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Journal Cover Bioorganic & Medicinal Chemistry
  [SJR: 1.064]   [H-I: 119]   [113 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0968-0896
   Published by Elsevier Homepage  [3043 journals]
  • Design and synthesis of bioactive compounds
    • Authors: Andrea Trabocchi
      First page: 5031
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
      Author(s): Andrea Trabocchi


      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2017.09.020
       
  • Identification of galiellalactone-based novel STAT3-selective inhibitors
           with cytotoxic activities against triple-negative breast cancer cell lines
           
    • Authors: Hyun Su Kim; Taewoo Kim; Hyejin Ko; Jeeyeon Lee; Yeong Shik Kim; Young-Ger Suh
      Pages: 5032 - 5040
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
      Author(s): Hyun Su Kim, Taewoo Kim, Hyejin Ko, Jeeyeon Lee, Yeong Shik Kim, Young-Ger Suh
      Signal transducer and activator of transcription 3 (STAT3) is phosphorylated in breast cancer cells, particularly triple-negative breast cancers (TNBCs). Therefore, the inhibition of constitutive phosphorylated STAT3 is a promising therapeutic for TNBC treatment. Recently, a series of novel STAT3 inhibitors based on natural (−)-galiellalactone have been identified to inhibit STAT3 phosphorylation at the Tyr705 residue. Interestingly, the truncation of the cyclohexene moiety of (−)-galiellalactone to [3.3] bicyclic lactone as a pharmacophoric core produced improved cytotoxic effects against TNBCs. The potent analogues 16 and 17, identified from a STAT3-mediated luciferase reporter assay, selectively inhibited the STAT3 signaling pathway without affecting STAT1 or STAT5.
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      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2017.06.036
       
  • Enhancing polo-like kinase 1 selectivity of polo-box domain-binding
           peptides
    • Authors: Xue Zhi Zhao; David Hymel; Terrence R. Burke
      Pages: 5041 - 5049
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
      Author(s): Xue Zhi Zhao, David Hymel, Terrence R. Burke
      An important goal in the development of polo-like kinase 1 (Plk1) polo-box domain (PBD) binding inhibitors is selectivity for Plk1 relative to Plk2 and Plk3. In our current work we show that Plk1 PBD selectivity can be significantly enhanced by modulating interactions within a previously discovered “cryptic pocket” and a more recently identified proximal “auxiliary pocket.”
      Graphical abstract image

      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2017.02.063
       
  • Azobenzene-containing photoswitchable proteasome inhibitors with selective
           activity and cellular toxicity
    • Authors: Beatriz Blanco; Kathryn A. Palasis; Alaknanda Adwal; David F. Callen; Andrew D. Abell
      Pages: 5050 - 5054
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
      Author(s): Beatriz Blanco, Kathryn A. Palasis, Alaknanda Adwal, David F. Callen, Andrew D. Abell
      A series of azobenzene-containing peptidic boronate esters was prepared and the activity of the thermally adapted states (TAS), enriched in trans isomer, and the photostationary states (PSS), enriched in cis isomer, for each compound were evaluated against β5 and β1 proteasome subunits. Compounds with a sterically demanding phenyl-substituted azobenzene at P2 (4c), and a less sterically demanding unsubstituted azobenzene at the N-terminus (5a), showed the greatest difference in activity between the two states. In both cases, the more active trans-enriched TAS had activity comparable to bortezomib and delanzomib. Furthermore, cis-enriched 4c inhibited tumor growth in both breast and colorectal carcinoma cell lines. Significantly, the initial trans-enriched TAS of 4c was not cytotoxic against the non-malignant MCF-10A cells.
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      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2017.06.011
       
  • Potential peptidic proteasome inhibitors by incorporation of an
           electrophilic trap based on amino acid derived α-substituted sulfonyl
           fluorides
    • Authors: Natalia Herrero Alvarez; Helmus van de Langemheen; Arwin J. Brouwer; Rob M.J. Liskamp
      Pages: 5055 - 5063
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
      Author(s): Natalia Herrero Alvarez, Helmus van de Langemheen, Arwin J. Brouwer, Rob M.J. Liskamp
      Peptido sulfonyl fluoride derivatives were designed and synthesized containing a substituent on the alpha position (αPSFs) with respect to the sulfonyl fluoride electrophilic trap. The chemical reactivity of these α-substituted amino sulfonyl fluorides was studied and compared with the previously described β-substituted amino sulfonyl fluorides in order to get a deeper insight into the importance of the immediate structural environment of the sulfonyl fluoride moiety. Unfortunately, the poor solubility of the resulting αPSFs precluded a proper evaluation of their biological activity.
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      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2017.07.019
       
  • Bortezomib inhibits mammalian carbonic anhydrases
    • Authors: Claudiu T. Supuran
      Pages: 5064 - 5067
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
      Author(s): Claudiu T. Supuran
      We investigated the carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the clinically used antitumor agent bortezomib, a marketed proteasome inhibitor, against all the catalytically active mammalian isoforms CA I–VII, IX, XII–XV. Bortezomib effectively inhibited all these CAs in the micromolar range. hCA II, the physiologically dominant cytosolic isoform showed the highest affinity for the drug, with a K I of 1.16μM. The cytosolic slow isoform hCA I was also effectively inhibited, with a K I of 1.29μM, whereas the next best affinity was observed for the membrane-anchored form mCA XV, with a K I of 2.68μM, followed by two transmembrane isoforms, hCA IX and XIV (K Is of 3.28–3.38μM). The remaining cytosolic (CA III, VII and XIII), membrane-anchored (CA IV), mitochondrial (CA VA, VB), transmembrane (CA XII) and secreted (CA VI) isoforms were slightly less inhibited by bortezomib compared to isoforms discussed above, with K Is ranging between 4.38 and 8.45μM. These data may shed some light on possible side effects and novel antitumor mechanisms of action of this drug.
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      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2016.10.023
       
  • Anticancer potential of aminomethylidene-diazinanes I. Synthesis of
           arylaminomethylidene of diazinetriones and its cytotoxic effects tested in
           glioblastoma cells
    • Authors: Nichole A. Pianovich; Mathew Dean; Adam Lassak; Krzysztof Reiss; Branko S. Jursic
      Pages: 5068 - 5076
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
      Author(s): Nichole A. Pianovich, Mathew Dean, Adam Lassak, Krzysztof Reiss, Branko S. Jursic
      Diazinane and aryl moieties with vinylamine linkers were synthesized to investigate the importance of their structural variations as potential anti-glioblastoma agents. Structural variations incorporated on to the diazinane moiety included oxa and thio derivatives, each with a variety of nitrogen-bound substituents. The size and shape of the aromatic moiety was varied, with the final variation introducing two carbonyl groups, yielding a substituted anthraquinone. Readily available diazinanes and aryl amines were used asan advantageous foundation. Several parameters were calculated whilst engineering these compounds, including: ClogP, molecular polarizability, polar surface area, minimal molecular projected area, and pKa. In addition, a simple and efficient procedure was developed to synthesize these compounds. It was demonstrated that a vinylamine with 1,3-diazinane-2,4,6-trione and 1-anthraquinone moiety is the most promising drug candidate causing almost 70% of LN229 tumor cell death at 1µg/ml. In addition, its molecular polarizability, polar surface area and minimal molecular projected area indicate a possible potential of this molecule for crossing BBB.
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      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2017.08.020
       
  • Design and synthesis of bicyclic acetals as Beta Secretase (BACE1)
           inhibitors
    • Authors: Riccardo Innocenti; Elena Lenci; Gloria Menchi; Alberto Pupi; Andrea Trabocchi
      Pages: 5077 - 5083
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
      Author(s): Riccardo Innocenti, Elena Lenci, Gloria Menchi, Alberto Pupi, Andrea Trabocchi
      Taking advantage of the structural similarity between aspartic proteases, small-molecule peptidomimetic inhibitors that already showed activity towards Secreted Aspartic Protease 2 as anti-Candida agents and HIV protease inhibitors were exploited as potential BACE1 inhibitors. A focused library of 6,8-dioxa-3-azabicyclo[3.2.1]-octane peptidomimetic scaffolds was synthesized and assayed towards BACE1 enzyme, resulting in the identification of a thiolactam-containing hit compound possessing IC50 in the low micromolar range, and confirming the bicyclic acetal portion as a potential transition state analogue in the interaction with catalytic aspartic acid residues.
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      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2017.03.030
       
