.2.1.1) of pharmacologic relevance, that is, the human (h) hCA I, II, IX and XII, drug targets for antiglaucoma (hCA II and XII) or antitumor (hCA IX/XII) agents. The compounds were moderate or inefficient hCA I inhibitors (off-target isoform for both applications), efficiently inhibited hCA II, whereas some of them were low nanomolar/subnanomolar hCA IX/XII inhibitors. One DTC showed excellent intraocular pressure (IOP) lowering properties in an animal model of glaucoma, with a two times better efficiency compared to the clinically used sulfonamide dorzolamide.
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      PubDate: 2015-05-06T13:33:05Z
       
  • Discovery of DS-5272 as a promising candidate: A potent and orally active
           p53–MDM2 interaction inhibitor
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Masaki Miyazaki , Kouichi Uoto , Yuuichi Sugimoto , Hiroyuki Naito , Keisuke Yoshida , Tooru Okayama , Haruko Kawato , Masaya Miyazaki , Mayumi Kitagawa , Takahiko Seki , Setsuko Fukutake , Masashi Aonuma , Tsunehiko Soga
      We have published p53–MDM2 interaction inhibitors possessing a novel dihydroimidazothiazole scaffold. Although our lead compound 1 showed strong antitumor activity with single oral administration on a xenograft model using MV4-11 cells harboring wild-type p53, it needed a higher dose (200mg/kg) for distinct efficacy. We executed further optimization with the aim of improvement of potency and physicochemical properties. Thus optimal compounds were furnished by introducing fluorine moieties onto the phenyl ring at the C-6 position and the pyrrolidine part at the C-2 substituent; and modifying the terminal piperazine to 4,7-diazaspiro[2,5]octane variants. Furthermore, replacing 4-chlorophenyl on the C-5 position with pyridyl variant decreased nonspecific cytotoxicity significantly. Our exploration afforded DS-5272 indicating excellent antitumor efficacy from a dose of 25mg/kg on SJSA-1 xenografted models with high safety and good PK profiles, which has appropriate potency as a clinical candidate.
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      PubDate: 2015-05-06T13:33:05Z
       
  • Systematic synthesis and anti-inflammatory activity of ω-carboxylated
           menaquinone derivatives—Investigations on identified and putative
           vitamin K2 metabolites
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Shinya Fujii , Akitaka Shimizu , Noriaki Takeda , Kazuki Oguchi , Tomoko Katsurai , Hitoshi Shirakawa , Michio Komai , Hiroyuki Kagechika
      Vitamin K is an essential nutrient for blood coagulation and bone homeostasis, and also functions in many physiological processes including inflammation and cancer progression. However, the nature and activities of its metabolites remain unclear. We report here systematic synthesis of ω-carboxylated derivatives of menaquinone (vitamin K2), including previously identified metabolites 5, K acid I (10), and K acid II (12), and evaluation of their inhibitory activity toward LPS-stimulated induction of inflammatory cytokines. These results should contribute to an improved understanding of the biochemistry and pharmacology of vitamin K.
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      PubDate: 2015-05-06T13:33:05Z
       
  • Synthesis, antinociceptive and anti-inflammatory effects of porphyrins
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Angel Josabad Alonso-Castro , Juan Ramón Zapata-Morales , Abigail Hernández-Munive , Nimsi Campos-Xolalpa , Salud Pérez-Gutiérrez , Cuauhtémoc Pérez-González
      Porphyrins are natural compounds with several biological activities. We report the synthesis and the evaluation of the anti-inflammatory and antinociceptive effects of 4 porphyrins: 5,10,15,20-tetraphenylporphyrin (TPP), 5,10,15,20-tetra(4′-fluorophenyl)porphyrin (TpFPP), 5,10,15,20-tetra(4′-chlorophenyl)porphyrin (TpClPP), and 5,10,15,20-tetra(4′-bromophenyl)porphyrin (TpBrPP). The in vitro anti-inflammatory effects were evaluated on heat-induced hemolysis. The antinociceptive effects were evaluated using the hot plate and formalin tests. The in vivo anti-inflammatory assays were tested on the acute and chronic TPA (12-O-tetradecanoylphorbol 13-acetate) method to induce ear edema. The anti-arthritic effects were evaluated using carrageenan kaolin induced arthritis (CKIA). All porphyrins inhibited hemolysis with similar potency than naproxen (NPX). In the antinociceptive tests, all porphyrins tested at 200mg/kg showed similar effects compared to 100mg/kg NPX. In the in vivo anti-inflammatory acute assay, only three porphyrins (TPP, TpFPP and TpBrPP) decreased inflammation with similar activity than 2mg/ear indomethacin (IND). Further anti-inflammatory experiments were carried out with TPP, TpFPP and TpBrPP. In the in vivo anti-inflammatory chronic assay, porphyrins decreased inflammation with similar activity than 8mg/kg IND. Porphyrins tested at 200mg/kg showed anti-arthritic effects. The antinociceptive, anti-inflammatory and arthritic activities of porphyrins suggest that these compounds might be a good alternative for the treatment of inflammatory diseases.
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      PubDate: 2015-05-06T13:33:05Z
       
