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  Subjects -> CHEMISTRY (Total: 762 journals)
    - ANALYTICAL CHEMISTRY (45 journals)
    - CHEMISTRY (527 journals)
    - CRYSTALLOGRAPHY (22 journals)
    - ELECTROCHEMISTRY (24 journals)
    - INORGANIC CHEMISTRY (40 journals)
    - ORGANIC CHEMISTRY (40 journals)
    - PHYSICAL CHEMISTRY (64 journals)

CHEMISTRY (527 journals)                  1 2 3 4 5 6 | Last

Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (30 followers)
ACS Catalysis     Full-text available via subscription   (21 followers)
ACS Chemical Neuroscience     Full-text available via subscription   (10 followers)
ACS Combinatorial Science     Full-text available via subscription   (6 followers)
ACS Macro Letters     Full-text available via subscription   (16 followers)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (16 followers)
ACS Nano     Full-text available via subscription   (152 followers)
ACS Photonics     Full-text available via subscription   (1 follower)
ACS Synthetic Biology     Full-text available via subscription   (7 followers)
Acta Chemica Iasi     Open Access  
Acta Chimica Slovaca     Open Access   (5 followers)
Acta Chromatographica     Full-text available via subscription   (9 followers)
Acta Facultatis Medicae Naissensis     Open Access   (1 follower)
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (2 followers)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (1 follower)
Adhesion Adhesives & Sealants     Hybrid Journal   (3 followers)
Adsorption Science & Technology     Full-text available via subscription   (5 followers)
Advanced Functional Materials     Hybrid Journal   (29 followers)
Advances in Chemical Engineering and Science     Open Access   (19 followers)
Advances in Chemical Science     Open Access   (6 followers)
Advances in Colloid and Interface Science     Full-text available via subscription   (12 followers)
Advances in Drug Research     Full-text available via subscription   (13 followers)
Advances in Fluorine Science     Full-text available via subscription   (6 followers)
Advances in Fuel Cells     Full-text available via subscription   (10 followers)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (6 followers)
Advances in Materials Physics and Chemistry     Open Access   (7 followers)
Advances in Nanoparticles     Open Access   (9 followers)
Advances in Organometallic Chemistry     Full-text available via subscription   (7 followers)
Advances in Polymer Science     Hybrid Journal   (35 followers)
Advances in Protein Chemistry     Full-text available via subscription   (4 followers)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (8 followers)
Advances in Quantum Chemistry     Full-text available via subscription   (3 followers)
African Journal of Chemical Education     Open Access  
African Journal of Pure and Applied Chemistry     Open Access  
Afrique Science : Revue Internationale des Sciences et Technologie     Open Access  
Agrokémia és Talajtan     Full-text available via subscription   (2 followers)
Alchemy     Open Access   (2 followers)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (3 followers)
AMB Express     Open Access   (1 follower)
Ambix     Hybrid Journal   (3 followers)
American Journal of Applied Sciences     Open Access   (27 followers)
American Journal of Biochemistry and Biotechnology     Open Access   (77 followers)
American Journal of Biochemistry and Molecular Biology     Open Access   (7 followers)
American Journal of Chemistry     Open Access   (14 followers)
American Journal of Plant Physiology     Open Access   (9 followers)
American Mineralogist     Full-text available via subscription   (2 followers)
Analyst     Full-text available via subscription   (33 followers)
Angewandte Chemie     Hybrid Journal   (12 followers)
Angewandte Chemie International Edition     Hybrid Journal   (140 followers)
Annales UMCS, Chemia     Open Access   (2 followers)
Annual Reports in Computational Chemistry     Full-text available via subscription   (1 follower)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (2 followers)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (4 followers)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (8 followers)
Annual Review of Food Science and Technology     Full-text available via subscription   (11 followers)
Anti-Infective Agents     Hybrid Journal   (1 follower)
Applied Organometallic Chemistry     Hybrid Journal   (3 followers)
Applied Spectroscopy     Full-text available via subscription   (11 followers)
Applied Surface Science     Hybrid Journal   (13 followers)