  • Potent haloperidol derivatives covalently binding to the dopamine D2
           receptor
    • Authors: Tobias Schwalbe; Jonas Kaindl; Harald Hübner; Peter Gmeiner
      Pages: 5084 - 5094
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
      Author(s): Tobias Schwalbe, Jonas Kaindl, Harald Hübner, Peter Gmeiner
      The dopamine D2 receptor (D2R) is a common drug target for the treatment of a variety of neurological disorders including schizophrenia. Structure based design of subtype selective D2R antagonists requires high resolution crystal structures of the receptor and pharmacological tools promoting a better understanding of the protein-ligand interactions. Recently, we reported the development of a chemically activated dopamine derivative (FAUC150) designed to covalently bind the L94C mutant of the dopamine D2 receptor. Using FAUC150 as a template, we elaborated the design and synthesis of irreversible analogs of the potent antipsychotic drug haloperidol forming covalent D2R-ligand complexes. The disulfide- and Michael acceptor-functionalized compounds showed significant receptor affinity and an irreversible binding profile in radioligand depletion experiments.
      Graphical abstract image

      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2017.06.034
       
  • Synthesis and in vitro evaluation of 5-substituted benzovesamicol analogs
           containing N-substituted amides as potential positron emission tomography
           tracers for the vesicular acetylcholine transporter
    • Authors: Sara Roslin; Maria De Rosa; Winnie Deuther-Conrad; Jonas Eriksson; Luke R. Odell; Gunnar Antoni; Peter Brust; Mats Larhed
      Pages: 5095 - 5106
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
      Author(s): Sara Roslin, Maria De Rosa, Winnie Deuther-Conrad, Jonas Eriksson, Luke R. Odell, Gunnar Antoni, Peter Brust, Mats Larhed
      Herein, new ligands for the vesicular acetylcholine transporter (VAChT), based on a benzovesamicol scaffold, are presented. VAChT is acknowledged as a marker for cholinergic neurons and a positron emission tomography tracer for VAChT could serve as a tool for quantitative analysis of cholinergic neuronal density. With an easily accessible triflate precursor, aminocarbonylations were utilized to evaluate the chemical space around the C5 position on the tetrahydronaphthol ring. Synthesized ligands were evaluated for their affinity and selectivity for VAChT. Small, preferably aromatic, N-substituents proved to be more potent than larger substituents. Of the fifteen compounds synthesized, benzyl derivatives (±)-7i and (±)-7l had the highest affinities for VAChT. Compound (±)-7i was chosen to investigate the importance of stereochemistry for binding to VAChT and selectivity toward the σ1 and σ2 receptors. Enantiomeric resolution gave (+)-7i and (−)-7i, and the eutomer showed seven times better affinity. Although racemate (±)-7i was initially promising, the affinity of (−)-7i for VAChT was not better than 56.7nM which precludes further preclinical evaluation. However, the nanomolar binding together with the ready synthesis of [11C]-(±)-7i shows that (−)-7i can serve as a scaffold for future optimizations to provide improved 11C-labelled VAChT PET tracers.
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      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2017.01.041
       
  • Do spiroindolines have the potential to replace vesamicol as lead compound
           for the development of radioligands targeting the vesicular acetylcholine
           transporter'
    • Authors: Marcel Lindemann; Winnie Deuther-Conrad; Rares Moldovan; Kondapalli Venkata Gowri Chandra Sekhar; Peter Brust; Barbara Wenzel
      Pages: 5107 - 5113
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
      Author(s): Marcel Lindemann, Winnie Deuther-Conrad, Rares Moldovan, Kondapalli Venkata Gowri Chandra Sekhar, Peter Brust, Barbara Wenzel
      The vesicular acetylcholine transporter (VAChT) is an important target for in vivo imaging of neurodegenerative processes using positron emission tomography (PET). So far the development of VAChT PET radioligands is based on the single known lead compound vesamicol. In this study we investigated a recently published spiroindoline based compound class (Sluder et al., 2012), which was suggested to have potential in the development of VAChT ligands. Therefore, we synthesized a small series of N,N-substituted spiro[indoline-3,4′-piperidine] derivatives and determined their in vitro binding affinities toward the VAChT. In order to investigate the selectivity, the off-target binding toward σ1 and σ2 receptors was determined. The compounds possessed VAChT affinities with K i values in the range of 39–376nM. Binding affinities toward the σ1 and σ2 receptors are in a similar range indicating that the strong structural difference between the spiroindolines and vesamicol did not improve the selectivity. The observed potential to additionally bind to σ receptors let us assume that the herein investigated spiroindolines are not suitable to replace vesamicol as lead compound for the development of VAChT ligands.
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      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2017.03.028
       
  • Design of novel HIV-1 protease inhibitors incorporating
           isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and
           X-ray structural studies of inhibitor-HIV-1 protease complex
    • Authors: Arun K. Ghosh; Margherita Brindisi; Prasanth R. Nyalapatla; Jun Takayama; Jean-Rene Ella-Menye; Sofiya Yashchuk; Johnson Agniswamy; Yuan-Fang Wang; Manabu Aoki; Masayuki Amano; Irene T. Weber; Hiroaki Mitsuya
      Pages: 5114 - 5127
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
      Author(s): Arun K. Ghosh, Margherita Brindisi, Prasanth R. Nyalapatla, Jun Takayama, Jean-Rene Ella-Menye, Sofiya Yashchuk, Johnson Agniswamy, Yuan-Fang Wang, Manabu Aoki, Masayuki Amano, Irene T. Weber, Hiroaki Mitsuya
      Based upon molecular insights from the X-ray structures of inhibitor-bound HIV-1 protease complexes, we have designed a series of isophthalamide-derived inhibitors incorporating substituted pyrrolidines, piperidines and thiazolidines as P2-P3 ligands for specific interactions in the S2-S3 extended site. Compound 4b has shown an enzyme Ki of 0.025nM and antiviral IC50 of 69nM. An X-ray crystal structure of inhibitor 4b-HIV-1 protease complex was determined at 1.33Å resolution. We have also determined X-ray structure of 3b-bound HIV-1 protease at 1.27Å resolution. These structures revealed important molecular insight into the inhibitor–HIV-1 protease interactions in the active site.
      Graphical abstract image

      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2017.04.005
       
  • Dual inhibitors of the human blood-brain barrier drug efflux transporters
           P-glycoprotein and ABCG2 based on the antiviral azidothymidine
    • Authors: Hilda A. Namanja-Magliano; Kelsey Bohn; Neha Agrawal; Meghan E. Willoughby; Christine A. Hrycyna; Jean Chmielewski
      Pages: 5128 - 5132
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
      Author(s): Hilda A. Namanja-Magliano, Kelsey Bohn, Neha Agrawal, Meghan E. Willoughby, Christine A. Hrycyna, Jean Chmielewski
      The brain provides a sanctuary site for HIV due, in part, to poor penetration of antiretroviral agents at the blood-brain barrier. This lack of penetration is partially attributed to drug efflux transporters such as P-glycoprotein (P-gp) and ABCG2. Inhibition of both ABCG2 and P-gp is critical for enhancing drug accumulation into the brain. In this work, we have developed a class of homodimers based on the HIV reverse transcriptase inhibitor azidothymidine (AZT) that effectively inhibits P-gp and ABCG2. These agents block transporter mediated efflux of the P-gp substrate calcein-AM and the ABCG2 substrate mitoxantrone. The homodimers function by interacting with the transporter drug binding sites as demonstrated by competition studies with the photo-affinity agent and P-gp/ABCG2 substrate [125I]iodoarylazidoprazosin. As such, these dual inhibitors of both efflux transporters provide a model for the future development of delivery vehicles for antiretroviral agents to the brain.
      Graphical abstract image

      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2017.07.001
       
  • Synthesis and biological evaluation of Aspergillomarasmine A derivatives
           as novel NDM-1 inhibitor to overcome antibiotics resistance
    • Authors: Jian Zhang; Sanshan Wang; Qi Wei; Qianqian Guo; Yingjie Bai; Shaoqiang Yang; Fuhang Song; Lixin Zhang; Xiaoguang Lei
      Pages: 5133 - 5141
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
      Author(s): Jian Zhang, Sanshan Wang, Qi Wei, Qianqian Guo, Yingjie Bai, Shaoqiang Yang, Fuhang Song, Lixin Zhang, Xiaoguang Lei
      The β-lactam antibiotic resistance of Gram-negative bacteria has shown to be a critical global health problem. One of the primary reasons for the drug resistance is the existence of β-lactamases especially metallo-β-lactamases such as New Delhi metallo-β-lactamase (NDM-1) and Verona Integron-encoded metallo-β-lactamase (VIM-2). The fungal natural product Aspergillomarasmine A (AMA) has proven to be a promising inhibitor of NDM-1 and VIM-2 both in vitro and in vivo. Seven new analogues of AMA were synthesized by utilizing different strategies. The biological evaluation of these analogues was performed to study the structure-activity relationship of AMA both in vitro and in vivo. Remarkably, the lead compound 4 showed synergistic effect in combination with Meropenem to overcome the antibiotic resistance of the Gram-negative bacteria such as K. pneumoniae (BAA-2146) expressing NDM-1.
      Graphical abstract image