  • Editorial board
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10




      PubDate: 2015-05-06T13:33:05Z
       
  • Graphical contents list
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10




      PubDate: 2015-05-06T13:33:05Z
       
  • Novel thiazolo[3,2-b]-1,2,4-triazoles derived from naproxen with
           analgesic/anti-inflammatory properties: Synthesis, biological evaluation
           and molecular modeling studies
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Deniz Sarigol , Ayse Uzgoren-Baran , Banu Cahide Tel , Elif Inci Somuncuoglu , Inci Kazkayasi , Keriman Ozadali-Sari , Oya Unsal-Tan , Gurol Okay , Mevlut Ertan , Birsen Tozkoparan
      3-Substituted-1,2,4-triazole-5-thiones are versatile synthetic intermediates for the preparation of several biologically active N-bridged heterocyclic compounds, given that they have two reactive sites, thiocarbonyl and an amine nitrogen (N1/N4). For several years, our interest has focused on the synthesis of novel heterocyclic systems derived from 3-substituted-1,2,4-triazole-5-thiones having analgesic/anti-inflammatory activity. In this study, a series of novel thiazolo[3,2-b]-1,2,4-triazole-6(5H)-one derivatives bearing naproxen was synthesized and evaluated for their in vivo analgesic and anti-inflammatory properties in acute experimental pain and inflammation models. The compounds were also tested for their ulcerogenic potential. Our findings showed that all the newly synthesized derivatives attenuate nociception and inflammation compared with a control. All the synthesized compounds exhibited much lower ulcerogenic risk than the standard drugs indomethacin and naproxen. Some compounds with significant analgesic and/or anti-inflammatory activities as well as low ulcer scores were further evaluated for in vitro COX-1 and COX-2 inhibitory potential in a COX-catalyzed prostaglandin biosynthesis assay. Among the tested compounds, compound 1q showed the highest selectivity index (SI) of 4.87. The binding mode for some of the tested compounds to the cyclooxygenase (COX) enzymes was predicted using docking studies.
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      PubDate: 2015-05-06T13:33:05Z
       
  • Discovery of potent and selective urea-based ROCK inhibitors: Exploring
           the inhibitor’s potency and ROCK2/PKA selectivity by 3D-QSAR,
           molecular docking and molecular dynamics simulations
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Ding Mei , Yan Yin , Fanhong Wu , Jiaxing Cui , Hong Zhou , Guofeng Sun , Yu Jiang , Yangbo Feng
      An activity model and a selectivity model from 3D-QSAR studies were established by CoMFA and CoMSIA to explore the SAR. Then docking was used to study the binding modes between ligand and kinases (ROCK2 and PKA), and the molecular docking results were further validated by MD simulations. Computational results suggested that substitution containing positive charge attached to the middle phenyl ring, or electropositive group in urea linker was favored for both activity and ROCK2/PKA selectivity. Finally, three compounds were designed, and biological evaluation demonstrated that these molecular models were effective for guiding the design of potent and selective ROCK inhibitors.
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      PubDate: 2015-05-06T13:33:05Z
       