Arabian Journal of Chemistry     Full-text available via subscription   (5 followers)
ARKIVOC     Open Access   (1 follower)
Asian Journal of Biochemistry     Open Access   (1 follower)
Australian Journal of Chemistry     Hybrid Journal   (4 followers)
Autophagy     Full-text available via subscription  
Avances en Quimica     Open Access   (1 follower)
Biocell     Open Access  
Biochemical Pharmacology     Hybrid Journal   (5 followers)
Biochemistry     Full-text available via subscription   (118 followers)
Biochemistry Insights     Open Access   (3 followers)
Biochemistry Research International     Open Access   (3 followers)
BioChip Journal     Hybrid Journal   (1 follower)
Bioinorganic Chemistry and Applications     Open Access   (4 followers)
Biointerface Research in Applied Chemistry     Open Access   (1 follower)
Biointerphases     Open Access  
Biomacromolecules     Full-text available via subscription   (16 followers)
Biomass Conversion and Biorefinery     Partially Free   (5 followers)
Biomedical Chromatography     Hybrid Journal   (7 followers)
Biomolecular NMR Assignments     Hybrid Journal   (2 followers)
BioNanoScience     Partially Free   (4 followers)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (26 followers)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (20 followers)
Bioorganic Chemistry     Hybrid Journal   (5 followers)
Biopolymers     Hybrid Journal   (12 followers)
Biosensors     Open Access   (3 followers)
Biotechnic and Histochemistry     Hybrid Journal   (1 follower)
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (1 follower)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (11 followers)
Canadian Association of Radiologists Journal     Full-text available via subscription   (3 followers)
Canadian Journal of Chemistry     Full-text available via subscription   (6 followers)
Canadian Mineralogist     Full-text available via subscription   (1 follower)
Carbohydrate Research     Hybrid Journal   (10 followers)
Carbon     Hybrid Journal   (33 followers)
Catalysis for Sustainable Energy     Open Access   (1 follower)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (3 followers)
Catalysis Science and Technology     Free   (3 followers)
Catalysis Surveys from Asia     Hybrid Journal   (3 followers)
Catalysts     Open Access   (5 followers)
Cellulose     Hybrid Journal   (4 followers)
Central European Journal of Chemistry     Hybrid Journal   (5 followers)

        1 2 3 4 5 6 | Last

Bioorganic & Medicinal Chemistry    [28 followers]  Follow    
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
     ISSN (Print) 0968-0896
     Published by Elsevier Homepage  [2556 journals]
  • Linear propargylic alcohol functionality attached to the
           indazole-7-carboxamide as a JAK1-specific linear probe group
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Mi Kyoung Kim , Heerim Shin , Seo Young Cho , Youhoon Chong
      Selective inhibition of JAK1 has recently been proposed as an appropriate therapeutic rationale for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). In this study, through pairwise comparison and 3D alignment of the JAK isozyme structures bound to the same inhibitor molecule, we reasoned that an alkynol functionality would serve as an isozyme-specific probe group, which would enable the resulting inhibitor to differentiate the ATP-binding site of JAK1 from those of other isozymes. The 3-alkynolyl-5-(4′-indazolyl)indazole-7-carboxamide derivatives were thus prepared, and in vitro evaluation of their inhibitory activity against the JAK isozymes revealed that the propargyl alcohol functionality endowed the 5-(4′-indazolyl)indazole-7-carboxamide scaffold with JAK1 selectivity over other JAK isozymes, particularly JAK2.
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      PubDate: 2014-01-23T23:23:36Z
       
  • Functional regulation of RNA-induced silencing complex by photoreactive
           oligonucleotides
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Yohei Matsuyama , Asako Yamayoshi , Akio Kobori , Akira Murakami
      We developed a novel method for regulation of RISC function by photoreactive oligonucleotides (Ps-Oligo) containing 2′-O-psoralenylmethoxyethyl adenosine (Aps). We observed that inhibitory effects of Ps-Oligos on RISC function were enhanced by UV-irradiation compared with 2′-O-methyl-oligonucleotide without Aps. These results suggest Ps-Oligo inhibited RISC function by cross-linking effect, and we propose that the concept described in this report may be promising and applicable one to regulate the small RNA-mediated post-transcriptional regulation.