      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2017.07.025
       
  • Facile access to pseudo-thio-1,2-dimannoside, a new glycomimetic DC-SIGN
           antagonist
    • Authors: Alice Tamburrini; Silvia Achilli; Francesca Vasile; Sara Sattin; Corinne Vivès; Cinzia Colombo; Franck Fieschi; Anna Bernardi
      Pages: 5142 - 5147
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
      Author(s): Alice Tamburrini, Silvia Achilli, Francesca Vasile, Sara Sattin, Corinne Vivès, Cinzia Colombo, Franck Fieschi, Anna Bernardi
      The synthesis and conformational analysis of pseudo-thio-1,2-dimannoside are described. This molecule mimics mannobioside (Manα(1,2)Man) and is an analog of pseudo-1,2-dimannoside, with expected increased stability to enzymatic hydrolysis. A short and efficient synthesis was developed based on an epoxide ring-opening reaction by a mannosyl thiolate, generated in situ from the corresponding thioacetate. NMR-NOESY studies supported by MM3∗ calculations showed that the pseudo-thio-1,2-dimannoside shares the conformational behavior of the pseudo-1,2-dimannoside and is a structural mimic of the natural disaccharide. Its affinity for DC-SIGN was measured by SPR and found to be comparable to the corresponding O-linked analog, offering good opportunities for further developments.
      Graphical abstract image

      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2017.03.046
       
  • α-Geminal disubstituted pyrrolidine iminosugars and their C-4-fluoro
           analogues: Synthesis, glycosidase inhibition and molecular docking studies
           
    • Authors: Kishor S. Gavale; Shrawan R. Chavan; Navanath Kumbhar; Sonali Kawade; Pooja Doshi; Ayesha Khan; Dilip D. Dhavale
      Pages: 5148 - 5159
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
      Author(s): Kishor S. Gavale, Shrawan R. Chavan, Navanath Kumbhar, Sonali Kawade, Pooja Doshi, Ayesha Khan, Dilip D. Dhavale
      A simple strategy for the synthesis of α-geminal disubstituted pyrrolidine iminosugars 3a-c and their C-4 fluorinated derivatives 4a-c has been described from d-glucose. The methodology involves the Corey-Link and Jocic-Reeve reaction with 3-oxo-α-d-glucofuranose and nucleophilic displacement reaction to get the furanose fused pyrrolidine ring skeleton with requisite CH2OH/CO2H functionalities at C-3. The fluorine substituent in target molecules was introduced by nucleophilic displacement of -OTf in 9a/9c with CsF. Appropriate manipulation of the anomeric carbon in the furanose fused pyrrolidine ring skeleton afforded α-geminal disubstituted pyrrolidine iminosugars 3a–c and C-4 fluoro derivatives 4a–c. The pyrrolidine iminosugars 3a and 3c were found to be potent inhibitors of α-galactosidase while, the fluoro derivatives 4a and 4b showed strong inhibition of β-glucosidase and β-galactosidase, respectively. These results were substantiated by in silico molecular docking studies.
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      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2017.07.026
       
  • Piperidine and octahydropyrano[3,4-c] pyridine scaffolds for drug-like
           molecular libraries of the European Lead Factory
    • Authors: Bharat D. Narhe; Arjen C. Breman; Jalindar Padwal; Dirk A.L. Vandenput; Joeri M. Scheidt; Jorg C.J. Benningshof; Gijsbert A. van der Marel; Herman S. Overkleeft; Mario van der Stelt; Dmitri V. Filippov
      Pages: 5160 - 5170
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
      Author(s): Bharat D. Narhe, Arjen C. Breman, Jalindar Padwal, Dirk A.L. Vandenput, Joeri M. Scheidt, Jorg C.J. Benningshof, Gijsbert A. van der Marel, Herman S. Overkleeft, Mario van der Stelt, Dmitri V. Filippov
      We report short and efficient scalable syntheses of enantiomerically pure (3R,4S)-3-(hydroxymethyl4-(hydroxyethyl))-piperidine and 1-hydroxymethyl-octahydro-1H-pyrano[3,4-c]pyridine scaffolds. The alkaloid core was readily synthesized from naturally occurring quinine and can serve as a valued starting point for drug-discovery. Cleavage of a terminal 1,2-diol and acid catalysed epoxide opening cyclization are the key steps involved. A number of members of a projected small-molecular library is synthesized for each scaffold.
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      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2017.07.016
       
  • Facile access to modified and functionalized PNAs through Ugi-based solid
           phase oligomerization
    • Authors: Jacques Saarbach; Daniela Masi; Claudio Zambaldo; Nicolas Winssinger
      Pages: 5171 - 5177
      Abstract: Publication date: 1 October 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
      Author(s): Jacques Saarbach, Daniela Masi, Claudio Zambaldo, Nicolas Winssinger
      Peptide nucleic acids (PNAs) derivatized with functional molecules are increasingly used in diverse biosupramolecular applications. PNAs have proven to be highly tolerant to modifications and different applications benefit from the use of modified PNAs, in particular modifications at the γ position. Herein we report simple protocols to access modified PNAs from iterative Ugi couplings which allow modular modifications at the α, β or γ position of the PNA backbone from simple starting materials. We demonstrate the utility of the method with the synthesis of several bioactive small molecules (a peptide ligand, a kinase inhibitor and a glycan)-PNA conjugates.
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      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2017.05.064
       
  • Benzofuran-Dihydropyridine Hybrids: A new class of potential bone anabolic
           agents
    • Authors: Ram K. Modukuri; Dharmendra Choudhary; Sampa Gupta; K. BhaskaraRao; SulekhaAdhikary; Tanuj Sharma; Mohammad Imran Siddiqi; Ritu Trivedi; Koneni V. Sashidhara
      Abstract: Publication date: Available online 17 October 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Ram K. Modukuri, Dharmendra Choudhary, Sampa Gupta, K. BhaskaraRao, SulekhaAdhikary, Tanuj Sharma, Mohammad Imran Siddiqi, Ritu Trivedi, Koneni V. Sashidhara
      A series of novel benzofuran-dihydropyridine hybrids were designed by molecular hybridization approach and evaluated for bone anabolic activities. Among the screened library, ethyl 4-(7-(sec-butyl)-2-(4-methylbenzoyl)benzofuran-5-yl)-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (compound 21) significantly enhanced the ALP production and mineralized nodule formation, which are primary requisites in the process of in-vitro osteogenesis. Oral administration of compound 21 at 10 mg.kg-1day-1 for two weeks led to restoration of trabecular bone microarchitecture in drill hole fracture model by significantly increasing BV/TV and Tb.N. Furthermore, histological and molecular studies showed compound 21 triggering the new bone regeneration in a drill hole defect site by increasing BMP expression. Furthermore, molecular modeling studies were performed to gain insight into the binding approach, which revealed that both benzofuran and dihydropyridine moieties are essential to show similar binding interactions to fit into the active site of BMP2 receptor, an important target of the osteogenic agents.Our results suggest that compound 21 stimulates BMP2 synthesis in osteoblast cells that promotes new bone formation (∼40%) at the fracture site which helps in shorten the healing period.
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      PubDate: 2017-10-17T14:19:17Z
      DOI: 10.1016/j.bmc.2017.10.018
       
  • Structure optimization of tetrahydropyridoindole-based aldose reductase
           inhibitors improved their efficacy and selectivity
    • Authors: Magdalena Majekova; Jana Ballekova; Marta Prnova; Milan Stefek
      Abstract: Publication date: Available online 16 October 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Magdalena Majekova, Jana Ballekova, Marta Prnova, Milan Stefek
      In our previous study, tetrahydropyridoindoles carboxymethylated in position 8 were identified as aldose reductase (ALR2) inhibitors with mild efficacy and selectivity yet with significant antioxidant activity. In the present study we proceeded with optimization of the tetrahydropyridoindole scaffold by shifting the carboxymethyl pharmacophore from position 8 to position 5, with the aim to improve the biological activity. Commercial databases were screened for the presence of tetrahydropyridoindoles carboxymethylated in position 5 and an experimental set of eight compounds was created. Mild inhibition characterized by IC50 in micromolar range was recorded for compound 8 with the isopropyl substituent at the piperidine nitrogen (position 2). This alkylated tertiary nitrogen is characterized by a rather high basicity (pKa ∼ 10.4) with complete protonization at physiological pH. On the other hand, ALR2 inhibition activity of the low basicity derivatives 3-7 with an acyl substituted nitrogen in position 2 (pKa ∼ -1 to -3) was characterized with IC50 values in low and medium nanomolar region. Docking into the binding site of human recombinant enzyme AKR1B1 performed for 3 revealed an interaction network responsible for the high affinity and selectivity. In ex vivo experiment, sorbitol accumulation in isolated rat eye lenses was significantly inhibited by 3 in the presence of high glucose, starting at a concentration as low as 0.1 μM. Moreover, in streptozotocin-induced diabetic rats, compound 3 administered intragastrically (i.g., 50 mg/kg/day) for five consecutive days significantly inhibited sorbitol accumulation in red blood cells and the sciatic nerve. Molecular obesity indices predicted along with water solubility point an excellent “lead-likeness” of compound 3, with prospects of further structure optimizations.
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      PubDate: 2017-10-17T14:19:17Z
      DOI: 10.1016/j.bmc.2017.10.005
       