  • Exploration of benzamidochromenone derivatives with conformational
           restrictor as interleukin-5 inhibitors
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Eeda Venkateswararao , Manoj Manickam , Pullareddy Boggu , Youngsoo Kim , Sang-Hun Jung
      Novel amidochromen-4-one analogs 8a–k and 9a–f were prepared and studied for their IL-5 inhibitory activity. Among the synthesized compounds, (6-benzamido-2-cyclohexyl-4-oxo-4H-chromen-3-yl)methyl acetate (8a, 95% inhibition at 30μM, IC50 =6.1μM) exhibited potent IL-5 inhibitory activity. The conformational restrictor at position 2 like bulky cyclohexyl group is favorable for the formation of effective conformer of side chain small ester like acetoxymethyl at position 3 of these chromenone analogs 8. In addition the hydrophobic planarity of benzamido group at position 6 should be important for the potent IL-5 inhibitory activity. Since replacing acetoxymethyl moiety with hydroxymethyl group at position 3 of chromenone decreases the activity, which indicates that the location of hydrogen bonding group should be near 4 atom distances away from chromenone ring is more optimum for the activity. Therefore, these benzamidochromen-4-one analogs 8 are novel scaffold for finding potent interleukin-5 inhibitors.
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      PubDate: 2015-05-06T13:33:05Z
       
  • Identification of apoptosis signal-regulating kinase 1 (ASK1) inhibitors
           among the derivatives of
           benzothiazol-2-yl-3-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Sergiy A. Starosyla , Galyna P. Volynets , Sergiy S. Lukashov , Oksana B. Gorbatiuk , Andriy G. Golub , Volodymyr G. Bdzhola , Sergiy M. Yarmoluk
      Apoptosis signal-regulating kinase 1 (ASK1) plays important roles in the pathogenesis of type 1 and type 2 diabetes, autoimmune disorders, cancer and neurodegenerative diseases suggesting that small compounds inhibiting ASK1 could be used for the treatment of these pathologies. We have identified novel chemical class of ASK1 inhibitors, namely benzothiazol-2-yl-3-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one, using molecular modeling techniques. It was found that the most active compound 1-(6-fluoro-benzothiazol-2-yl)-3-hydroxy-5-[3-(3-methyl-butoxy)-phenyl]-4-(2-methyl-2,3-dihydro-benzofuran-5-carbonyl)-1,5-dihydro-pyrrol-2-one (BPyO-34) inhibits ASK1 with IC50 of 0.52μM in vitro in kinase assay. The structure–activity relationships of 34 derivatives of benzothiazol-2-yl-3-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one have been studied and binding mode of this chemical class has been proposed.
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      PubDate: 2015-05-06T13:33:05Z
       
  • Structure activity relationship of selective GABA uptake inhibitors
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Stine B. Vogensen , Lars Jørgensen , Karsten K. Madsen , Andreas Jurik , Nrupa Borkar , Emiliano Rosatelli , Birgitte Nielsen , Gerhard F. Ecker , Arne Schousboe , Rasmus P. Clausen
      A series of β-amino acids with lipophilic diaromatic side chain was synthesized and characterized pharmacologically on mouse γ-amino butyric acid (GABA) transporter subtypes mGAT1-4 in order to investigate structure activity relationships (SAR) for mGAT2 (corresponding to hBGT-1). Variation in the lipophilic diaromatic side chain was probed to understand the role of the side chain for activity. This yielded several selective compounds of which the best (1R,2S)-5a was more than 10 fold selective towards other subtypes, although potency was moderate. A docking study was performed to investigate possible binding modes of the compounds in mGAT2 suggesting a binding mode similar to that proposed for Tiagabine in hGAT1. Specific interactions between the transporter and the amino acid part of the ligands may account for a reverted preference towards mGAT2 over mGAT1.
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      PubDate: 2015-05-06T13:33:05Z
       