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      PubDate: 2014-01-23T23:23:36Z
       
  • Binding ability of a thymine-functionalized oligolysine towards nucleic
           acids
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Giovanni N. Roviello , Domenica Musumeci , Cristian D’Alessandro , Carlo Pedone
      In this Letter, we investigated the binding properties towards nucleic acids of a thymine-functionalized oligolysine, composed of nucleobase-bearing amino acid moieties and underivatized l-lysine residues alternate in the backbone. The basic nucleopeptide proved to be well soluble in water and able to interact with both DNA and RNA, as suggested by circular dichroism, UV and surface plasmon resonance studies performed on the thymine-containing oligomer with both adenine-containing DNA (dA12) and RNA (rA12 and poly rA) molecules. In both cases the thymine-functionalized oligolysine was proven to form complexes characterized by a 1:1 T/A stoichiometric ratio, as evidenced by CD titration. UV melting experiments revealed that the complex formed between the homothymine oligolysine and rA12 RNA was more stable than the complex with dA12 DNA probably due to the additional H-bonding of the 2′-OH groups in RNA, that reinforces the overall interaction with the nucleopeptide. Finally, human serum stability assays were conducted on the thymine-bearing nucleopeptide which showed a half-life of 45min.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Synthesis and evaluation of Strychnos alkaloids as MDR reversal agents for
           cancer cell eradication
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Surendrachary Munagala , Gopal Sirasani , Praveen Kokkonda , Manali Phadke , Natalia Krynetskaia , Peihua Lu , Frances J. Sharom , Sidhartha Chaudhury , Mohamed Diwan M. Abdulhameed , Gregory Tawa , Anders Wallqvist , Rogelio Martinez , Wayne Childers , Magid Abou-Gharbia , Evgeny Krynetskiy , Rodrigo B. Andrade
      Natural products represent the fourth generation of multidrug resistance (MDR) reversal agents that resensitize MDR cancer cells overexpressing P-glycoprotein (Pgp) to cytotoxic agents. We have developed an effective synthetic route to prepare various Strychnos alkaloids and their derivatives. Molecular modeling of these alkaloids docked to a homology model of Pgp was employed to optimize ligand–protein interactions and design analogues with increased affinity to Pgp. Moreover, the compounds were evaluated for their (1) binding affinity to Pgp by fluorescence quenching, and (2) MDR reversal activity using a panel of in vitro and cell-based assays and compared to verapamil, a known inhibitor of Pgp activity. Compound 7 revealed the highest affinity to Pgp of all Strychnos congeners (K d =4.4μM), the strongest inhibition of Pgp ATPase activity, and the strongest MDR reversal effect in two Pgp-expressing cell lines. Altogether, our findings suggest the clinical potential of these synthesized compounds as viable Pgp modulators justifies further investigation.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • New melatonin (MT1/MT2) ligands: Design and synthesis of
           (8,9-dihydro-7H-furo[3,2-f]chromen-1-yl) derivatives
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Elodie Landagaray , Mohamed Ettaoussi , Véronique Leclerc , Balla Traoré , Valérie Perez , Olivier Nosjean , Jean A. Boutin , Daniel-Henri Caignard , Philippe Delagrange , Pascal Berthelot , Saïd Yous
      Herein we describe the synthesis of novel tricyclic analogues issued from the rigidification of the methoxy group of the benzofuranic analogue of melatonin as MT1 and MT2 ligands. Most of the synthesized compounds displayed high binding affinities at MT1 and MT2 receptors subtypes. Compound 6b (MT1, K i =0.07nM; MT2, K i =0.08nM) exhibited with the vinyl 6c and allyl 6d the most interesting derivatives of this series. Functional activity of these compounds showed full agonist activity with EC50 in the nanomolar range. Compounds 6a (EC50 =0.8nM and E max =98%) and 6b (EC50 =0.2nM and E max =121%) exhibited good pharmacological profiles.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Small molecule mimetics of an interferon-α receptor interacting
           domain
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Angelica M. Bello , Lianhu Wei , Beata Majchrzak-Kita , Noruê Salum , Meena K. Purohit , Eleanor N. Fish , Lakshmi P. Kotra