  • Discovery of New Antimalarial Agents: Second-Generation Dual Inhibitors
           against FP-2 and PfDHFR via Fragments Assembely
    • Authors: Wenhua Chen; Zhenghui Huang; Wanyan Wang; Fei Mao; Longfei Guan; Yun Tang; Hualiang Jiang; Jian Li; Jin Huang; Lubin Jiang; Jin Zhu
      Abstract: Publication date: Available online 16 October 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Wenhua Chen, Zhenghui Huang, Wanyan Wang, Fei Mao, Longfei Guan, Yun Tang, Hualiang Jiang, Jian Li, Jin Huang, Lubin Jiang, Jin Zhu
      Malaria parasites are a leading cause of worldwide mortality from infectious disease. Cysteine protease falcipain-2 (FP-2) and Plasmodium falciparum dihydrofolate reductase (PfDHFR) play vital roles, which are absolutely essential, in the parasite life cycle. In this study, based on the structures of uniform fragments of reported PfDHFR inhibitors and the first-generation dual inhibitors against FP-2 and PfDHFR, we identified a novel series of dual inhibitors through fragments assembly. Lead optimization led to the discovery of 24, which showed high potency against FP-2 (IC50=10.0 µM), PfDHFR (IC50= 84.1 nM), P. falciparum 3D7 (IC50= 53.1 nM), clinical isolated strains Fab9 (IC50= 14.2 nM) and GB4 (IC50= 23.4 nM). The in vivo inhibition assays against P. berghei in 10 days indicated 24 had a more beneficial effect on the growth inhibition of P. berghei than artemisinin and an identical effect with pyrimethamine. Additionally, 24 moderately inhibited the proliferation of chloroquine-resistant P. falciparum Dd2 strain. Collectively, these data revealed that 24 could be an excellent lead compound as FP-2 and PfDHFR dual inhibitor for the treatment of malaria.
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      PubDate: 2017-10-17T14:19:17Z
      DOI: 10.1016/j.bmc.2017.10.017
       
  • Novel analogs of PSNCBAM-1 as allosteric modulators of cannabinoid CB1
           receptor
    • Authors: Simone Bertini; Andrea Chicca; Francesca Gado; Chiara Arena; Daniela Nieri; Maria Digiacomo; Giuseppe Saccomanni; Pingwei Zhao; Mary E. Abood; Marco Macchia; Jürg Ghertsch; Clementina Manera
      Abstract: Publication date: Available online 16 October 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Simone Bertini, Andrea Chicca, Francesca Gado, Chiara Arena, Daniela Nieri, Maria Digiacomo, Giuseppe Saccomanni, Pingwei Zhao, Mary E. Abood, Marco Macchia, Jürg Ghertsch, Clementina Manera
      In this work, we explored the molecular framework of the known CB1R allosteric modulator PSNCBAM-1 with the aim to generate new bioactive analogs and to deepen the structure-activity relationships of this type of compounds. In particular, the introduction of a NH group between the pyridine ring and the phenyl nucleus generated the amino-phenyl-urea derivative SN15b that behaved as a positive allosteric modulator (PAM), increasing the CB1R binding affinity of the orthosteric ligand CP55,940. The functional activity was evaluated using serum response element (SRE) assay, which assesses the CB1R-dependent activation of the MAPK/ERK signaling pathway. SN15b and the biphenyl-urea analog SC4a significantly inhibited the response produced by CP55,940 in the low µM range, thus behaving as negative allosteric modulators (NAMs). The new derivatives presented here provide further insights about the modulation of CB1R binding and functional activity by allosteric ligands.
      Graphical abstract image

      PubDate: 2017-10-17T14:19:17Z
      DOI: 10.1016/j.bmc.2017.10.015
       
  • Design and synthesis of p-carborane-containing sulfamates as multitarget
           anti-breast cancer agents
    • Authors: Asako Kaise; Kiminori Ohta; Chinami Shirata; Yasuyuki Endo
      Abstract: Publication date: Available online 16 October 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Asako Kaise, Kiminori Ohta, Chinami Shirata, Yasuyuki Endo
      The development of multitarget anticancer agents is of high interest to medicinal chemists in terms of overcoming drug resistance and preventing cancer-cell migration. Based on the structure of the potent carborane-containing estrogen BE120, non-steroidal multitarget anti-breast cancer agent candidates 1a–1j were designed and synthesized. Compound 1f shows potent STS-inhibitory activity (IC50 = 1.8 μM), cell-growth-inhibitory (CGI) activity against 39 human cancer cell lines (MG-MID = 2.8 μM), and tubulin-polymerization-inhibitory (TPI) activity. An analysis of the DNA content for MDA-MB-453 breast cancer cells revealed that 1f arrests the cell cycle in the G2/M phase and induces apoptosis. Accordingly, 1f should be a promising therapeutic agent for hormone-dependent breast cancer.
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      PubDate: 2017-10-17T14:19:17Z
      DOI: 10.1016/j.bmc.2017.10.013
       
  • Selenium-containing analogues of WC-9 are extremely potent inhibitors of
           Trypanosoma cruzi proliferation
    • Authors: María N. Chao; Melissa Storey; Catherine Li; Maricel G. Rodríguez; Florencia Di Salvo; Sergio H. Szajnman; Silvia N.J. Moreno; Roberto Docampo; Juan B. Rodriguez
      Abstract: Publication date: Available online 16 October 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): María N. Chao, Melissa Storey, Catherine Li, Maricel G. Rodríguez, Florencia Di Salvo, Sergio H. Szajnman, Silvia N.J. Moreno, Roberto Docampo, Juan B. Rodriguez
      The obligate intracellular parasite, Trypanosoma cruzi is the etiologic agent of Chagas disease or American trypanosomiasis, which is the most prevalent parasitic disease in the Americas. The present chemotherapy to control this illness is still deficient particularly in the chronic stage of the disease. The ergosterol biosynthesis pathway has received much attention as a molecular target for the development of new drugs for Chagas disease. Especially, inhibitors of the enzymatic activity of squalene synthase were shown to be effective compounds on T. cruzi proliferation in in vitro assays. In the present study we designed, synthesized and evaluated the effect of a number of isosteric analogues of WC-9 (4-phenoxyphenoxyethyl thiocyanate), a known squalene synthase inhibitor, on T. cruzi growth in tissue culture cells. The selenium-containing derivatives turned out to be extremely potent inhibitors of T. cruzi growth. Certainly, 3-phenoxyphenoxyethyl, 4-phenoxyphenoxyethyl, 4-(3-fluorophenoxy)phenoxyethyl, 3-(3-fluorophenoxy)phenoxyethyl selenocyanates and (±)-5-phenoxy-2-(selenocyanatomethyl)-2,3-dihydrobenzofuran arose as relevant members of this family of compounds, which exhibited effective ED50 values of 0.084 µM, 0.11 µM, 0.083, µM, 0.085, and 0.075 µM, respectively. The results indicate that compounds bearing the selenocyanate moiety are at least two orders of magnitude more potent than the corresponding skeleton counterpart bearing the thiocyanate group. Surprisingly, these compounds exhibited excellent selectively index values ranging from 900 to 1,800 making these molecules promising candidates as antiparasitic agents.
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      PubDate: 2017-10-17T14:19:17Z
      DOI: 10.1016/j.bmc.2017.10.016
       
  • Ability of higenamine and related compounds to enhance glucose uptake in
           L6 cells
    • Authors: Eisuke Kato; Shunsuke Kimura; Jun Kawabata
      Abstract: Publication date: Available online 14 October 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Eisuke Kato, Shunsuke Kimura, Jun Kawabata
      β2-adrenergic receptor (β2AR) agonists are employed as bronchodilators to treat pulmonary disorders, but are attracting attention for their modulation of glucose handling and energy expenditure. Higenamine is a tetrahydroisoquinoline present in several plant species and has β2AR agonist activity, but the involvement of each functional groups in β2AR agonist activity and its effectiveness compared with endogenous catecholamines (dopamine, epinephrine, and norepinephrine) has rarely been studied. Glucose uptake of muscle cells are known to be induced through β2AR activation. Here, the ability to enhance glucose uptake of higenamine was compared with that of several methylated derivatives of higenamine or endogenous catecholamines. We found that: (i) the functional groups of higenamine except for the 4'-hydroxy group are required to enhance glucose uptake; (ii) higenamine shows a comparable ability to enhance glucose uptake with that of epinephrine and norepinephrine; (iii) the S-isomer shows a greater ability to enhance glucose uptake compared with that of the R-isomer.
      Graphical abstract image