  • Peptide based DNA nanocarriers incorporating a cell-penetrating peptide
           derived from neurturin protein and poly-l-lysine dendrons
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Nurlina Rosli , Michelle P. Christie , Peter M. Moyle , Istvan Toth
      Multicomponent gene delivery systems incorporating cell-penetrating peptides (CPP) from the human neurturin protein (NRTN-30, NRTN(132-161); NRTN-17, NRTN(145-161)) and a poly-l-lysine (PLL) dendron, were synthesized and characterized for plasmid DNA (pDNA) delivery. Acetylated NRTN peptides (Ac-CPP) and peptides conjugated to a PLL dendron (DEN-CPP) efficiently condensed and stabilized pDNA. Complexes between pDNA and DEN-CPP formed smaller and more stable nanoparticles. Flow cytometry experiments showed that pDNA–DEN-CPPs were taken up more efficiently into HeLa cells. There was also no significant difference between NRTN-30 and NRTN-17 for pDNA uptake, indicating that the truncated peptide alone is sufficient as a CPP for pDNA delivery.
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      PubDate: 2015-05-06T13:33:05Z
       
  • Structure-based discovery of small molecule hepsin and HGFA protease
           inhibitors: Evaluation of potency and selectivity derived from distinct
           binding pockets
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Francisco M. Franco , Darin E. Jones , Peter K.W. Harris , Zhenfu Han , Scott A. Wildman , Cassie M. Jarvis , James W. Janetka
      Hepatocyte growth factor activator (HGFA), matriptase and hepsin are all S1 trypsin-like serine endopeptidases. HGFA is a plasma protease while hepsin and matriptase are type II transmembrane proteases (TTSPs). Upregulated expression and activity of all three proteases is associated with aberrant cancer cell signaling through c-MET and RON tyrosine kinase cell-signaling pathways in cancer. We modeled known benzamidine protease inhibitor scaffolds into the active sites of matriptase, hepsin and HGFA to design new non-peptide inhibitors of hepsin and HGFA. First, we used a docking model of the irreversible inhibitor, Nafamostat, bound to the active site of HGFA in order to explore structure activity relationships (SAR). Compounds were screened for inhibition of HGFA activity in a kinetic enzyme assay using a chromogenic substrate. Next, we designed matched pair compound libraries of 3-amidino and 4-amidino phenylalanine (benzamidine) arginine peptidomimetics based on the structure of matriptase inhibitor, CJ-672. Compounds were screened for inhibition of HGFA, matriptase, and hepsin enzyme activity using fluorogenic substrates. Using this strategy we have discovered the first reported non-peptide small molecule inhibitors of both HGFA and hepsin. These inhibitors have differential potency and selectivity towards all three proteases. A subset of piperazinyl ureas highlighted by 25a, have excellent potency and selectivity for hepsin over matriptase and HGFA.
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      PubDate: 2015-05-06T13:33:05Z
       
  • Anti-parallel triplexes: Synthesis of 8-aza-7-deazaadenine nucleosides
           with a 3-aminopropynyl side-chain and its corresponding LNA analog
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Tamer R. Kosbar , Mamdouh A. Sofan , Mohamed A. Waly , Erik B. Pedersen
      The phosphoramidites of DNA monomers of 7-(3-aminopropyn-1-yl)-8-aza-7-deazaadenine (Y) and 7-(3-aminopropyn-1-yl)-8-aza-7-deazaadenine LNA (Z) are synthesized, and the thermal stability at pH 7.2 and 8.2 of anti-parallel triplexes modified with these two monomers is determined. When, the anti-parallel TFO strand was modified with Y with one or two insertions at the end of the TFO strand, the thermal stability was increased 1.2°C and 3°C at pH 7.2, respectively, whereas one insertion in the middle of the TFO strand decreased the thermal stability 1.4°C compared to the wild type oligonucleotide. In order to be sure that the 3-aminopropyn-1-yl chain was contributing to the stability of the triplex, the nucleobase X without the aminopropynyl group was inserted in the same positions. In all cases the thermal stability was lower than the corresponding oligonucleotides carrying the 3-aminopropyn-1-yl chain, especially at the end of the TFO strand. On the other hand, the thermal stability of the anti-parallel triplex was dramatically decreased when the TFO strand was modified with the LNA monomer analog Z in the middle of the TFO strand (ΔTm =−9.1°C). Also the thermal stability decreased about 6.1°C when the TFO strand was modified with Z and the Watson–Crick strand with adenine-LNA (AL ). The molecular modeling results showed that, in case of nucleobases Y and Z a hydrogen bond (1.69 and 1.72Ǻ, respectively) was formed between the protonated 3-aminopropyn-1-yl chain and one of the phosphate groups in Watson–Crick strand. Also, it was shown that the nucleobase Y made a good stacking and binding with the other nucleobases in the TFO and Watson–Crick duplex, respectively. In contrast, the nucleobase Z with LNA moiety was forced to twist out of plane of Watson–Crick base pair which is weakening the stacking interactions with the TFO nucleobases and the binding with the duplex part.
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      PubDate: 2015-05-06T13:33:05Z
       
