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  Subjects -> CHEMISTRY (Total: 830 journals)
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    - CHEMISTRY (580 journals)
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CHEMISTRY (580 journals)                  1 2 3 4 5 6 | Last

2D Materials     Hybrid Journal   (Followers: 4)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 31)
ACS Catalysis     Full-text available via subscription   (Followers: 27)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 15)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 9)
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: 380)
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  
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: 32)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 228)
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: 286)
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: 5)
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: 12)
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: 22)
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: 290)
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: 2)
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)
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)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 6)

        1 2 3 4 5 6 | Last

Journal Cover   Bioorganic & Medicinal Chemistry
  [32 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0968-0896
   Published by Elsevier Homepage  [2705 journals]
  • The relationship between target-class and the physicochemical properties
           of antibacterial drugs
    • Abstract: Publication date: Available online 28 April 2015
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Grace Mugumbate , John P. Overington
      The discovery of novel mechanism of action (MOA) antibacterials has been associated with the concept that antibacterial drugs occupy a differentiated region of physicochemical space compared to human-targeted drugs. With, in broad terms, antibacterials having higher molecular weight, lower logP and higher polar surface area (PSA). By analysing the physicochemical properties of about 1,700 approved drugs listed in the ChEMBL database, we show, that antibacterials for whose targets are riboproteins (i.e. composed of a complex of RNA and protein) fall outside the conventional human ‘drug-like’ chemical space; whereas antibacterials that modulate bacterial protein targets, generally comply with the ‘rule-of-five’ guidelines for classical oral human drugs. Our analysis suggests a strong target-class association for antibacterials – either protein-targeted or riboprotein-targeted. There is much discussion in the literature on the failure of screening approaches to deliver novel antibacterial lead series, and linkage of this poor success rate for antibacterials with the chemical space properties of screening collections. Our analysis suggests that consideration of target-class may be an underappreciated factor in antibacterial lead discovery, and that in fact bacterial protein-targets may well have similar binding site characteristics to human protein targets, and questions the assumption that larger, more polar compounds are a key part of successful future antibacterial discovery.
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      PubDate: 2015-05-03T05:05:45Z
       
  • 18F-AmBF3-MJ9: A novel radiofluorinated bombesin derivative for prostate
           cancer imaging
    • Abstract: Publication date: 1 April 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 7
      Author(s): Maral Pourghiasian , Zhibo Liu , Jinhe Pan , Zhengxing Zhang , Nadine Colpo , Kuo-Shyan Lin , David M. Perrin , François Bénard
      A novel radiofluorinated derivative of bombesin, 18F-AmBF3-MJ9, was synthesized and evaluated for its potential to image prostate cancer by targeting the gastrin releasing peptide receptor (GRPR). AmBF3-MJ9 was prepared from an ammoniomethyl-trifluoroborate (AmBF3) conjugated alkyne 2 and azidoacetyl-MJ9 via a copper-catalyzed click reaction, and had good binding affinity for GRPR (K i =0.5±0.1nM). The 18F-labeling was performed via a facile one-step 18F–19F isotope exchange reaction, and 18F-AmBF3-MJ9 was obtained in 23±5% (n =3) radiochemical yield in 25min with >99% radiochemical purity and 100±32GBq/μmol specific activity. 18F-AmBF3-MJ9 was stable in mouse plasma, and was partially (22–30%) internalized after binding to GRPR. Positron emission tomography (PET) imaging and biodistribution studies in mice showed fast renal excretion and good uptake of 18F-AmBF3-MJ9 by GRPR-expressing pancreas and PC-3 prostate cancer xenografts. Tumor uptake was 1.37±0.25%ID/g at 1h, and 2.20±0.13%ID/g at 2h post-injection (p.i.) with low background uptake and excellent tumor visualization (tumor-to-muscle ratios of 75.4±5.5). These data suggest that 18F-AmBF3-MJ9 is a promising PET tracer for imaging GRPR-expressing prostate cancers.
      Graphical abstract image

      PubDate: 2015-04-29T10:23:11Z
       
  • A peptide affinity reagent for isolating an intact and catalytically
           active multi-protein complex from mammalian cells
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Hinnerk Saathoff , Mattias Brofelth , Anne Trinh , Benjamin L. Parker , Daniel P. Ryan , Jason K.K. Low , Sarah R. Webb , Ana P.G. Silva , Joel P. Mackay , Nicholas E. Shepherd
      We have developed an approach for directly isolating an intact multi-protein chromatin remodeling complex from mammalian cell extracts using synthetic peptide affinity reagent 4. FOG1(1–15), a short peptide sequence known to target subunits of the nucleosome remodeling and deacetylase (NuRD) complex, was joined via a 35-atom hydrophilic linker to the StreptagII peptide. Loading this peptide onto Streptactin beads enabled capture of the intact NuRD complex from MEL cell nuclear extract. Gentle biotin elution yielded the desired intact complex free of significant contaminants and in a form that was catalytically competent in a nucleosome remodeling assay. The efficiency of 4 in isolating the NuRD complex was comparable to other reported methods utilising recombinantly produced GST–FOG1(1–45).
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      PubDate: 2015-04-29T10:23:11Z
       
  • Enhanced detection of type C botulinum neurotoxin by the Endopep-MS assay
           through optimization of peptide substrates
    • Abstract: Publication date: Available online 10 April 2015
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Dongxia Wang , Joan Krilich , Jakub Baudys , John R. Barr , Suzanne R. Kalb
      It is essential to have a simple, quick and sensitive method for the detection and quantification of botulinum neurotoxins, the most toxic substances and the causative agents of botulism. Type C botulinum neurotoxin (BoNT/C) represents one of the seven members of distinctive BoNT serotypes (A to G) that cause botulism in animals and avians. Here we report the development of optimized peptide substrates for improving the detection of BoNT/C and /CD mosaic toxins using an Endopep-MS assay, a mass spectrometry-based method that is able to rapidly and sensitively detect and differentiate all types of BoNTs by extracting the toxin with specific antibodies and detecting the unique cleavage products of peptide substrates. Based on the sequence of a short SNAP-25 peptide, we conducted optimization through a comprehensive process including length determination, terminal modification, single and multiple amino acid residue substitution, and incorporation of unnatural amino acid residues. Our data demonstrate that an optimal peptide provides a more than 200-fold improvement over the substrate currently used in the Endopep-MS assay for the detection of BoNT/C1 and /CD mosaic. Using the new substrate in a four-hour cleavage reaction, the limit of detection for the BoNT/C1 complex spiked in buffer, serum and milk samples was determined to be 0.5, 0.5 and 1mouseLD50/mL, respectively, representing a similar or higher sensitivity than that obtained by traditional mouse bioassay.
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      PubDate: 2015-04-29T10:23:11Z
       
  • Structure–activity studies in the development of a hydrazone based
           inhibitor of adipose-triglyceride lipase (ATGL)
    • Abstract: Publication date: Available online 4 March 2015
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Nicole Mayer , Martina Schweiger , Michaela-Christina Melcher , Christian Fledelius , Rudolf Zechner , Robert Zimmermann , Rolf Breinbauer
      Adipose triglyceride lipase (ATGL) catalyzes the degradation of cellular triacylglycerol stores and strongly determines the concentration of circulating fatty acids (FAs). High serum FA levels are causally linked to the development of insulin resistance and impaired glucose tolerance, which eventually progresses to overt type 2 diabetes. ATGL-specific inhibitors could be used to lower circulating FAs, which can counteract the development of insulin resistance. In this article, we report about structure–activity relationship (SAR) studies of small molecule inhibitors of ATGL based on a hydrazone chemotype. The SAR indicated that the binding pocket of ATGL requests rather linear compounds without bulky substituents. The best inhibitor showed an IC50 =10μM in an assay with COS7-cell lysate overexpressing murine ATGL.
      Graphical abstract image