      PubDate: 2017-10-17T14:19:17Z
      DOI: 10.1016/j.bmc.2017.10.011
       
  • Synthesis and biological evaluation of novel radioiodinated benzimidazole
           derivatives for imaging α-synuclein aggregates
    • Authors: Hiroyuki Watanabe; Taisuke Ariyoshi; Akihiko Ozaki; Masafumi Ihara; Masahiro Ono; Hideo Saji
      Abstract: Publication date: Available online 14 October 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Hiroyuki Watanabe, Taisuke Ariyoshi, Akihiko Ozaki, Masafumi Ihara, Masahiro Ono, Hideo Saji
      α -Synuclein (α -syn) aggregates are commonly found in the brains of patients with Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and some other diseases. Therefore, in vivo imaging of α -syn aggregates would aid in drug development, early diagnosis, and monitoring of disease status. In order to develop imaging probes targeting α -syn aggregates, we synthesized and evaluated three novel radioiodinated benzoimidazole (BI) derivatives for selective imaging of α -syn aggregates. In binding experiments, BI-2 exhibited the highest selective binding affinity for α -syn aggregates among the BI derivatives. In addition, BI-2 clearly stained Lewy bodies in PD brain sections, but did not label senile plaques deposited in AD brain sections. However, in the biodistribution study using normal mice, [125I]BI-2 did not demonstrate high brain uptake (0.56%ID/g at 2-min post-injection). Further structural modifications of the BI derivatives are needed, but the BI scaffold may be an attractive candidate for developing α -syn imaging probes.
      Graphical abstract image

      PubDate: 2017-10-17T14:19:17Z
      DOI: 10.1016/j.bmc.2017.10.010
       
  • Design, Synthesis and Biological Activity of
           3–Pyrazine-4-yl-oxazolidin-2-ones as Novel, Potent and Selective
           Inhibitors of Mutant Isocitrate Dehydrogenase 1
    • Authors: Tianfang Ma; Fangxia Zou; Stefan Pusch; Lijun Yang; Qihua Zhu; Yungen Xu; Yueqing Gu; Andreas von Deimling; Xiaoming Zha
      Abstract: Publication date: Available online 13 October 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Tianfang Ma, Fangxia Zou, Stefan Pusch, Lijun Yang, Qihua Zhu, Yungen Xu, Yueqing Gu, Andreas von Deimling, Xiaoming Zha
      Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) generating carbon dioxide and NADPH/NADH. Evidence suggests that the specific mutations in IDH1 are critical to the growth and reproduction of some tumor cells such as gliomas and acute myeloid leukemia, emerging as an attractive antitumor target. In order to discovery potent new mutant IDH1 inhibitors, we designed, synthesized and evaluated a series of allosteric mIDH1 inhibitors harboring the scaffold of 3–pyrazine-4-yl-oxazolidin-2-ones. All tested compounds effectively suppress the D-2-hydroxyglutarate (D-2-HG) production in cells transfected with IDH1-R132H and IDH1-R132C mutations at 10 μM and 50 μM. Importantly, compound 3g owns the similar inhibitory activity to the positive agent NI-1 and shows no significant toxicity at the two concentrations. The parallel artificial membrane permeation assay of the blood-brain barrier (PAMPA-BBB) identified 3g with a good ability to penetrate the blood-brain barrier (BBB). These findings indicate that 3g deserves further optimization as a lead compound for the treatment of patients with IDH1 mutated brain cancers.
      Graphical abstract image

      PubDate: 2017-10-17T14:19:17Z
      DOI: 10.1016/j.bmc.2017.10.009
       
  • Synthesis and optical properties of pyrrolidinyl peptide nucleic acid
           bearing a base discriminating fluorescence nucleobase
           8-(pyrene-1-yl)-ethynyladenine
    • Authors: Duangrat Nim-anussornkul; Tirayut Vilaivan
      Abstract: Publication date: Available online 13 October 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Duangrat Nim-anussornkul, Tirayut Vilaivan
      A combination of fluorophore and nucleobase through a π-conjugated rigid linker integrates the base pairing and the fluorescence change into a single event. Such base discriminating fluorophore can change its fluorescence as a direct response to the base pairing event and therefore have advantages over tethered label or base surrogates lacking the hydrogen-bonding ability. 8-(Pyrene-1-yl)ethynyl-adenine (APyE) has been extensively used as fluorescence labels in DNA and LNA, but it showed little discrimination between different nucleobases. Herein we investigated the synthesis, base pairing ability and optical properties of APyE in pyrrolidinyl peptide nucleic acid – a DNA mimic that shows much stronger affinity and specificity towards DNA than natural oligonucleotides. The APyE in PNA pairs specifically with thymine in the DNA strand, and resulted in 1.5–5.2 fold enhanced and blue-shifted fluorescence emission. Fluorescence quenching was observed in the presence of mismatched base or abasic site directly opposite to the APyE. The behavior of APyE in acpcPNA is distinctively different from DNA whereby a fluorescence was increased selectively upon duplex formation with complementary DNA and therefore emphasizing the unique advantages of using PNA as alternative oligonucleotide probes. Applications as color-shifting probe for detection of trinucleotide repeats in DNA were demonstrated, and the performance of the probe was further improved by combination with reduced graphene oxide as an external nanoquencher.
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      PubDate: 2017-10-17T14:19:17Z
      DOI: 10.1016/j.bmc.2017.10.008
       
  • Development of a safe and scalable route towards a tau PET tracer
           precursor
    • Authors: Bjoern Bartels; Philipp Cueni; Dieter Muri; Matthias Koerner
      Abstract: Publication date: Available online 12 October 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Bjoern Bartels, Philipp Cueni, Dieter Muri, Matthias Koerner
      A scalable 5-step synthesis of the diazacarbazole derivative 1 used as tau PET tracer precursor is reported. Key features of this synthesis include a Buchwald-Hartwig amination, a Pd catalyzed C-H activation and a Suzuki-Miyaura cross-coupling.
      Graphical abstract image

      PubDate: 2017-10-17T14:19:17Z
      DOI: 10.1016/j.bmc.2017.10.007
       
  • Novel p-carborane-containing multitarget anticancer agents inspired by the
           metabolism of 17β-estradiol
    • Authors: Asako Kaise; Kiminori Ohta; Yasuyuki Endo
      Abstract: Publication date: Available online 12 October 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Asako Kaise, Kiminori Ohta, Yasuyuki Endo
      The female hormone 17 β-estradiol (E2) is synthesized from estrone by steroid sulfatase (STS), and metabolized into 2-methoxyestradiol (2-ME), whereby the biological activity of the latter is substantially different from that of E2. Based on the metabolic pathways of E2, a carborane-containing 2-ME mimic (1c) and its derivatives (1 and 2) were designed and synthesized as novel multitarget anticancer agents. Bissulfamate 1f exhibited potent STS-inhibitory activity and tubulin-polymerization-inhibitory activity. Moreover, the cell-growth-inhibitory (CGI) activity of 1f was similar to that of 2-ME in a panel screening against 39 human cancer cell lines. Accordingly, 1f should be a promising perspective therapeutic agent for hormone-dependent breast tissue.
      Graphical abstract image

      PubDate: 2017-10-17T14:19:17Z
      DOI: 10.1016/j.bmc.2017.10.006
       
  • Astemizole analogues with reduced hERG inhibition as potent antimalarial
           compounds
    • Authors: Junjun Tian; Leen Vandermosten Steve Peigneur Lien Moreels Jef Rozenski
      Abstract: Publication date: Available online 7 October 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Junjun Tian, Leen Vandermosten, Steve Peigneur, Lien Moreels, Jef Rozenski, Jan Tytgat, Piet Herdewijn, Philippe E. Van den Steen, Steven De Jonghe
      Astemizole is a H1-antagonist endowed with antimalarial activity, but has hERG liabilities. Systematic structural modifications of astemizole led to the discovery of analogues that display very potent activity as inhibitors of the growth of the Plasmodium parasite, but show a decreased hERG inhibition, when compared to astemizole. These compounds can be used as starting point for the development of a new class of antimalarials.
      Graphical abstract image