  • Synthesis of new N-benzylpiperidine derivatives as cholinesterase
           inhibitors with β-amyloid anti-aggregation properties and beneficial
           effects on memory in vivo
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Anna Więckowska , Krzysztof Więckowski , Marek Bajda , Boris Brus , Kinga Sałat , Paulina Czerwińska , Stanislav Gobec , Barbara Filipek , Barbara Malawska
      Due to the complex nature of Alzheimer’s disease, multi-target-directed ligand approaches are one of the most promising strategies in the search for effective treatments. Acetylcholinesterase, butyrylcholinesterase and β-amyloid are the predominant biological targets in the search for new anti-Alzheimer’s agents. Our aim was to combine both anticholinesterase and β-amyloid anti-aggregation activities in one molecule, and to determine the therapeutic potential in vivo. We designed and synthesized 28 new compounds as derivatives of donepezil that contain the N-benzylpiperidine moiety combined with the phthalimide or indole moieties. Most of these test compounds showed micromolar activities against cholinesterases and aggregation of β-amyloid, combined with positive results in blood–brain barrier permeability assays. The most promising compound 23 (2-(8-(1-(3-chlorobenzyl)piperidin-4-ylamino)octyl)isoindoline-1,3-dione) is an inhibitor of butyrylcholinesterase (IC50 =0.72μM) that has β-amyloid anti-aggregation activity (72.5% inhibition at 10μM) and can cross the blood–brain barrier. Moreover, in an animal model of memory impairment induced by scopolamine, the activity of 23 was comparable to that of donepezil. The selected compound 23 is an excellent lead structure in the further search for new anti-Alzheimer’s agents.
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      PubDate: 2015-05-06T13:33:05Z
       
  • Identification of N-ethylmethylamine as a novel scaffold for inhibitors of
           soluble epoxide hydrolase by crystallographic fragment screening
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Yasushi Amano , Eiki Tanabe , Tomohiko Yamaguchi
      Soluble epoxide hydrolase (sEH) is a potential target for the treatment of inflammation and hypertension. X-ray crystallographic fragment screening was used to identify fragment hits and their binding modes. Eight fragment hits were identified via soaking of sEH crystals with fragment cocktails, and the co-crystal structures of these hits were determined via individual soaking. Based on the binding mode, N-ethylmethylamine was identified as a promising scaffold that forms hydrogen bonds with the catalytic residues of sEH, Asp335, Tyr383, and Tyr466. Compounds containing this scaffold were selected from an in-house chemical library and assayed. Although the starting fragment had a weak inhibitory activity (IC50: 800μM), we identified potent inhibitors including 2-({[2-(adamantan-1-yl)ethyl]amino}methyl)phenol exhibiting the highest inhibitory activity (IC50: 0.51μM). This corresponded to a more than 1500-fold increase in inhibitory activity compared to the starting fragment. Co-crystal structures of the hit compounds demonstrate that the binding of N-ethylmethylamine to catalytic residues is similar to that of the starting fragment. We therefore consider crystallographic fragment screening to be appropriate for the identification of weak but promising fragment hits.
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      PubDate: 2015-05-06T13:33:05Z
       