      PubDate: 2015-04-29T10:23:11Z
       
  • Towards the computational design of protein post-translational regulation
    • Abstract: Publication date: Available online 25 April 2015
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Marta Strumillo , Pedro Beltrao
      Protein post-translational modifications (PTMs) are a fast and versatility mechanism used by the cell to regulate the function of proteins in response to changing conditions. PTMs can alter the activity of proteins by allosteric regulation or by controlling protein interactions, localization and abundance. Recent advances in proteomics have revealed the extent of regulation by PTMs and the different mechanisms used in nature to exert control over protein function via PTMs. These developments can serve as the foundation for the rational design of protein regulation. Here we review the advances in methods to determine the function of PTMs, protein allosteric control and examples of rational design of PTM regulation. These advances create an opportunity to move synthetic biology forward by making use of a level of regulation that is of yet unexplored.
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      PubDate: 2015-04-29T10:23:11Z
       
  • Reversible and irreversible small molecule inhibitors of monoamine oxidase
           B (MAO-B) investigated by biophysical techniques
    • Abstract: Publication date: 15 February 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 4
      Author(s): Rafael J. Rojas , Dale E. Edmondson , Terri Almos , Roderick Scott , Mark E. Massari
      Monoamine oxidase B (MAO-B) plays a key role in the metabolism of dopamine, a neurotransmitter critical for the maintenance of cognitive function. Consequently, MAO-B is an important therapeutic target for disorders characterized by a decline in dopaminergic neurotransmission, including Parkinson’s disease (PD). An emerging strategy in drug discovery is to utilize the biophysical approaches of thermal shift and isothermal titration calorimetry (ITC) to gain insight into binding modality and identify thermodynamically privileged chemical scaffolds. Described here is the development of such approaches for reversible and irreversible small molecule inhibitors of MAO-B. Investigation of soluble recombinant MAO-B revealed mechanism-based differences in the thermal shift and binding thermodynamic profiles of MAO-B inhibitors. Irreversible inhibitors demonstrated biphasic protein melt curves, large enthalpically favorable and entropically unfavorable binding, in contrast to reversible compounds, which were characterized by a dose-dependent increase in thermal stability and enthalpically-driven binding. The biophysical approaches described here aim to facilitate the discovery of next-generation MAO-B inhibitors.
      Graphical abstract image

      PubDate: 2015-04-29T10:23:11Z
       
  • Stereoselective synthesis of a natural product inspired
           tetrahydroindolo[2,3-a]-quinolizine compound library
    • Abstract: Publication date: Available online 17 January 2015
      Source:Bioorganic & Medicinal Chemistry
      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: 2015-04-29T10:23:11Z
       
  • Branching cascades provide access to two amino-oxazoline compound
           libraries
    • Abstract: Publication date: Available online 13 January 2015
      Source:Bioorganic & Medicinal Chemistry
      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.
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      PubDate: 2015-04-29T10:23:11Z
       
  • Ligand-based virtual screening identifies a family of selective
           cannabinoid receptor 2 agonists
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Matteo Gianella-Borradori , Ivy Christou , Carole J.R. Bataille , Rebecca L. Cross , Graham M. Wynne , David R. Greaves , Angela J. Russell
      The cannabinoid receptor 2 (CB2R) has been linked with the regulation of inflammation, and selective receptor activation has been proposed as a target for the treatment of a range of inflammatory diseases such as atherosclerosis and arthritis. In order to identify selective CB2R agonists with appropriate physicochemical and ADME properties for future evaluation in vivo, we first performed a ligand-based virtual screen. Subsequent medicinal chemistry optimisation studies led to the identification of a new class of selective CB2R agonists. Several examples showed high levels of activity (EC50 <200nM) and binding affinity (K i <200nM) for the CB2R, and no detectable activity at the CB1R. The most promising example, DIAS2, also showed favourable in vitro metabolic stability and absorption properties along with a clean selectivity profile when evaluated against a panel of GPCRs and kinases.
      Graphical abstract image

      PubDate: 2015-04-29T10:23:11Z
       
  • Perspective: Challenges and opportunities in TB drug discovery from
           phenotypic screening
    • Abstract: Publication date: Available online 24 December 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Ujjini H. Manjunatha , Paul W. Smith
      Tuberculosis poses a major global health problem and multi-drug resistant strains are increasingly prevalent. Hence there is an urgent need to discover new TB drugs. Cell based phenotypic screening represents a powerful approach to identify anti-mycobacterial compounds and elucidate novel targets. Three high throughput phenotypic screens were performed at NITD against mycobacterium. Hits were identified and chemical series selected for optimisation. This produced compounds with good in vitro anti-mycobacterial activity and pharmacokinetic properties. Some compounds displayed oral activity in mouse efficacy models of TB. Herein, we review the TB discovery efforts at NITD and share experiences in optimisation of phenotypic hits, describing challenges encountered and lessons learned. We also offer perspectives to facilitate future selection and advancement of phenotypic hits.
      Graphical abstract image

      PubDate: 2015-04-29T10:23:11Z
       
  • Synthesis and evaluation of the 2,4-diaminoquinazoline series as
           anti-tubercular agents
    • Abstract: Publication date: 15 December 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 24
      Author(s): Joshua Odingo , Theresa O’Malley , Edward A. Kesicki , Torey Alling , Mai Ann Bailey , Julie Early , Juliane Ollinger , Suryakanta Dalai , Naresh Kumar , Ravindra Vikram Singh , Philip A. Hipskind , Jeffrey W. Cramer , Thomas Ioerger , James Sacchettini , Richard Vickers , Tanya Parish
      The 2,4-diaminoquinazoline class of compounds has previously been identified as an effective inhibitor of Mycobacterium tuberculosis growth. We conducted an extensive evaluation of the series for its potential as a lead candidate for tuberculosis drug discovery. Three segments of the representative molecule N-(4-fluorobenzyl)-2-(piperidin-1-yl)quinazolin-4-amine were examined systematically to explore structure–activity relationships influencing potency. We determined that the benzylic amine at the 4-position, the piperidine at 2-position and the N-1 (but not N-3) are key activity determinants. The 3-deaza analog retained similar activity to the parent molecule. Biological activity was not dependent on iron or carbon source availability. We demonstrated through pharmacokinetic studies in rats that good in vivo compound exposure is achievable. A representative compound demonstrated bactericidal activity against both replicating and non-replicating M. tuberculosis. We isolated and sequenced M. tuberculosis mutants resistant to this compound and observed mutations in Rv3161c, a gene predicted to encode a dioxygenase, suggesting that the compound may act as a pro-drug.
      Graphical abstract image

      PubDate: 2015-04-29T10:23:11Z
       
  • Synthesis of aminoacylated N6,N6-dimethyladenosine solid support for
           efficient access to hydrolysis-resistant 3′-charged tRNA mimics
    • Abstract: Publication date: 15 December 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 24
      Author(s): Sandro Neuner , Ronald Micura
      RNA-amino acid and RNA-peptide conjugates that mimic charged tRNA 3′-ends are valuable substrates for structural and functional investigations of ribosomal complexes. To obtain such conjugates, most synthetic approaches that are found in the literature make use of puromycin. This well available aminonucleoside antibiotic contains a dimethylamino group at the nucleobase and a methylated tyrosine that is connected via an amide linkage to the ribose moiety. To increase structural diversity, we present the synthesis of a N 6,N 6-dimethylated 3′-azido-3′-deoxyadenosine precursor that can be coupled to any amino acid. Further derivatization results in the solid support that is eligible for the preparation of stable 3′-aminoacyl- or 3′-peptidyl-tRNA termini with an amide instead of the natural ester linkage. The present work expands our previously established route that delivered a broad range of peptidyl-tRNA mimics to the corresponding counterparts with N 6,N 6-dimethylation pattern of the terminal adenosine (A76). This aspect is of significance to modulate the binding preferences of the mimics for ribosomal A- versus P-site.
      Graphical abstract image