      PubDate: 2017-10-10T13:46:25Z
       
  • Development of a microarray-based assay for efficient testing of new
           HSP70/DnaK inhibitors
    • Authors: Sona Mohammadi-Ostad-Kalayeh; Vjaceslavs Hrupins Sabine Helmsen Frank Stahl Thomas Scheper
      Abstract: Publication date: Available online 7 October 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Sona Mohammadi-Ostad-Kalayeh, Vjaceslavs Hrupins, Sabine Helmsen, Frank Stahl, Thomas Scheper, Matthias Preller, Frank Surup, Marc Stadler, Andreas Kirschning, Carsten Zeilinger
      A facile method for testing ATP binding in a highly miniaturized microarray environment using human HSP70 and DnaK from Mycobacterium tuberculosis as biological targets is reported. Supported by molecular modelling studies we demonstrate that the position of the fluorescence label on ATP has a strong influence on the binding to human HSP70. Importantly, the label has to be positioned on the adenine ring and not to the terminal phosphate group. Unlabelled ATP displaced bound Cy5-ATP from HSP70 in the micromolar range. The affinity of a well-known HSP70 inhibitor VER155008 for the ATP binding site in HSP70 was determined, with a EC50 in the micromolar range, whereas reblastin, a HSP90-inhibitor, did not compete for ATP in the presence of HSP70. The applicability of the method was demonstrated by screening a small compound library of natural products. This unraveled that terphenyls rickenyl A and D, recently isolated from cultures of the fungus Hypoxylon rickii, are inhibitors of HSP70. They compete with ATP for the chaperone in the range of 29 µM (Rickenyl D) and 49 µM (Rickenyl A). Furthermore, the microarray-based test system enabled protein-protein interaction analysis using full-length HSP70 and HSP90 proteins. The labelled full-length human HSP90 binds with a half-maximal affinity of 5.5 µg/ml (∼40 µM) to HSP70. The data also demonstrate that the microarray test has potency for many applications from inhibitor screening to target-oriented interaction studies.
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      PubDate: 2017-10-10T13:46:25Z
       
  • Preparation of regio- and stereoisomeric di- and
           tetrahydrogeranylgeraniols and identification of esterifying groups in
           natural (bacterio)chlorophylls
    • Authors: Hitoshi Tamiaki; Kota Nomura Tadashi Mizoguchi
      Abstract: Publication date: Available online 6 October 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Hitoshi Tamiaki, Kota Nomura, Tadashi Mizoguchi
      All regioisomeric di- and tetrahydrogeranylgeraniols possessing the C2=C3 double bond were prepared as authentic samples. The synthetic C20-isoprenoid alcohols were separated well by gas chromatography. Based on the chromatographic analysis, the enzymatic reduction pathway of a geranylgeranyl group was investigated to identify the last stage of (bacterio)chlorophyll biosynthesis in phototrophs. The geranylgeranyl group was triply reduced to the phytyl group through the first regio- and stereospecific hydrogenation of C10=C11 to C10H–C11(S)H, the second of C6=C7 to C6H–C7(S)H, and the third of C14=C15 to C14H–C15H. The identification of the reduction sequence completes the biosynthetic pathways for naturally occurring chlorophyll-a and bacteriochlorophyll-a bearing a phytyl group as the esterifying moiety in the 17-propionate residues.
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      PubDate: 2017-10-10T13:46:25Z
       
  • Development of photoaffinity derivatives of the antitumor macrolide
           aplyronine A, a PPI-inducer between actin and tubulin
    • Authors: Masaki Kita; Kota Yamagishi; Kota Tsuchiya; Yu Seguchi; Hiroki Nakane; Hideo Kigoshi
      Abstract: Publication date: Available online 4 October 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Masaki Kita, Kota Yamagishi, Kota Tsuchiya, Yu Seguchi, Hiroki Nakane, Hideo Kigoshi
      The antitumor and actin-depolymerizing marine macrolide aplyronine A (ApA) synergistically binds to tubulin in association with actin, and prevents spindle formation and mitosis. While the crystal structure of the actin–ApA complex was solved in 2006, its interaction with the tubulin heterodimer has not been clarified. To investigate the binding modes of ApA as a unique protein–protein interaction (PPI)-inducer between these two cytoskeletal proteins, we prepared its photoaffinity acetylene and fluorescent derivatives with the aid of molecular modeling studies for probe design. Among these three derivatives, the ApA–PPA–TAMRA probe specifically photoreacted with both actin and tubulin in vitro. However, the photolabeling yield of tubulin was quite low (up to ∼1%), and one of the major side-reactions was the addition of a water molecule to the carbene species generated from an aryldiazirine moiety on the hydrophilic surface of actin.
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      PubDate: 2017-10-10T13:46:25Z
      DOI: 10.1016/j.bmc.2017.09.044
       
  • Design and Synthesis of Benzimidazole-based Rho Kinase inhibitors for the
           treatment of Glaucoma
    • Authors: Vasudha Abbhi; Lovneet Saini; Srishti Mishra; Gautam Sethi; Alan Prem Kumar; Poonam Piplani
      Abstract: Publication date: Available online 4 October 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Vasudha Abbhi, Lovneet Saini, Srishti Mishra, Gautam Sethi, Alan Prem Kumar, Poonam Piplani
      Rho kinase inhibitors (ROCK II) play a key role in glaucoma management attributed to their IOP lowering ability and neuroprotective effects. In the present study, a series of novel benzimidazole derivatives (9a-m) has been synthesized and evaluated for their IOP lowering, Rho kinase inhibitory and antioxidant properties. The synthesized compounds were found to be lipophilic and showed a significant IOP lowering effect both in the treated and the contralateral eye comparable to the reference standard fasudil. The nitrophenyl piperazine substituted compound 9j exhibited significant IOP lowering (51.56%) and an inhibition of 57.25 and 77.92% towards ROCK II enzyme at a concentration of 0.5 and 1 mM respectively. It possessed a considerable free radical scavenging activity exhibiting an IC50 value of 95.49 µg/mL in DPPH assay. The molecular docking studies of compound 9j indicated the binding of the compound at the active site of recombinant human ROCK II which makes it a promising antiglaucoma agent.
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      PubDate: 2017-10-10T13:46:25Z
      DOI: 10.1016/j.bmc.2017.09.045
       
  • Synthesis and anti-influenza virus evaluation of triterpene-sialic acid
           conjugates
    • Authors: Mitsuru Tsuji; Nongluk Sriwilaijaroen; Hideo Inoue; Kazuhiko Miki; Kaoru Kinoshita; Kiyotaka Koyama; Kimio Furuhata; Yasuo Suzuki; Kunio Takahashi
      Abstract: Publication date: Available online 3 October 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Mitsuru Tsuji, Nongluk Sriwilaijaroen, Hideo Inoue, Kazuhiko Miki, Kaoru Kinoshita, Kiyotaka Koyama, Kimio Furuhata, Yasuo Suzuki, Kunio Takahashi
      We are interested in new non-natural glycosides with sialic acid conjugates and their biological activities. We report the synthesis of eleven non-natural occurring glycosides, which are triterpene (glycyrrhetinic acid and its derivatives)-sialic acid conjugates, and their inhibitory activities against influenza virus sialidases and influenza virus multiplication in MDCK host cells. Deoxoglycyrrhetol-sialic acid conjugates (6d and 6e) and oleanolic acid-sialic acid conjugates (7d and 7e) showed strong inhibitory activities against three subtypes of influenza virus sialidases. These four compounds (6d, 6e, 7d and 7e) showed clear inhibition to influenza virus multiplication but not to MDCK host cell survival.
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      PubDate: 2017-10-10T13:46:25Z
      DOI: 10.1016/j.bmc.2017.09.038
       
  • 3’-Hydroxy-3,4’-dimethoxyflavone Blocks Tubulin Polymerization and is
           a Potent Apoptotic Inducer in Human SK-MEL-1 Melanoma Cells
    • Authors: Francisco Estévez-Sarmiento; Mercedes Said; Ignacio Brouard; Francisco León; Celina García; José Quintana; Francisco Estévez
      Abstract: Publication date: Available online 3 October 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Francisco Estévez-Sarmiento, Mercedes Said, Ignacio Brouard, Francisco León, Celina García, José Quintana, Francisco Estévez
      Flavonoids are naturally occurring polyphenolic compounds and are among the most promising anticancer agents. A series of flavonols and their 3-methyl ether derivatives were synthesized and assessed for cytotoxicity. It was found that 3’-hydroxy-3,4’-dimethoxyflavone (flavonoid 7a) displayed strong cytotoxicity against human SK-MEL-1 melanoma cells and blocked tubulin polymerization, but had no significant cytotoxic effects against quiescent or proliferating human peripheral blood mononuclear cells. Our analyses showed that flavonoid 7a induces G2-M cell cycle arrest and apoptosis in melanoma cells which is associated with cytochrome c release and activation of both extrinsic and intrinsic apoptotic pathways of cell death.
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      PubDate: 2017-10-10T13:46:25Z
      DOI: 10.1016/j.bmc.2017.09.043
       