  • New indolizines with phenanthroline skeleton: Synthesis, structure,
           antimycobacterial and anticancer evaluation
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Ramona Danac , Cristina M. Al Matarneh , Sergiu Shova , Teofil Daniloaia , Mihaela Balan , Ionel I. Mangalagiu
      We report herein a feasible study concerning the design, synthesis, structure and in vitro antimycobacterial and anticancer activity of two new classes (containing four and five fused rings) of indolizine with phenanthroline skeleton. The preparation is straight and efficient, involving a Huisgen [3+2] dipolar cycloaddition of cycloimmonium ylides to alkynes or alkenes dipolarophiles. The cycloaddition reactions are highly stereo- or regioselective, according with the dipolarophiles nature. The structure of the new compounds was assigned unambiguously, X-ray analysis including. The primary antimycobacterial screening reveals that one of the thirteen tested compounds had a good activity against Mycobacterium tuberculosis H37Rv under aerobic conditions. The antiproliferative evaluation against a NCI 60 human tumor cell line panel, revealed that two indolizine with phenanthroline skeleton exhibit a selective and significant antitumor growth inhibitory activity against Breast Cancer (MCF7 and T-47D) and a slightly moderate activity against some forms of Leukemia, Non-Small Cell Lung Cancer, Renal Cancer and Breast Cancer (MDA-MB-468). The X-ray diffraction study of the indolizines with phenanthroline skeleton prove a flat coplanar structure which, corroborated with their anticancer activity, allow us to suggest that an interaction with DNA (via an intercalation mechanism) would be reasonable.
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      PubDate: 2015-05-06T13:33:05Z
       
  • Discovery of novel spiro 1,3,4-thiadiazolines as potent, orally
           bioavailable and brain penetrant KSP inhibitors
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Umar Faruk Mansoor , Angie R. Angeles , Chaoyang Dai , Liping Yang , Dilrukshi Vitharana , Andrea D. Basso , Kimberly Gray , Huadong Tang , Ming Liu , Lianzhu Liang , Omaira Allbritton , M. Arshad Siddiqui
      Kinesin spindle protein (KSP) is a mitotic kinesin that is expressed only in proliferating cells and plays a key role in spindle pole separation, formation of a bipolar mitotic spindle, as well as centrosome separation and maturation. Inhibition of KSP has the potential to provide anti-tumor activity while avoiding peripheral neuropathy associated with some microtubule-targeted drugs. Based on MK-0731 and related heterocyclic compounds targeting the KSP monastrol binding site, structurally constrained spiro-cyclic KSP inhibitors were designed. In particular, rapid evaluation and optimization of the novel spiro 1,3,4-thiadiazolines resulted in a series of potent KSP inhibitors demonstrating mechanism based activities in cells, including induction of the mitotic marker phospho-histone H3 and induction of monaster spindle formation. Further optimization of the pharmacokinetic (PK) properties afforded MK-8267 as a potent, orally bioavailable and brain penetrant KSP inhibitor which showed anti-tumor activity in preclinical xenograft models.
      Graphical abstract image

      PubDate: 2015-05-06T13:33:05Z
       
  • Diarylsulfonamides and their bioisosteres as dual inhibitors of alkaline
           phosphatase and carbonic anhydrase: Structure activity relationship and
           molecular modelling studies
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Mariya al-Rashida , Syeda Abida Ejaz , Sharafat Ali , Aisha Shaukat , Mehwish Hamayoun , Maqsood Ahmed , Jamshed Iqbal
      The effect of bioisosteric replacement of carboxamide linking group with sulfonamide linking group, on alkaline phosphatase (AP) and carbonic anhydrase (CA) inhibition activity of aromatic benzenesulfonamides was investigated. A series of carboxamide linked aromatic benzenesulfonamides 1a–1c, 2a–2d and their sulfonamide linked bioisosteres 3a–3d, 4a–4d was synthesized and evaluated for inhibitory activity against bovine tissue non-specific alkaline phosphatase (TNAP), intestinal alkaline phosphatase (IAP) and bCA II. A significant increase in CA inhibition activity was observed upon bioisosteric replacement of carboxamide linking group with a sulfonamide group. Some of these compounds were identified as highly potent and selective AP inhibitors. Compounds 1b, 2b, 3d, 4d 5b and 5c were found to be selective bTNAP inhibitors, whereas compounds 1a, 1c, 2a, 2c, 2d, 3a, 3c, 4a, 4b, 4c, 5a were found to be selective bIAP inhibitors. For most active AP inhibitor 3b, detailed kinetic studies indicated a competitive mode of inhibition against tissue non-specific alkaline phosphatase (TNAP) and non-competitive mode of inhibition against intestinal alkaline phosphatase (IAP). Molecular docking studies were carried out to rationalize important binding site interactions.
      Graphical abstract image