      PubDate: 2015-04-29T10:23:11Z
       
  • Computational identification of a phospholipidosis toxicophore using 13C
           and 15N NMR-distance based fingerprints
    • Abstract: Publication date: 1 December 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 23
      Author(s): Svetoslav H. Slavov , Jon G. Wilkes , Dan A. Buzatu , Naomi L. Kruhlak , James M. Willard , Joseph P. Hanig , Richard D. Beger
      Modified 3D-SDAR fingerprints combining 13C and 15N NMR chemical shifts augmented with inter-atomic distances were used to model the potential of chemicals to induce phospholipidosis (PLD). A curated dataset of 328 compounds (some of which were cationic amphiphilic drugs) was used to generate 3D-QSDAR models based on tessellations of the 3D-SDAR space with grids of different density. Composite PLS models averaging the aggregated predictions from 100 fully randomized individual models were generated. On each of the 100 runs, the activities of an external blind test set comprised of 294 proprietary chemicals were predicted and averaged to provide composite estimates of their PLD-inducing potentials (PLD+ if PLD is observed, otherwise PLD−). The best performing 3D-QSDAR model utilized a grid with a density of 8ppm×8ppm in the C–C region, 8ppm×20ppm in the C–N region and 20ppm×20ppm in the N–N region. The classification predictive performance parameters of this model evaluated on the basis of the external test set were as follows: accuracy=0.70, sensitivity=0.73 and specificity=0.66. A projection of the most frequently occurring bins on the standard coordinate space suggested a toxicophore composed of an aromatic ring with a centroid 3.5–7.5Å distant from an amino-group. The presence of a second aromatic ring separated by a 4–5Å spacer from the first ring and at a distance of between 5.5Å and 7Å from the amino-group was also associated with a PLD+ effect. These models provide comparable predictive performance to previously reported models for PLD with the added benefit of being based entirely on non-confidential, publicly available training data and with good predictive performance when tested in a rigorous, external validation exercise.
      Graphical abstract image

      PubDate: 2015-04-29T10:23:11Z
       
  • 2- and 3-substituted imidazo[1,2-a]pyrazines as inhibitors of bacterial
           type IV secretion
    • Abstract: Publication date: 15 November 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 22
      Author(s): James R. Sayer , Karin Walldén , Thomas Pesnot , Frederick Campbell , Paul J. Gane , Michela Simone , Hans Koss , Floris Buelens , Timothy P. Boyle , David L. Selwood , Gabriel Waksman , Alethea B. Tabor
      A novel series of 8-amino imidazo[1,2-a]pyrazine derivatives has been developed as inhibitors of the VirB11 ATPase HP0525, a key component of the bacterial type IV secretion system. A flexible synthetic route to both 2- and 3-aryl substituted regioisomers has been developed. The resulting series of imidazo[1,2-a]pyrazines has been used to probe the structure–activity relationships of these inhibitors, which show potential as antibacterial agents.
      Graphical abstract image

      PubDate: 2015-04-29T10:23:11Z
       
  • Neuraminidase inhibitory activities of quaternary isoquinoline alkaloids
           from Corydalis turtschaninovii rhizome
    • Abstract: Publication date: 1 November 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 21
      Author(s): Jang Hoon Kim , Young Bae Ryu , Woo Song Lee , Young Ho Kim
      Clostridium perfringens is a Gram-positive spore-forming bacterium that causes food poisoning. The neuraminidase (NA) protein of C. perfringens plays a pivotal role in bacterial proliferation and is considered a novel antibacterial drug target. Based on screens for novel NA inhibitors, a 95% EtOH extract of Corydalis turtschaninovii rhizome showed NA inhibitory activity (68% at 30μg/ml), which resulted in the isolation of 10 isoquinoline alkaloids; namely, palmatine (1), berberine (2), coptisine (3), pseudodehydrocorydaline (4), jatrorrhizine (5), dehydrocorybulbine (6), pseudocoptisine (7), glaucine (8), corydaline (9) and tetrahydrocoptisine (10). Interestingly, seven quaternary isoquinoline alkaloids 1–7 (IC50 =12.8±1.5 to 65.2±4.5μM) showed stronger NA inhibitory activity than the tertiary alkaloids 8–10. In addition, highly active compounds 1 and 2 showed reversible non-competitive behavior based on a kinetic study. Molecular docking simulations using the Autodock 4.2 software increased our understanding of receptor–ligand binding of these compounds. In addition, we demonstrated that compounds 1 and 2 suppressed bacterial growth.
      Graphical abstract image

      PubDate: 2015-04-29T10:23:11Z
       
  • Design, synthesis and SAR exploration of tri-substituted 1,2,4-triazoles
           as inhibitors of the annexin A2–S100A10 protein interaction
    • Abstract: Publication date: 1 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 19
      Author(s): Tummala R.K. Reddy , Chan Li , Xiaoxia Guo , Peter M. Fischer , Lodewijk V. Dekker
      Recent target validation studies have shown that inhibition of the protein interaction between annexin A2 and the S100A10 protein may have potential therapeutic benefits in cancer. Virtual screening identified certain 3,4,5-trisubstituted 4H-1,2,4-triazoles as moderately potent inhibitors of this interaction. A series of analogues were synthesized based on the 1,2,4-triazole scaffold and were evaluated for inhibition of the annexin A2–S100A10 protein interaction in competitive binding assays. 2-[(5-{[(4,6-Dimethylpyrimidin-2-yl)sulfanyl]methyl}-4-(furan-2-ylmethyl)-4H-1,2,4-triazol-3-yl)sulfanyl]-N-[4-(propan-2-yl)phenyl]acetamide (36) showed improved potency and was shown to disrupt the native complex between annexin A2 and S100A10.
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      PubDate: 2015-04-29T10:23:11Z
       
  • A C-14 labeled Py–Im polyamide localizes to a subcutaneous prostate
           cancer tumor
    • Abstract: Publication date: 15 August 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 16
      Author(s): Jevgenij A. Raskatov , James W. Puckett , Peter B. Dervan
      In an effort to quantitate Py–Im polyamide concentrations in vivo, we synthesized the C-14 radioactively labeled compounds 1–3, and investigated their tumor localization in a subcutaneous xenograft model of prostate cancer (LNCaP). Tumor concentrations were compared with representative host tissues, and exhibited a certain degree of preferential localization to the xenograft. Compound accumulation upon repeated administration was measured. Py–Im polyamide 1 was found to accumulate in LNCaP tumors at concentrations similar to the IC50 value for this compound in cell culture experiments.
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      PubDate: 2015-04-29T10:23:11Z
       
  • An azido-oxazolidinone antibiotic for live bacterial cell imaging and
           generation of antibiotic variants
    • Abstract: Publication date: 15 August 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 16
      Author(s): Wanida Phetsang , Mark A.T. Blaskovich , Mark S. Butler , Johnny X. Huang , Johannes Zuegg , Sreeman K. Mamidyala , Soumya Ramu , Angela M. Kavanagh , Matthew A. Cooper
      An azide-functionalised analogue of the oxazolidinone antibiotic linezolid was synthesised and shown to retain antimicrobial activity. Using facile ‘click’ chemistry, this versatile intermediate can be further functionalised to explore antimicrobial structure–activity relationships or conjugated to fluorophores to generate fluorescent probes. Such probes can report bacteria and their location in a sample in real time. Modelling of the structures bound to the cognate 50S ribosome target demonstrates binding to the same site as linezolid is possible. The fluorescent probes were successfully used to image Gram-positive bacteria using confocal microscopy.
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      PubDate: 2015-04-29T10:23:11Z
       
  • Inhibition by active site directed covalent modification of human
           glyoxalase I
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Ronald J. Holewinski , Donald J. Creighton
      The glyoxalase pathway is responsible for conversion of cytotoxic methylglyoxal (MG) to d-lactate. MG toxicity arises from its ability to form advanced glycation end products (AGEs) on proteins, lipids and DNA. Studies have shown that inhibitors of glyoxalase I (GLO1), the first enzyme of this pathway, have chemotherapeutic effects both in vitro and in vivo, presumably by increasing intracellular MG concentrations leading to apoptosis and cell death. Here, we present the first molecular inhibitor, 4-bromoacetoxy-1-(S-glutathionyl)-acetoxy butane (4BAB), able to covalently bind to the free sulfhydryl group of Cys60 in the hydrophobic binding pocket adjacent to the enzyme active site and partially inactivate the enzyme. Our data suggests that partial inactivation of homodimeric GLO1 is due to the modification at only one of the enzymatic active sites. Although this molecule may have limited use pharmacologically, it may serve as an important template for the development of new GLO1 inhibitors that may combine this strategy with ones already reported for high affinity GLO1 inhibitors, potentially improving potency and specificity.
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      PubDate: 2015-04-29T10:23:11Z
       