  • Binding of triazole-linked galactosyl arylsulfonamides to galectin-3
           affects Trypanosoma cruzi cell invasion
    • Authors: Marcelo Fiori Marchiori; Thalita B. Riul; Leandro Oliveira Bortot; Peterson Andrade; Getúlio G. Junqueira; Giuseppina Foca; Nunzianna Doti; Menotti Ruvo; Marcelo Dias-Baruffi; Ivone Carvalho; Vanessa Leiria Campo
      Abstract: Publication date: Available online 30 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Marcelo Fiori Marchiori, Thalita B. Riul, Leandro Oliveira Bortot, Peterson Andrade, Getúlio G. Junqueira, Giuseppina Foca, Nunzianna Doti, Menotti Ruvo, Marcelo Dias-Baruffi, Ivone Carvalho, Vanessa Leiria Campo
      The synthesis of the O-3 triazole-linked galactosyl arylsulfonamides 1-7 as potential inhibitors of Trypanosoma cruzi cell invasion is described. These target compounds were synthesized by Cu(I)-catalysed azide-alkyne cycloaddition reaction (‘click chemistry’) between different azide arylsulfonamides and the alkyne-based sugar 3-O-propynyl-βGalOMe. Inhibition assays of T. cruzi cell invasion with compounds 1-7 showed reduced values of infection index (∼20) for compounds 3 and 5, bearing the corresponding 5-methylisoxazole and 2,4-dimethoxypyrimidine groups, which also presented higher binding affinities to galectin-3 (EC50 17-18 μM) in Corning Epic label-free assays. In agreement with experimental results, the assessment of the theoretical binding of compounds 1-7 to galectin-3 by MM/PBSA method displayed higher affinities for compounds 3 (-9.7 Kcal/ mol) and 5 (-11.1 Kcal/ mol). Overall, these achievements highlight compounds 3 and 5 as potential T. cruzi cell invasion blockers by means of a galectin-3 binding-related mechanism, revealing galectin-3 as an important host target for design of novel anti-trypanosomal agents.
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      PubDate: 2017-10-02T09:04:54Z
      DOI: 10.1016/j.bmc.2017.09.042
       
  • Phosphamide-Containing Diphenylpyrimidine Analogues (PA-DPPYs) as Potent
           Focal Adhesion Kinase (FAK) Inhibitors with Enhanced Activity against
           Pancreatic Cancer Cell Lines
    • Authors: He Liu; Bin Wu; Yang Ge; Jiaxin Xu; Shijie Song; Changyuan Wang; Jihong Yao; Kexin Liu; Yanxia Li; Xiuli Sun; Xiaodong Ma
      Abstract: Publication date: Available online 30 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): He Liu, Bin Wu, Yang Ge, Jiaxin Xu, Shijie Song, Changyuan Wang, Jihong Yao, Kexin Liu, Yanxia Li, Xiuli Sun, Xiaodong Ma
      A family of phosphamide-containing diphenylpyrimidine analogues (PA-DPPYs) were synthesized as potent focal adhesion kinase (FAK) inhibitors. The PA-DPPY derivatives could significantly inhibit the FAK enzymatic activity within concentrations of lower than 10.69 nM. Among them, compounds 7a and 7e were two of the most active FAK inhibitors, possessing IC50 values of 4.25 nM and 4.65 nM, respectively. In particular, compound 7e also displayed strong activity against AsPC cell line, with an IC50 of 1.66 μM, but show low activity against the normal HPDE6-C7 cells (IC50 > 20 μM), indicating its low cell cytoxicity. Additionally, flow cytometry analysis showed that after treatment of 7e (8 μM, 72 h), both AsPC and Panc cells were almost totally inhibited, with a cell viability rate of 16.8% and 18.1%, respectively. Overall, compound 7e may be served as a valuable FAK inhibitor for the treatment of pancreatic cancer.
      Graphical abstract image

      PubDate: 2017-10-02T09:04:54Z
      DOI: 10.1016/j.bmc.2017.09.041
       
  • Peptides for optical medical imaging and steps towards therapy
    • Authors: Matteo Staderini; Alicia Megia-Fernandez; Kevin Dhaliwal; Mark Bradley
      Abstract: Publication date: Available online 30 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Matteo Staderini, Alicia Megia-Fernandez, Kevin Dhaliwal, Mark Bradley
      Optical medical imaging is a rapidly growing area of research and development that offers a multitude of healthcare solutions both diagnostically and therapeutically. In this review some of the most recently described peptide-based optical probes are reviewed with a special emphasis on their in vivo use and potential application in a clinical setting.
      Graphical abstract image

      PubDate: 2017-10-02T09:04:54Z
      DOI: 10.1016/j.bmc.2017.09.039
       
  • Teixobactin as a scaffold for unlimited new antimicrobial peptides: SAR
           study
    • Authors: Shimaa A. H. Abdel Monaim; Yahya E. Jad; Ayman El-Faham; Beatriz G. de la Torre; Fernando Albericio
      Abstract: Publication date: Available online 30 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Shimaa A. H. Abdel Monaim, Yahya E. Jad, Ayman El-Faham, Beatriz G. de la Torre, Fernando Albericio
      It looks that a new era of antimicrobial peptides (AMPs) started with the discovery of teixobactin, which is a “head to side-chain” cyclodepsipeptide. It was isolated from a soil gram-negative b-proteobacteria by means of a revolutionary technique. Since there, several groups have developed synthetic strategies for efficient synthesis of this peptide and its analogues as well. Herein, all chemistries reported as well as the biological activity of the analogues are analyzed. Finally, some inputs regarding new trends for the next generation of analogues are discussed.
      Graphical abstract image

      PubDate: 2017-10-02T09:04:54Z
      DOI: 10.1016/j.bmc.2017.09.040
       
  • The antitubercular activity of various nitro(triazole/imidazole)-based
           compounds
    • Authors: Maria V. Papadopoulou; William D. Bloomer; Howard S. Rosenzweig
      Abstract: Publication date: Available online 28 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Maria V. Papadopoulou, William D. Bloomer, Howard S. Rosenzweig
      Twenty three 3-nitrotriazole- and five nitroimidazole-based compounds, mostly amides, were screened for antitubercular activity against Mycobacterium tuberculosis H37Rv (Mtb H37Rv) under aerobic or low oxygen conditions, intracellular activity in murine J774 macrophages or THP-1 cells, activity against resistant Mtb strains as well as cytotoxicity in normal cells. Compounds with a Minimum Inhibitory Concentration (MIC) less than 10 μM and 10-50 μM were characterized as active and moderately active, respectively, whereas compounds with a MIC > 50 μM were characterized inactive. Fifteen 3-nitrotriazole-based compounds were active or moderately active against aerobic Mtb and thirteen of them were bactericidal, however, only four 3-nitrotriazoles were moderately active against anaerobic Mtb. All examined 2-nitroimidazole-based compounds were inactive against aerobic Mtb, and from the ones examined against anaerobic Mtb, only one was found moderately active. All examined compounds demonstrated intracellular activity and lack of cross-resistance. The five active 3-nitrotriazoles demonstrated good selectivity for Mtb. In conclusion, these classes of 3-nitrotriazole-based compounds merit further investigation as potential antitubercular agents.
      Graphical abstract image

      PubDate: 2017-10-02T09:04:54Z
      DOI: 10.1016/j.bmc.2017.09.037
       
  • Design, synthesis, and evaluation of salicyladimine derivatives as
           multitarget-directed ligands against Alzheimer’s disease
    • Authors: Hua-Li Yang; Pei Cai; Qiao-Hong Liu; Xue-Lian Yang; Si-Qiang Fang; Yan-Wei Tang; Cheng Wang; Xiao-Bing Wang; Ling-Yi Kong
      Abstract: Publication date: Available online 27 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Hua-Li Yang, Pei Cai, Qiao-Hong Liu, Xue-Lian Yang, Si-Qiang Fang, Yan-Wei Tang, Cheng Wang, Xiao-Bing Wang, Ling-Yi Kong
      A series of salicyladimine derivatives were designed, synthesized and evaluated as multi-target-directed ligands for the treatment of Alzheimer’s disease (AD). Biological activity results demonstrated that some derivatives possessed significant inhibitory activities against amyloid-β (Aβ) aggregation and human monoamine oxidase B (hMAO-B) as well as remarkable antioxidant effects and low cell toxicity. The optimal compound, 5, exhibited excellent potency for inhibition of self-induced Aβ 1-42 aggregation (91.3±2.1%, 25 μM), inhibition of hMAO-B (IC50, 1.73±0.39 μM), antioxidant effects (43.4±2.6 μM of IC50 by DPPH method, 0.67±0.06 trolox equivalent by ABTS method), metal chelation and BBB penetration. Furthermore, compound 5 had neuroprotective effects against ROS generation, H2O2-induced apoptosis, 6-OHDA-induced cell injury, and a significant in vitro anti-inflammatory activity. Collectively, these findings highlighted that compound 5 was a potential balanced multifunctional neuroprotective agent for the development of anti-AD drugs.
      Graphical abstract image