      PubDate: 2015-05-06T13:33:05Z
       
  • The β-carbonic anhydrase from the malaria mosquito Anopheles gambiae
           is highly inhibited by sulfonamides
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Leo Syrjänen , Marianne Kuuslahti , Martti Tolvanen , Daniela Vullo , Seppo Parkkila , Claudiu T. Supuran
      A β-carbonic anhydrase (CA, EC 4.2.1.1) was cloned, purified and characterized from Anopheles gambiae, the mosquito species mainly involved in the transmission of malaria. The new enzyme, AgaCA, showed a significant catalytic activity for the physiologic reaction, CO2 hydration to bicarbonate and protons, with a k cat of 7.2×105 s−1 and k cat/K m of 5.6×107 M−1 s−1, being thus similar to parasite β-CAs which were discovered earlier as drug targets for antifungal or anti-protozoan agents. An inhibition study of AgaCA with a panel of aromatic, aliphatic and heterocyclic sulfonamides allowed us to identify several low nanomolar inhibitors of the enzyme. Benzolamide and aminobenzolamide showed inhibition constants of 6.8–9.8nM, whereas a structurally related aromatic derivative, 4-(2-hydroxymethyl-4-nitrophenyl-sulfonamidoethyl)-benzenesulfonamide was the strongest inhibitor with a K I of 6.1nM. As β-CAs are not present in mammals, including humans, finding effective and selective A. gambiae CA inhibitors may lead to alternative procedures for controlling malaria by impairing the growth of its transmission vector, the mosquito.
      Graphical abstract image

      PubDate: 2015-05-06T13:33:05Z
       
  • The design, synthesis and biological evaluation of conformationally
           restricted 4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as
           multi-targeted receptor tyrosine kinase and microtubule inhibitors as
           potential antitumor agents
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Xin Zhang , Sudhir Raghavan , Michael Ihnat , Ernest Hamel , Cynthia Zammiello , Anja Bastian , Susan L. Mooberry , Aleem Gangjee
      A series of eleven conformationally restricted, 4-substituted 2,6-dimethylfuro[2,3-d]pyrimidines was designed to explore the bioactive conformation required for dual inhibition of microtubule assembly and receptor tyrosine kinases (RTKs), and their biological activities are reported. All three rotatable single bonds in the lead compound 1 were sequentially restricted to address the role of each in SAR for microtubule and RTK inhibitory effects. Compounds 2, 3, 7 and 10 showed microtubule depolymerizing activity comparable to or better than the lead 1, some with nanomolar EC50 values. While compound 8 had no effect on microtubules, 8 and 10 both showed potent RTK inhibition with nanomolar IC50s. These compounds confirm that the bioactive conformation for RTK inhibition is different from that for tubulin inhibition. The tetrahydroquinoline analog 10 showed the most potent dual tubulin and RTK inhibitory activities (low nanomolar inhibition of EGFR, VEGFR2 and PDGFR-β). Compound 10 has highly potent activity against many NCI cancer cell lines, including several chemo-resistant cell lines, and could serve as a lead for further preclinical studies.
      Graphical abstract image

      PubDate: 2015-05-06T13:33:05Z
       
  • Novel pyrrole carboxamide inhibitors of JAK2 as potential treatment of
           myeloproliferative disorders
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Maria Gabriella Brasca , Paola Gnocchi , Marcella Nesi , Nadia Amboldi , Nilla Avanzi , Jay Bertrand , Simona Bindi , Giulia Canevari , Daniele Casero , Marina Ciomei , Nicoletta Colombo , Sabrina Cribioli , Gabriele Fachin , Eduard R. Felder , Arturo Galvani , Antonella Isacchi , Ilaria Motto , Achille Panzeri , Daniele Donati
      Compound 1, a hit from the screening of our chemical collection displaying activity against JAK2, was deconstructed for SAR analysis into three regions, which were explored. A series of compounds was synthesized leading to the identification of the potent and orally bioavailable JAK2 inhibitor 16 (NMS-P830), which showed an encouraging tumour growth inhibition in SET-2 xenograft tumour model, with evidence for JAK2 pathway suppression demonstrated by in vivo pharmacodynamic effects.
      Graphical abstract image