  • Inhibitory effects of novel synthetic methimazole derivatives on mushroom
           tyrosinase and melanogenesis
    • Abstract: Publication date: 1 May 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 9
      Author(s): Chin-Feng Chan , Shih-Ting Lai , Yi-Cin Guo , Ming-Jen Chen
      In this study, we synthesized 4 methimazole (2-mercapto-1-methylimidazole, MMI) derivatives. The kinetics of inhibition on mushroom tyrosinase by methimazole and its derivatives were investigated. The results indicated that tert-butyl 3-methyl-2-sulfanylidene-2,3-dihydro-1H-imidazole-1-carboxylate (compound 3; 3), 2-mercaptoimidazole (MI; compound 1; 1) and MMI (compound 2; 2) significantly inhibited tyrosinase activity in a dose-dependent manner, exhibiting an IC50 value of 1.50mM, 4.11mM, and 1.43mM. However, compound 4 (4), compound 5 (5), and compound 6 (6) exerted no inhibitory effect on mushroom tyrosinase activity. Kinetic analysis indicated that 3 was a noncompetitive tyrosinase inhibitor, whereas both 1 and 2 were exhibited as mixed-type tyrosinase inhibitors. Furthermore, 3 exerted a potent inhibitory effect on intracellular melanin formation in the B16/F10 murine melanoma cells and did not cause cytotoxicity, as 1 and 2 did.
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      PubDate: 2015-04-29T10:23:11Z
       
  • Chemically defined polyethylene glycol siRNA conjugates with enhanced gene
           silencing effect
    • Abstract: Publication date: 1 April 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 7
      Author(s): Zuzana Gaziova , Volker Baumann , Anna-Maria Winkler , Johannes Winkler
      The therapeutic application of siRNA suffers from poor bioavailability caused by rapid degradation and elimination. The covalent attachment of PEG is a universal concept to increase molecular size and enhance the pharmacokinetic properties of biomacromolecules. We devised a facile approach for attachment of PEG molecules with a defined molecular weight, and successful purification of the resulting conjugates. We directly conjugated structurally defined PEG chains with twelve ethylene glycol units to the 3′-terminal hydroxyl group of both sense and antisense strands via an aminoalkyl linker. The conjugates were easily purified by HPLC and successful PEGylation and molecule integrity were confirmed by ESI-MS. The evaluation of in vitro gene knockdown of two different targets in MCF-7 breast cancer cells showed stable pharmacologic activity when combined with a standard transfection reagent. Sense strand PEGylation even increased the silencing potency of a CRCX4-siRNA which had modest activity in its wild-type form. The results indicate that PEG chains at the 3′-terminus of both strands of siRNA are well tolerated by the RNAi effector. The attachment of short, chemically defined PEG chains is a feasible approach to improve the pharmacokinetic properties of siRNA, and can be combined with other targeted and untargeted delivery vehicles.
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      PubDate: 2015-04-29T10:23:11Z
       
  • Lipoic acid analogs with enhanced pharmacological activity
    • Abstract: Publication date: 1 January 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 1
      Author(s): Steven A. Kates , Ralph A. Casale , Alexander Baguisi , Reinier Beeuwkes III
      Lipoic acid (1,2-dithiolane-3-pentanoic acid) is a pharmacophore with unique antioxidant and cytoprotective properties. We synthesized a library based upon the condensation of natural and unnatural amino acids with the carboxylic acid moiety of lipoic acid. SAR studies were conducted using a cardiac ischemia-reperfusion animal model. Cytoprotective efficacy was associated with the R-enantiomer of the dithiolane. Potency of library compounds was dictated by the acidic strength of the adduct. α-N-[(R)-1,2-dithiolane-3-pentanoyl]-l-glutamyl-l-alanine, designated CMX-2043, was chosen for further pharmacologic evaluation.
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      PubDate: 2015-04-29T10:23:11Z
       
  • Differential response of orthologous l,l-diaminopimelate aminotransferases
           (DapL) to enzyme inhibitory antibiotic lead compounds
    • Abstract: Publication date: 1 January 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 1
      Author(s): Shaun M.K. McKinnie , Eva M. Rodriguez-Lopez , John C. Vederas , Jennifer M. Crowther , Hironori Suzuki , Renwick C.J. Dobson , Thomas Leustek , Alexander J. Triassi , Matthew S. Wheatley , André O. Hudson
      l,l-Diaminopimelate aminotransferase (DapL) is an enzyme required for the biosynthesis of meso-diaminopimelate (m-DAP) and l-lysine (Lys) in some bacteria and photosynthetic organisms. m-DAP and Lys are both involved in the synthesis of peptidoglycan (PG) and protein synthesis. DapL is found in specific eubacterial and archaeal lineages, in particular in several groups of pathogenic bacteria such as Leptospira interrogans (LiDapL), the soil/water bacterium Verrucomicrobium spinosum (VsDapL) and the alga Chlamydomonas reinhardtii (CrDapL). Here we present the first comprehensive inhibition study comparing the kinetic activity of DapL orthologs using previously active small molecule inhibitors formerly identified in a screen with the DapL of Arabidopsis thaliana (AtDapL), a flowering plant. Each inhibitor is derived from one of four classes with different central structural moieties: a hydrazide, a rhodanine, a barbiturate, or a thiobarbituate functionality. The results show that all five compounds tested were effective at inhibiting the DapL orthologs. LiDapL and AtDapL showed similar patterns of inhibition across the inhibitor series, whereas the VsDapL and CrDapL inhibition patterns were different from that of LiDapL and AtDapL. CrDapL was found to be insensitive to the hydrazide (IC50 >200μM). VsDapL was found to be the most sensitive to the barbiturate and thiobarbiturate containing inhibitors (IC50 ∼5μM). Taken together, the data shows that the homologs have differing sensitivities to the inhibitors with IC50 values ranging from 4.7 to 250μM. In an attempt to understand the basis for these differences the four enzymes were modeled based on the known structure of AtDapL. Overall, it was found that the enzyme active sites were conserved, although the second shell of residues close to the active site were not. We conclude from this that the altered binding patterns seen in the inhibition studies may be a consequence of the inhibitors forming additional interactions with residues proximal to the active site, or that the inhibitors may not act by binding to the active site. Compounds that are specific for DapL could be potential biocides (antibiotic, herbicide or algaecide) that are nontoxic to animals since animals do not contain the enzymes necessary for PG or Lys synthesis. This study provides important information to expand our current understanding of the structure/activity relationship of DapL and putative inhibitors that are potentially useful for the design and or discovery of novel biocides.
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      PubDate: 2015-04-29T10:23:11Z
       
  • Antioxidant action of propolis on mouse lungs exposed to short-term
           cigarette smoke
    • Abstract: Publication date: 15 December 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 24
      Author(s): Alan Aguiar Lopes , Thiago Santos Ferreira , Renata Tiscoski Nesi , Manuella Lanzetti , Karla Maria Pereira Pires , Ari Miranda Silva , Ricardo Moreira Borges , Antonio Jorge Ribeiro Silva , Samuel Santos Valença , Luís Cristóvão Porto
      Propolis is a natural product with antioxidant properties. In this study, we tested the efficacy of propolis against acute lung inflammation (ALI) caused by cigarette smoke (CS). C57BL6 male mice were exposed to CS and treated with propolis (200mg/kg orally, CS+P) or only with propolis (P). A Control group treated with propolis was sham-smoked (Control+P). We collected the lungs for histological and biochemical analyses. We observed an increase in alveolar macrophages and neutrophils in the CS group compared with the Control+P. These counts reduced in the CS+P group compared to the CS group. The treatment with propolis normalized all biochemical parameters in the CS+P group compared with the CS group, including nitrite, myeloperoxidase level, antioxidant enzyme activities (superoxide dismutase, catalase and glutathione peroxidase), reduced glutathione/oxidized glutathione ratio and malondialdehyde. Additionally, TNF-α expression reduced in the CS+P group when compared with the CS group. These data imply a potential antioxidant and anti-inflammatory role for propolis with regard to ALI caused by CS in mice.
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      PubDate: 2015-04-29T10:23:11Z
       