      PubDate: 2017-10-02T09:04:54Z
      DOI: 10.1016/j.bmc.2017.08.048
       
  • Rationally designed hecogenin thiosemicarbazone analogs as novel MEK
           inhibitors for the control of breast malignancies
    • Authors: Heba E. Elsayed; Hassan Y. Ebrahim; Eman G. Haggag; Amel M. Kamal; Khalid A. El Sayed
      Abstract: Publication date: Available online 27 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Heba E. Elsayed, Hassan Y. Ebrahim, Eman G. Haggag, Amel M. Kamal, Khalid A. El Sayed
      Natural products have documented oncology success history as valuable scaffolds for selective target modulation. Herein, the sapogenin hecogenin (1) was screened for its anti-breast cancer inhibitory capacity using in vitro assays, including proliferation, cytotoxicity, migration, invasion assays, and western blotting. The results identified 1 as a propitious hit with modest activities attributed to the concurrent down regulation of mitogen activated protein kinase kinase/extracellular signal-regulated kinase (MEK) distinctive downstream effectors. Guided by in silico 3D-structural insights of MAPK kinase domain, an extension-strategy was adopted at 1's C-3 and C-12 aimed at the design of novel hecogenin-based analogs with improved target binding affinity. Thirty-three analogs were prepared and tested, among which hecogenin 12-(3'-methylphenyl thiosemicarbazone) (30) displayed the most potent selective anticancer effects. Analog 30 demonstrated antiproliferative, antimigratory and anti-invasive activities at low μM level, compared to the negligible effect on the non-tumorigenic MCF-10A mammary epithelial cells. Durable regression of breast tumor xenografts in athymic nude mice was observed after treatments with 30, compared to its parent hecogenin at the same dose regimen, confirmed the hit-to-lead promotion of this analog. Hecogenin-12-thiosemicarbazones, represented by 30, is a novel MEK inhibitory lead class to control breast neoplasms.
      Graphical abstract image

      PubDate: 2017-10-02T09:04:54Z
      DOI: 10.1016/j.bmc.2017.09.033
       
  • Recently Reported Biological Activities of Pyrazole Compounds
    • Authors: Jéssica Venância Faria; Percilene Fazolin Vegi; Ana Gabriella Carvalho Miguita; Maurício Silva dos Santos; Nubia Boechat; Alice Maria Rolim Bernardino
      Abstract: Publication date: Available online 23 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Jéssica Venância Faria, Percilene Fazolin Vegi, Ana Gabriella Carvalho Miguita, Maurício Silva dos Santos, Nubia Boechat, Alice Maria Rolim Bernardino
      The pyrazole nucleus is an aromatic azole heterocycle with two adjacent nitrogen atoms. Pyrazole derivatives have exhibited a broad spectrum of biological activities, and approved pyrazole-containing drugs include celecoxib, antipyrine, phenylbutazone, rimonabant, and dipirone. Many research groups have synthesized and evaluated pyrazoles against several biological agents. This review examines recent publications relating the structures of pyrazoles with their corresponding biological activities.
      Graphical abstract image

      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2017.09.035
       
  • A Rhodamine B-based fluorescent probe for imaging Cu2+ in maize roots
    • Authors: Ting Lv; Yongqian Xu; Hongjuan Li; Fengyu Liu; Shiguo Sun
      Abstract: Publication date: Available online 23 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Ting Lv, Yongqian Xu, Hongjuan Li, Fengyu Liu, Shiguo Sun
      A new Rhodamine B-based fluorescent probe (RBO) is successfully designed and synthesized, which is a higher selective and sensitive chemosensor for Cu2+ than other ions. Under physiological conditions (pH = 7.0), the non emission RBO displays a rapid fluorescence increase together with a color change after addition of Cu2+ and the detection limit is down to 28 nM, which can clearly illustrate the distribution of Cu2+ with the help of laser scanning confocal microscope in plant tissues. Eventually, it confirmed that the Cu2+ accumulates mostly in the vascular cylinder and very less in the epidermal cells of maize roots, which is important to understand how the plants take up, transport and store in the Cu2+.
      Graphical abstract image

      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2017.09.026
       
  • In vivo Programming of Endogenous Antibodies via Oral Administration of
           Adaptor Ligands
    • Authors: Masanobu Nagano; Nancy Carrillo; Nobumasa Otsubo; Wataru Hakamata; Hitoshi Ban; Roberta F. Fuller; Nasir K. Bashiruddin; Carlos F. Barbas
      Abstract: Publication date: Available online 23 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Masanobu Nagano, Nancy Carrillo, Nobumasa Otsubo, Wataru Hakamata, Hitoshi Ban, Roberta F. Fuller, Nasir K. Bashiruddin, Carlos F. Barbas
      Vaccination is a reliable method of prophylaxis and a crucial measure for public health. However, the majority of vaccines cannot be administered orally due to their degradation in the harsh gut environment or inability to cross the GI tract. In this study, we report the first proof-of-concept study of orally producible chemically programmed antibodies via specific conjugation of adaptor ligands to endogenous antibodies, in vivo. Pre-immuniztion with 2,4-dinitrophenyl (DNP), or the reactive hapten, 1,3-diketone (DK), or a novel reactive hapten, vinyl sulfone (VS) in mice, followed by oral administration of adaptor ligands composed of the hapten and biotin to the pre-immunized mice resulted in successful in vivo formation of the biotin-hapten-antibody complexes within 2 hours. Pharmacokinetic evaluations revealed that apparent serum concentrations of programmed antibodies were up to 144 nM and that the serum half-lives reached up to 34.4 h. These findings show promise for the future development of orally bioavailable drug-hapten-antibody complexes as a strategy to quickly and easily modulate immune targets for aggressive pathogens as well as cancer.
      Graphical abstract image

      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2017.09.010
       
  • Synthesis and photophysical properties of a fluorescent cyanoquinoline
           probe for profiling ERBB2 kinase inhibitor response
    • Authors: Heajin Lee; Ralf Landgraf; James N. Wilson
      Abstract: Publication date: Available online 23 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Heajin Lee, Ralf Landgraf, James N. Wilson
      A fluorescent probe targeting the ERBB2 receptor tyrosine was designed, synthesized and evaluated as reporter of ERBB2 dynamics in overexpressing BT474, i.e. Her2(+), cells. Two cyanoquinazoline (CQ) probes modeled after type-I (CQ1) or active state and type-II (CQ2) or inactive state inhibitors were designed and synthesized with extended π systems that impart binding-induced, turn-on fluorescence. Solution spectroscopy revealed that CQ1 exhibited attractive photophysical properties and displayed turn-on emission in the presence of purified, soluble ERBB2 kinase domain, while CQ2 was found to be non-emissive, likely due to quenching via a photoinduced electron transfer mechanism. Live cell imaging with CQ1 revealed that this probe targeted an intracellular population of ERBB2, which increased following treatment with type-I inhibitors, gefinitib and canertinib, but showed no response to type-II inhibitors. CQ1 thus provides a novel means of imaging the dynamic response of ERBB2(+) cells to kinase inhibitors.
      Graphical abstract image

      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2017.09.034
       
  • A ‘catch and release’ strategy towards HPLC-free purification of
           synthetic oligonucleotides by a combination of the strain-promoted
           alkyne-azide cycloaddition and the photocleavage
    • Authors: Yosuke Igata; Noriko Saito-Tarashima; Daiki Matsumoto; Kazuyuki Sagara; Noriaki Minakawa
      Abstract: Publication date: Available online 21 September 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Yosuke Igata, Noriko Saito-Tarashima, Daiki Matsumoto, Kazuyuki Sagara, Noriaki Minakawa
      A convenient strategy to purify oligonucleotides (ONs) synthesized by solid phase synthesis on an automatic DNA/RNA synthesizer was described. By attaching a photocleavable azide linker as the last phosphoramidite unit in the ON synthesis, only the desired full-length sequence was ‘caught’ on a controlled pore glass (CPG) resin possessing an aza-dimethoxycyclooctyne (DIBAC) derivative. Washing the resulting CPG resin to remove all unbounded species, the subsequent photoirradiation allowed the pure ONs to be ‘released’ without leaving any chemical modifications on native ON structure or chemical reagents from the solid phase ON synthesis.
      Graphical abstract image

      PubDate: 2017-09-25T07:00:19Z
      DOI: 10.1016/j.bmc.2017.09.014
       
 
 
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