      PubDate: 2015-05-06T13:33:05Z
       
  • Synthesis and biological evaluation of open-chain analogs of cyclic
           peptides as inhibitors of cellular Shp2 activity
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Xiao-li Zhen , Wen-hui Yin , Xia Tian , Zhen-jie Ma , Shi-ming Fan , Jian-rong Han , Shouxin Liu
      A series of open-chain analogs of cyclic peptides was designed and synthesized using sansalvamide A as a model compound. All compounds exhibited low antitumor activity. Furthermore, the evaluation of their inhibitory potency toward IMPDH, SHP2, ACHE, proteasome, MAGL, and cathepsin B showed that all of the compounds were potent against protein tyrosine phosphatase Shp2. Specifically, compounds 1a, 1d, 2b, and 2f were found to inhibit SHP2 with IC50 values in the low micromolar range and good selectivity. Based on the molecular docking results, the binding modes of the chain cyclic peptides in the active center of SHP2 were discussed.
      Graphical abstract image

      PubDate: 2015-05-06T13:33:05Z
       
  • Synthesis and biological evaluation of novel selective androgen receptor
           modulators (SARMs). Part I
    • Abstract: Publication date: 15 May 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 10
      Author(s): Katsuji Aikawa , Toshio Miyawaki , Takenori Hitaka , Yumi N. Imai , Takahito Hara , Junichi Miyazaki , Masuo Yamaoka , Masami Kusaka , Naoyuki Kanzaki , Akihiro Tasaka , Mitsuru Shiraishi , Satoshi Yamamoto
      To develop effective drugs for hypogonadism, sarcopenia, and cachexia, we designed, synthesized, and evaluated selective androgen receptor modulators (SARMs) that exhibit not only anabolic effects on organs such as muscles and the central nervous system (CNS) but also neutral or antagonistic effects on the prostate. Based on the information obtained from a docking model with androgen receptor (AR), we modified a hit compound A identified through high-throughput screening. Among the prepared compounds, 1-(4-cyano-1-naphthyl)-2,3-disubstituted pyrrolidine derivatives 17h, 17m, and 17j had highly potent AR agonistic activities in vitro and good tissue selectivity in vivo. These derivatives increased the weight of the levator ani muscle without influencing the prostate and seminal vesicle. In addition, these compounds induced sexual behavior in castrated rats, indicating that the compounds could also act as agonists on the CNS.
      Graphical abstract image

      PubDate: 2015-05-06T13:33:05Z
       
  • Synthesis and evaluation of novel amide amino-β-lactam derivatives as
           cholesterol absorption inhibitors
    • Abstract: Publication date: Available online 30 March 2015
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Tonko Dražić , Vinay Sachdev , Christina Leopold , Jay V. Patankar , Martina Malnar , Silva Hećimović , Sanja Levak-Frank , Ivan Habuš , Dagmar Kratky
      The β-lactam cholesterol absorption inhibitor ezetimibe is so far the only representative of this class of compounds on the market today. The goal of this work was to synthesize new amide ezetimibe analogs from trans-3-amino-(3R,4R)-β-lactam and to test their cytotoxicity and activity as cholesterol absorption inhibitors. We synthesized six new amide ezetimibe analogs. All new compounds exhibited low toxicity in MDCKIIwt, hNPC1L1/MDCKII and HepG2 cell lines and showed significant inhibition of cholesterol uptake in hNPC1L1/MDCKII cells. In addition, we determined the activity of the three compounds to inhibit cholesterol absorption in vivo. Our results demonstrate that these compounds considerably reduce cholesterol concentrations in liver and small intestine of mice. Thus, our newly synthesized amide ezetimibe analogs are cholesterol absorption inhibitors in vitro and in vivo.
      Graphical abstract image

      PubDate: 2015-04-19T06:58:24Z
       
 
 
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