  • Discovery of a novel activator of 5-lipoxygenase from an anacardic acid
           derived compound collection
    • Abstract: Publication date: 15 December 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 24
      Author(s): Rosalina Wisastra , Petra A.M. Kok , Nikolaos Eleftheriadis , Matthew P. Baumgartner , Carlos J. Camacho , Hidde J. Haisma , Frank J. Dekker
      Lipoxygenases (LOXs) and cyclooxygenases (COXs) metabolize poly-unsaturated fatty acids into inflammatory signaling molecules. Modulation of the activity of these enzymes may provide new approaches for therapy of inflammatory diseases. In this study, we screened novel anacardic acid derivatives as modulators of human 5-LOX and COX-2 activity. Interestingly, a novel salicylate derivative 23a was identified as a surprisingly potent activator of human 5-LOX. This compound showed both non-competitive activation towards the human 5-LOX activator adenosine triphosphate (ATP) and non-essential mixed type activation against the substrate linoleic acid, while having no effect on the conversion of the substrate arachidonic acid. The kinetic analysis demonstrated a non-essential activation of the linoleic acid conversion with a K A of 8.65μM, αK A of 0.38μM and a β value of 1.76. It is also of interest that a comparable derivative 23d showed a mixed type inhibition for linoleic acid conversion. These observations indicate the presence of an allosteric binding site in human 5-LOX distinct from the ATP binding site. The activatory and inhibitory behavior of 23a and 23d on the conversion of linoleic compared to arachidonic acid are rationalized by docking studies, which suggest that the activator 23a stabilizes linoleic acid binding, whereas the larger inhibitor 23d blocks the enzyme active site.
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      PubDate: 2015-04-29T10:23:11Z
       
  • Exploring a potential palonosetron allosteric binding site in the 5-HT3
           receptor
    • Abstract: Publication date: 1 December 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 23
      Author(s): Marta Del Cadia , Francesca De Rienzo , David A. Weston , Andrew J. Thompson , Maria Cristina Menziani , Sarah C.R. Lummis
      Palonosetron (Aloxi) is a potent second generation 5-HT3 receptor antagonist whose mechanism of action is not yet fully understood. Palonosetron acts at the 5-HT3 receptor binding site but recent computational studies indicated other possible sites of action in the extracellular domain. To test this hypothesis we mutated a series of residues in the 5-HT3A receptor subunit (Tyr73, Phe130, Ser163, and Asp165) and in the 5-HT3B receptor subunit (His73, Phe130, Glu170, and Tyr143) that were previously predicted by in silico docking studies to interact with palonosetron. Homomeric (5-HT3A) and heteromeric (5-HT3AB) receptors were then expressed in HEK293 cells to determine the potency of palonosetron using both fluorimetric and radioligand methods to test function and ligand binding, respectively. The data show that the substitutions have little or no effect on palonosetron inhibition of 5-HT-evoked responses or binding. In contrast, substitutions in the orthosteric binding site abolish palonosetron binding. Overall, the data support a binding site for palonosetron at the classic orthosteric binding pocket between two 5-HT3A receptor subunits but not at allosteric sites previously identified by in silico modelling and docking.
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      PubDate: 2015-04-29T10:23:11Z
       
  • 5-Deazaflavin derivatives as inhibitors of p53 ubiquitination by HDM2
    • Abstract: Publication date: 15 November 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 22
      Author(s): Michael P. Dickens , Patricia Roxburgh , Andreas Hock , Mokdad Mezna , Barrie Kellam , Karen H. Vousden , Peter M. Fischer
      Based on previous reports of certain 5-deazaflavin derivatives being capable of activating the tumour suppressor p53 in cancer cells through inhibition of the p53-specific ubiquitin E3 ligase HDM2, we have conducted an structure–activity relationship (SAR) analysis through systematic modification of the 5-deazaflavin template. This analysis shows that HDM2-inhibitory activity depends on a combination of factors. The most active compounds (e.g., 15) contain a trifluoromethyl or chloro substituent at the deazaflavin C9 position and this activity depends to a large extent on the presence of at least one additional halogen or methyl substituent of the phenyl group at N10. Our SAR results, in combination with the HDM2 RING domain receptor recognition model we present, form the basis for the design of drug-like and potent activators of p53 for potential cancer therapy.
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      PubDate: 2015-04-29T10:23:11Z
       
  • Discovery of a novel 5-carbonyl-1H-imidazole-4-carboxamide class of
           inhibitors of the HIV-1 integrase–LEDGF/p75 interaction
    • Abstract: Publication date: 1 October 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 19
      Author(s): Erik Serrao , Zhong-Liang Xu , Bikash Debnath , Frauke Christ , Zeger Debyser , Ya-Qiu Long , Nouri Neamati
      Though much progress has been made in the inhibition of HIV-1 integrase catalysis, clinical resistance mutations have limited the promise of long-term drug prescription. Consequently, allosteric inhibition of integrase activity has emerged as a promising approach to antiretroviral discovery and development. Specifically, inhibitors of the interaction between HIV-1 integrase and cellular cofactor LEDGF/p75 have been validated to diminish proviral integration in cells and deliver a potent reduction in viral replicative capacity. Here, we have contributed to the development of novel allosteric integrase inhibitors with a high-throughput AlphaScreen-based random screening approach, with which we have identified novel 5-carbonyl-1H-imidazole-4-carboxamides capable of inhibiting the HIV-1 integrase–LEDGF/p75 interaction in vitro. Following a structure–activity relationship analysis of the initial 1H-imidazole-4,5-dicarbonyl core, we optimized the compound’s structure through an industrial database search, and we went further to synthesize a selective and non-cytotoxic panel of inhibitors with enhanced potency.
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      PubDate: 2015-04-29T10:23:11Z
       
  • Enantioselective binding of chiral 1,14-dimethyl[5]helicene–spermine
           ligands with B- and Z-DNA
    • Abstract: Publication date: 1 October 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 19
      Author(s): Genichiro Tsuji , Kyoko Kawakami , Shigeki Sasaki
      Duplex DNA adopts a right-handed B-DNA conformation under physiological conditions. Z-DNA, meanwhile, has a left-handed helical structure and is in equilibrium with right-handed B-DNA. We recently reported that the bisnaphthyl maleimide–spermine conjugate (1) induced a B- to Z-DNA transition with high efficiency at low salt concentrations. It was also found that the bisnaphthyl ligand (1) spontaneously transformed into the corresponding [5]helicene derivative (2). Because [5]helicene 2 can potentially be chiral and because the chiral discrimination of B- and Z-DNA is also of interest, we became interested in whether enatiomerically pure [5]helicene–spermine conjugates might discriminate the chirality of B- or Z-DNA. In this study, we have demonstrated an efficient synthesis of chiral DNA-binding ligands by the conjugation of a [5]helicene unit with a spermine unit. These chiral helicene ligands exhibited recognition of B- and Z-DNA, with (P)-3 displaying preference for B-DNA and (M)-3 for Z-DNA. The characteristic features of the helicene–spermine ligands developed in this study include two points: the cationic spermine portion produces electrostatic interactions along the phosphate backbone of the minor groove, and the helicene forms complexes in an end-stacking mode. Such binding modes, together with the thermodynamic parameters, account for the mode of chiral recognition of (P)- and (M)-3 for B- and Z-DNA.
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      PubDate: 2015-04-29T10:23:11Z
       
  • Synthesis and evaluation of heteroaryl substituted diazaspirocycles as
           scaffolds to probe the ATP-binding site of protein kinases
    • Abstract: Publication date: 15 September 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 18
      Author(s): Charlotte E. Allen , Chiau L. Chow , John J. Caldwell , Isaac M. Westwood , Rob L. M. van Montfort , Ian Collins
      With the success of protein kinase inhibitors as drugs to target cancer, there is a continued need for new kinase inhibitor scaffolds. We have investigated the synthesis and kinase inhibition of new heteroaryl-substituted diazaspirocyclic compounds that mimic ATP. Versatile syntheses of substituted diazaspirocycles through ring-closing metathesis were demonstrated. Diazaspirocycles directly linked to heteroaromatic hinge binder groups provided ligand efficient inhibitors of multiple kinases, suitable as starting points for further optimization. The binding modes of representative diazaspirocyclic motifs were confirmed by protein crystallography. Selectivity profiles were influenced by the hinge binder group and the interactions of basic nitrogen atoms in the scaffold with acidic side-chains of residues in the ATP pocket. The introduction of more complex substitution to the diazaspirocycles increased potency and varied the selectivity profiles of these initial hits through engagement of the P-loop and changes to the spirocycle conformation, demonstrating the potential of these core scaffolds for future application to kinase inhibitor discovery.
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      PubDate: 2015-04-29T10:23:11Z
       
  • Investigation of acyclic uridine amide and 5′-amido nucleoside
           analogues as potential inhibitors of the Plasmodium falciparum dUTPase
    • Abstract: Publication date: 15 September 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 18
      Author(s): Shahienaz E. Hampton , Alessandro Schipani , Cristina Bosch-Navarrete , Eliseo Recio , Marcel Kaiser , Pia Kahnberg , Dolores González-Pacanowska , Nils Gunnar Johansson , Ian H. Gilbert
      Previously we have shown that trityl and diphenyl deoxyuridine derivatives and their acyclic analogues can inhibit Plasmodium falciparum dUTPase (PfdUTPase). We report the synthesis of conformationally restrained amide derivatives as inhibitors PfdUTPase, including both acyclic and cyclic examples. Activity was dependent on the orientation and location of the amide constraining group. In the case of the acyclic series, we were able to obtain amide-constrained analogues which showed similar or greater potency than the unconstrained analogues. Unfortunately these compounds showed lower selectivity in cellular assays.
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      PubDate: 2015-04-29T10:23:11Z
       
  • Quantification of free ligand conformational preferences by NMR and their
           relationship to the bioactive conformation
    • Abstract: Publication date: 1 September 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 17
      Author(s): Charles D. Blundell , Martin J. Packer , Andrew Almond
      Accurate unbound solution 3D-structures of ligands provide unique opportunities for medicinal chemistry and, in particular, a context to understand binding thermodynamics and kinetics. Previous methods of deriving these 3D-structures have had neither the accuracy nor resolution needed for drug design and have not yet realized their potential. Here, we describe and apply a NMR methodology to the aminoglycoside streptomycin that can accurately quantify accessible 3D-space and rank the occupancy of observed conformers to a resolution that enables medicinal chemistry understanding and design. Importantly, it is based upon conventional small molecule NMR techniques and can be performed in physiologically-relevant solvents. The methodology uses multiple datasets, an order of magnitude more experimental data than previous NMR approaches and a dynamic model during refinement, is independent of computational chemistry and avoids the problem of virtual conformations. The refined set of solution 3D-shapes for streptomycin can be grouped into two major families, of which the most populated is almost identical to the 30S ribosomal subunit bioactive shape. We therefore propose that accurate unbound ligand solution conformations may, in some cases, provide a subsidiary route to bioactive shape without crystallography. This experimental technique opens up new opportunities for drug design and more so when complemented with protein co-crystal structures, SAR data and pharmacophore modeling.
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      PubDate: 2015-04-29T10:23:11Z
       
  • Exploring pyrimidine-substituted curcumin analogues: Design, synthesis and
           effects on EGFR signaling
    • Abstract: Publication date: 1 September 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 17
      Author(s): Peiju Qiu , Lingling Xu , Lei Gao , Meng Zhang , Shixi Wang , Sheng Tong , Yue Sun , Lijuan Zhang , Tao Jiang
      Epidermal growth factor receptor (EGFR) is an effective molecular target of anti-cancer therapies. Curcumin inhibits cancer cell growth in vitro by suppressing gene expression of EGFR and reduces tumor growth in various animal models. To overcome instable and insoluble properties of curcumin as therapeutics, we designed and synthesized six novel pyrimidine-substituted curcumin analogues with or without a hydroxyl group originally present in curcumin. The cell viability tests indicated that IC50 of the analogues containing hydroxyl group were 3 to 8-fold lower than those of the analogues without hydroxyl group in two colon cancer cell lines tested. Western blot analysis indicates the analogues containing hydroxyl group inhibited expression and tyrosine phosphorylation of EGFR. Further protein analyses showed that the analogues had anti-cellular proliferation, pro-apoptosis, and cell cycle arrest properties associated with suppressed EGFR expression. These results indicate that the hydroxyl groups in curcumin and the analogues were critical for observed biological activities.
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      PubDate: 2015-04-29T10:23:11Z
       
  • Synthesis of novel isothiazolopyridines and their in vitro evaluation
           against Mycobacterium and Propionibacterium acnes
    • Abstract: Publication date: 1 September 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 17
      Author(s): Wiesław Malinka , Piotr Świątek , Małgorzata Śliwińska , Bogumiła Szponar , Andrzej Gamian , Zbigniew Karczmarzyk , Andrzej Fruziński
      In this paper we describe synthesis, structures and some physicochemical properties of 20 isothiazolopyridines 8–13 substituted differently into an isothiazole ring as well as their in vitro antibacterial assays against Mycobacterium tuberculosis H37Rv, Mycobacterium fortuitum PCM 672 and Propionibacterium acnes PCM 2400. Compound 13a was found to be the most active derivative against M. tuberculosis H37Rv, demonstrating 100% growth inhibition of microorganisms in the primary screen (minimum inhibitory concentration [MIC] 6.25μg/mL). Nineteen of the prepared compounds were evaluated against M. fortuitum PCM 672 and P. acnes PCM 2400 and only compounds 9 and 12d exhibited excellent activity against individual strains of microorganisms with MIC90 <1μg/mL. The inhibitory action of the remaining isothiazolopyridines towards the tested strains of the microorganism was low, absent, or a non-linear correlation prohibited accurate determination of MIC values. Unexpectedly, seven of the remaining isothiazolopyridines tested against M. fortuitum and P. acnes stimulated growth of the microorganisms in the range 10–50% or even more (10b) under experimental conditions.
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      PubDate: 2015-04-29T10:23:11Z
       
  • Gene suppression via U1 small nuclear RNA interference (U1i) machinery
           using oligonucleotides containing
           2′-modified-4′-thionucleosides
    • Abstract: Publication date: 1 September 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 17
      Author(s): Yusaku Kikuchi , Naoshi Yamazaki , Noriko Tarashima , Kazuhiro Furukawa , Yoshiharu Takiguchi , Kohji Itoh , Noriaki Minakawa
      Gene suppression via U1 small nuclear RNA interference (U1i) is considered to be one of the most attractive approaches, and takes the place of general antisense, RNA interference (RNAi), and anti-micro RNA machineries. Since the U1i can be induced by short oligonucleotides (ONs), namely U1 adaptors consisting of a ‘target domain’ and a ‘U1 domain’, we prepared adaptor ONs using 2′-modified-4′-thionucleosides developed by our group, and evaluated their U1i activity. As a result, the desired gene suppression via U1i was observed in ONs prepared as a combination of 2′-fluoro-4′-thionucleoside and 2′-fluoronucleoside units as well as only 2′-fluoronucleoside units, while those prepared as combination of 2′-OMe nucleoside/2′-OMe-4′-thionucleoside and 2′-fluoronucleoside units did not show significant activity. Measurement of T m values indicated that a higher hybridization ability of adaptor ONs with complementary RNA is one of the important factors to show potent U1i activity.
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      PubDate: 2015-04-29T10:23:11Z
       
  • A sphingosine 1-phosphate receptor 2 selective allosteric agonist
    • Abstract: Publication date: 1 September 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 17
      Author(s): Hideo Satsu , Marie-Therese Schaeffer , Miguel Guerrero , Adrian Saldana , Christina Eberhart , Peter Hodder , Charmagne Cayanan , Stephan Schürer , Barun Bhhatarai , Ed Roberts , Hugh Rosen , Steven J. Brown
      Molecular probe tool compounds for the Sphingosine 1-phosphate receptor 2 (S1PR2) are important for investigating the multiple biological processes in which the S1PR2 receptor has been implicated. Amongst these are NF-κB-mediated tumor cell survival and fibroblast chemotaxis to fibronectin. Here we report our efforts to identify selective chemical probes for S1PR2 and their characterization. We employed high throughput screening to identify two compounds which activate the S1PR2 receptor. SAR optimization led to compounds with high nanomolar potency. These compounds, XAX-162 and CYM-5520, are highly selective and do not activate other S1P receptors. Binding of CYM-5520 is not competitive with the antagonist JTE-013. Mutation of receptor residues responsible for binding to the zwitterionic headgroup of sphingosine 1-phosphate (S1P) abolishes S1P activation of the receptor, but not activation by CYM-5520. Competitive binding experiments with radiolabeled S1P demonstrate that CYM-5520 is an allosteric agonist and does not displace the native ligand. Computational modeling suggests that CYM-5520 binds lower in the orthosteric binding pocket, and that co-binding with S1P is energetically well tolerated. In summary, we have identified an allosteric S1PR2 selective agonist compound.
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      PubDate: 2015-04-29T10:23:11Z
       
  • Effect of single pyrrole replacement with β-alanine on DNA binding
           affinity and sequence specificity of hairpin pyrrole/imidazole polyamides
           targeting 5′-GCGC-3′
    • Abstract: Publication date: 1 September 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 17
      Author(s): Yong-Woon Han , Gengo Kashiwazaki , Hironobu Morinaga , Tomoko Matsumoto , Kaori Hashiya , Toshikazu Bando , Yoshie Harada , Hiroshi Sugiyama
      N-Methylpyrrole (Py)–N-methylimidazole (Im) polyamides are small organic molecules that can recognize predetermined DNA sequences with high sequence specificity. As many eukaryotic promoter regions contain highly GC-rich sequences, it is valuable to synthesize and characterize Py–Im polyamides that recognize GC-rich motifs. In this study, we synthesized four hairpin Py–Im polyamides 1–4, which recognize 5′-GCGC-3′ and investigated their binding behavior with surface plasmon resonance assay. Py–Im polyamides 2–4 contain two, one, and one β-alanine units, replacing the Py units of 1, respectively. The binding affinities of 2–4 to the target DNA increased 430, 390, and 610-fold, respectively, over that of 1. The association and dissociation rates of 2 to the target DNA were improved by 11 and 37-fold, respectively, compared with those of 1. Interestingly, the association and dissociation rates of 3 and 4 were higher than those of 2, even though the binding affinities of 2, 3, and 4 to the target DNA were comparable to each other. The binding affinity of 2 to DNA with a 2bp mismatch was reduced by 29-fold, compared with that to the matched DNA. Moreover, the binding affinities of 3 and 4 to the same mismatched DNA were reduced by 270 and 110-fold, respectively, indicating that 3 and 4 have greater specificities than 2 and are suitable as DNA-binding modules for engineered epigenetic regulation.
      Graphical abstract image

      PubDate: 2015-04-29T10:23:11Z
       
  • Synthesis and α-glucosidase inhibitory activity evaluation of
           N-substituted aminomethyl-β-d-glucopyranosides
    • Abstract: Publication date: 1 September 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 17
      Author(s): Xiaoli Bian , Xiangni Fan , Changhu Ke , Yajun Luan , Guilan Zhao , Aiguo Zeng
      A series of N-substituted 1-aminomethyl-β-d-glucopyranoside derivatives was prepared. These novel synthetic compounds were assessed in vitro for inhibitory activity against yeast α-glucosidase and both rat intestinal α-glucosidases maltase and sucrase. Most of the compounds displayed α-glucosidase inhibitory activity, with IC50 values covering the wide range from 2.3μM to 2.0mM. Compounds 19a (IC50 =2.3μM) and 19b (IC50 =5.6μM) were identified as the most potent inhibitors for yeast α-glucosidase, while compounds 16 (IC50 =7.7 and 15.6μM) and 19e (IC50 =5.1 and 10.4μM) were the strongest inhibitors of rat intestinal maltase and sucrase. Analysis of the kinetics of enzyme inhibition indicated that 19e inhibited maltase and sucrase in a competitive manner. The results suggest that the aminomethyl-β-d-glucopyranoside moiety can mimic the substrates of α-glucosidase in the enzyme catalytic site, leading to competitive enzyme inhibition. Moreover, the nature of the N-substituent has considerable influence on inhibitory potency.
      Graphical abstract image

      PubDate: 2015-04-29T10:23:11Z
       
  • A one-pot enzymatic approach to the O-fluoroglucoside of
           N-methylanthranilate
    • Abstract: Publication date: 15 August 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 16
      Author(s): Lorenzo Caputi , Martin Rejzek , Thomas Louveau , Ellis C. O’Neill , Lionel Hill , Anne Osbourn , Robert A. Field
      In connection with prospective 18F-PET imaging studies, the potential for enzymatic synthesis of fluorine-labelled glycosides of small molecules was investigated. Approaches to the enzymatic synthesis of anomeric phosphates of d-gluco-configured fluorosugars proved ineffective. In contrast, starting in the d-galacto series and relying on the consecutive action of Escherichia coli galactokinase (GalK), galactose-1-phosphate uridylyltransferase (GalPUT), uridine-5′-diphosphogalactose 4-epimerase (GalE) and oat root glucosyltransferase (SAD10), a quick and effective synthesis of 6-deoxy-6-fluoro-d-glucosyl N-methylanthranilate ester was achieved.
      Graphical abstract image

      PubDate: 2015-04-29T10:23:11Z
       
  • Multimerized CHR-derived peptides as HIV-1 fusion inhibitors
    • Abstract: Publication date: 1 August 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 15
      Author(s): Wataru Nomura , Chie Hashimoto , Takaharu Suzuki , Nami Ohashi , Masayuki Fujino , Tsutomu Murakami , Naoki Yamamoto , Hirokazu Tamamura
      To date, several HIV-1 fusion inhibitors based on the carboxy-terminal leucine/isoleucine heptad repeat (CHR) region of an HIV-1 envelope protein gp41 have been discovered. We have shown that a synthetic peptide mimetic of a trimer form of the CHR-derived peptide C34 has potent inhibitory activity against the HIV-1 fusion mechanism, compared to a monomer C34 peptide. The present study revealed that a dimeric form of C34 is evidently structurally critical for fusion inhibitors, and that the activity of multimerized CHR-derived peptides in fusion inhibition is affected by the properties of the unit peptides C34, SC34EK, and T20. The fluorescence-based study suggested that the N36-interactive sites of the C34 trimer, including hydrophobic residues, are exposed outside the trimer and that trimerization of C34 caused a remarkable increase in fusion inhibitory activity. The present results could be useful in the design of fusion inhibitors against viral infections which proceed via membrane fusion with host cells.
      Graphical abstract image

      PubDate: 2015-04-29T10:23:11Z
       
  • Control of the intracellular levels of prostaglandin E2 through inhibition
           of the 15-hydroxyprostaglandin dehydrogenase for wound healing
    • Abstract: Publication date: 1 August 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 15
      Author(s): Dubok Choi , Yu Lan Piao , Ying Wu , Hoon Cho
      Excessive scar formation is an aberrant form of wound healing and is an indication of an exaggerated function of fibroblasts and excess accumulation of extracellular matrix during wound healing. Much experimental data suggests that prostaglandin E2 (PGE2) plays a role in the prevention of excessive scarring. However, it has a very short half-live in blood, its oxidization to 15-ketoprostaglandins is catalyzed by 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Previously, we reported that 15-PGDH inhibitors significantly increased PGE2 levels in A549 cells. In our continuing attempts to develop highly potent 15-PGDH inhibitors, we newly synthesized various thiazolidine-2,4-dione derivatives. Compound 27, 28, 29, and 30 demonstrated IC50 values of 0.048, 0.020, 0.038 and 0.048μM, respectively. They also increased levels of PGE2 in A549 cells. Especially, compound 28 significantly increased level of PGE2 at 260pg/mL, which was approximately fivefold higher than that of control. Scratch wounds were analyzed in confluent monolayers of HaCaT cells. Cells exposed to compound 28 showed significantly improved wound healing with respect to control.
      Graphical abstract image

      PubDate: 2015-04-29T10:23:11Z
       
  • Chemically modified siRNAs and miRNAs bearing urea/thiourea-bridged
           aromatic compounds at their 3′-end for RNAi therapy
    • Abstract: Publication date: 1 August 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 15
      Author(s): Yoshiaki Kitamura , Yuki Masegi , Shunsuke Ogawa , Remi Nakashima , Yukihiro Akao , Yoshihito Ueno , Yukio Kitade
      We have developed chemically modified siRNAs and miRNAs bearing urea/thiourea-bridged aromatic compounds at their 3′-end for RNAi therapy. Chemically modified RNAs possessing urea/thiourea-bridged aromatic compounds instead of naturally occurring dinucleotides at the 3′-overhang region were easily prepared in good yields and were more resistant to nucleolytic hydrolysis than unmodified RNA. siRNAs containing urea or thiourea derivatives showed the desired knockdown effect. Furthermore, modified miR-143 duplexes carrying the urea/thiourea compounds in the 3′-end of each strand were able to inhibit the growth of human bladder cancer T24 cells.
      Graphical abstract image

      PubDate: 2015-04-29T10:23:11Z
       
  • Synthesis, biological evaluation, X-ray molecular structure and molecular
           docking studies of RGD mimetics containing
           6-amino-2,3-dihydroisoindolin-1-one fragment as ligands of integrin
           αIIbβ3
    • Abstract: Publication date: 1 August 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 15
      Author(s): Andrei A. Krysko , Georgiy V. Samoylenko , Pavel G. Polishchuk , Marina S. Fonari , Victor Ch. Kravtsov , Sergei A. Andronati , Tatyana A. Kabanova , Janusz Lipkowski , Tetiana M. Khristova , Victor E. Kuz’min , Vladimir M. Kabanov , Olga L. Krysko , Alexandre A. Varnek
      A series of novel RGD mimetics containing phthalimidine fragment was designed and synthesized. Their antiaggregative activity determined by Born’s method was shown to be due to inhibition of fibrinogen binding to αIIbβ3. Molecular docking of RGD mimetics to αIIbβ3 receptor showed the key interactions in this complex, and also some correlations have been observed between values of biological activity and docking scores. The single crystal X-ray data were obtained for five mimetics.
      Graphical abstract image

      PubDate: 2015-04-29T10:23:11Z
       
  • Microwave assisted solid phase synthesis of highly functionalized
           N-alkylated oligobenzamide α-helix mimetics
    • Abstract: Publication date: 15 July 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
      Author(s): Kérya Long , Thomas A. Edwards , Andrew J. Wilson
      Protein–protein interactions (PPIs) mediate cellular pathways and are implicated in numerous aberrant conditions. α-Helix mimetics—small molecules that reproduce the spatial projection of key residues from an α-helix involved in a PPI—are attractive generic templates for development of screening libraries, however library syntheses of α-helix mimetics with diverse functionality are less established. This manuscript describes the automated, microwave assisted solid phase synthesis based on one such scaffold; an N-alkylated oligobenzamide.
      Graphical abstract image

      PubDate: 2015-04-29T10:23:11Z
       
  • 20(S)-Protopanaxadiol (PPD) analogues chemosensitize multidrug-resistant
           cancer cells to clinical anticancer drugs
    • Abstract: Publication date: 15 July 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
      Author(s): Junhua Liu , Xu Wang , Peng Liu , Rongxin Deng , Min Lei , Wantao Chen , Lihong Hu
      Novel 20(S)-protopanoxadiol (PPD) analogues were designed, synthesized, and evaluated for the chemosensitizing activity against a multidrug resistant (MDR) cell line (KBvcr) overexpressing P-glycoprotein (P-gp). Structure–activity relationship analysis showed that aromatic substituted aliphatic amine at the 24-positions (groups V) effectively and significantly sensitized P-gp overexpressing multidrug resistant (MDR) cells to anticancer drugs, such as docetaxel (DOC), vincristine (VCR), and adriamycin (ADM). PPD derivatives 12 and 18 showed 1.3–2.6 times more effective reversal ability than verapamil (VER) for DOC and VCR. Importantly, no cytotoxicity was observed by the active PPD analogues (5μM) against both non-MDR and MDR cells, suggesting that PPD analogues serve as novel lead compounds toward a potent and safe resistance modulator. Moreover, a preliminary mechanism study demonstrated that the chemosensitizing activity of PPD analogues results from inhibition of P-glycoprotein (P-gp) overexpressed in MDR cancer cells.
      Graphical abstract image

      PubDate: 2015-04-29T10:23:11Z
       
  • Development and characterization of a promising fluorine-18 labelled
           radiopharmaceutical for in vivo imaging of fatty acid amide hydrolase
    • Abstract: Publication date: 15 July 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
      Author(s): Oleg Sadovski , Justin W. Hicks , Jun Parkes , Roger Raymond , José Nobrega , Sylvain Houle , Mariateresa Cipriano , Christopher J. Fowler , Neil Vasdev , Alan A. Wilson
      Fatty acid amide hydrolase (FAAH), the enzyme responsible for terminating signaling by the endocannabinoid anandamide, plays an important role in the endocannabinoid system, and FAAH inhibitors are attractive drugs for pain, addiction, and neurological disorders. The synthesis, radiosynthesis, and evaluation, in vitro and ex vivo in rat, of an 18F-radiotracer designed to image FAAH using positron emission tomography (PET) is described. Fluorine-18 labelled 3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate, [18F]5, was synthesized at high specific activity in a one-pot three step reaction using a commercial module with a radiochemical yield of 17–22% (from [18F]fluoride). In vitro assay using rat brain homogenates showed that 5 inhibited FAAH in a time-dependent manner, with an IC50 value of 0.82nM after a preincubation of 60min. Ex vivo biodistribution studies and ex vivo autoradiography in rat brain demonstrated that [18F]5 had high brain penetration with standard uptake values of up to 4.6 and had a regional distribution which correlated with reported regional FAAH enzyme activity. Specificity of binding to FAAH with [18F]5 was high (>90%) as demonstrated by pharmacological challenges with potent and selective FAAH inhibitors and was irreversible as demonstrated by radioactivity measurements on homogenized brain tissue extracts. We infer from these results that [18F]5 is a highly promising candidate radiotracer with which to image FAAH in human subjects using PET and clinical studies are proceeding.
      Graphical abstract image

      PubDate: 2015-04-29T10:23:11Z
       
  • Reaction of 3′,5′-di-O-acetyl-2′-deoxyguansoine with
           hypobromous acid
    • Abstract: Publication date: 1 July 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 13
      Author(s): Toshinori Suzuki , Asuka Nakamura , Michiyo Inukai
      Hypobromous acid (HOBr) is formed by eosinophil peroxidase and myeloperoxidase in the presence of H2O2, Cl−, and Br− in the host defense system of humans, protecting against invading bacteria. However, the formed HOBr may cause damage to DNA and its components in the host. When a guanine nucleoside (3′,5′-di-O-acetyl-2′-deoxyguansoine) was treated with HOBr at pH 7.4, spiroiminodihydantoin, guanidinohydantoin/iminoallantoin, dehydro-iminoallantoin, diimino-imidazole, amino-imidazolone, and diamino-oxazolone nucleosides were generated in addition to an 8-bromoguanine nucleoside. The major products were spiroiminodihydantoin under neutral conditions and guanidinohydantoin/iminoallantoin under mildly acidic conditions. All the products were formed in the reaction with HOCl in the presence of Br−. These products were also produced by eosinophil peroxidase or myeloperoxidase in the presence of H2O2, Cl−, and Br−. The results suggest that the products other than 8-bromoguanine may also have importance for mutagenesis by the reaction of HOBr with guanine residues in nucleotides and DNA.
      Graphical abstract image

      PubDate: 2015-04-29T10:23:11Z
       
  • Novel 1H-imidazol-2-amine derivatives as potent and orally active vascular
           adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema treatment
           
    • Abstract: Publication date: 1 July 2013
      Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 13
      Author(s): Takayuki Inoue , Masataka Morita , Takashi Tojo , Akira Nagashima , Ayako Moritomo , Hiroshi Miyake
      Novel thiazole derivatives were synthesized and evaluated as vascular adhesion protein-1 (VAP-1) inhibitors. Although we previously identified a compound (2) with potent VAP-1 inhibitory activity in rats, the human activity was relatively weak. Here, to improve the human VAP-1 inhibitory activity of compound 2, we first evaluated the structure–activity relationships of guanidine bioisosteres as simple small molecules and identified a 1H-benzimidazol-2-amine (5) with potent activity compared to phenylguanidine (1). Based on the structure of compound 5, we synthesized a highly potent VAP-1 inhibitor (37b; human IC50 =0.019μM, rat IC50 =0.0051μM). Orally administered compound 37b also markedly inhibited ocular permeability in streptozotocin-induced diabetic rats after oral administration, suggesting it is a promising compound for the treatment of diabetic macular edema.
      Graphical abstract image

      PubDate: 2015-04-29T10:23:11Z
       
  • 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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