      Small molecules that mimic IFN-α epitopes that interact with the cell surface receptor, IFNAR, would be useful therapeutics. One such 8-amino acid region in IFN-α2, designated IRRP-1, was used to derive 11 chemical compounds that belong to 5 distinct chemotypes, containing the molecular features represented by the key residues Leu30, Arg33, and Asp35 in IRRP-1. Three of these compounds exhibited potential mimicry to IRRP-1 and, in cell based assays, as predicted, effectively inhibited IFNAR activation by IFN-α. Of these, compound 3 did not display cell toxicity and reduced IFN-α-inducible STAT1 phosphorylation and STAT-DNA binding. Based on physicochemical properties’ analyses, our data suggest that moieties with acidic pKa on the small molecule may be a necessary element for mimicking the carboxyl group of Asp35 in IRRP-1. Our data confirm the relevance of this strategy of molecular mimicry of ligand–receptor interaction domains of protein partners for small molecule drug discovery.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Morpholylureas are a new class of potent and selective inhibitors of the
           type 5 17-β-hydroxysteroid dehydrogenase (AKR1C3)
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Jack U. Flanagan , Graham J. Atwell , Daniel M. Heinrich , Darby G. Brooke , Shevan Silva , Laurent J.M. Rigoreau , Elisabeth Trivier , Andrew P. Turnbull , Tony Raynham , Stephen M.F. Jamieson , William A. Denny
      Inhibitors of the aldo–keto reductase enzyme AKR1C3 are of interest as potential drugs for leukemia and hormone-related cancers. A series of non-carboxylate morpholino(phenylpiperazin-1-yl)methanones were prepared by palladium-catalysed coupling of substituted phenyl or pyridyl bromides with the known morpholino(piperazin-1-yl)methanone, and shown to be potent (IC50 ∼100nM) and very isoform-selective inhibitors of AKR1C3. Lipophilic electron-withdrawing substituents on the phenyl ring were positive for activity, as was an H-bond acceptor on the other terminal ring, and the ketone moiety (as a urea) was essential. These structure–activity relationships are consistent with an X-ray structure of a representative compound bound in the AKR1C3 active site, which showed H-bonding between the carbonyl oxygen of the drug and Tyr55 and His117 in the ‘oxyanion hole’ of the enzyme, with the piperazine bridging unit providing the correct twist to allow the terminal benzene ring to occupy the lipophilic pocket and align with Phe311.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Synthesis, biophysical characterization and anti-HIV activity of d(TG3AG)
           Quadruplexes bearing hydrophobic tails at the 5′-end
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Valeria Romanucci , Danilo Milardi , Tiziana Campagna , Maria Gaglione , Anna Messere , Alessandro D’Urso , Emanuela Crisafi , Carmelo La Rosa , Armando Zarrelli , Jan Balzarini , Giovanni Di Fabio
      Novel conjugated G-quadruplex-forming d(TG3AG) oligonucleotides, linked to hydrophobic groups through phosphodiester bonds at 5′-end, have been synthesized as potential anti-HIV aptamers, via a fully automated, online phosphoramidite-based solid-phase strategy. Conjugated quadruplexes showed pronounced anti-HIV activity with some preference for HIV-1, with inhibitory activity invariably in the low micromolar range. The CD and DSC monitored thermal denaturation studies on the resulting quadruplexes, indicated the insertion of lipophilic residue at the 5′-end, conferring always improved stability to the quadruplex complex (20<ΔTm<40°C). The data suggest no direct functional relationship between the thermal stability and anti-HIV activity of the folded conjugated G-quartets. It would appear that the nature of the residue at 5′ end of the d(TG3AG) quadruplexes plays an important role in the thermodynamic stabilization but a minor influence on the anti-HIV activity. Moreover, a detailed CD and DSC analyses indicate a monophasic behaviour for sequences I and V, while for ODNs (II–IV) clearly show that these quadruplex structures deviate from simple two-state melting, supporting the hypothesis that intermediate states along the dissociation pathway may exist.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • 7-Azaindole-1-carboxamides as a new class of PARP-1 inhibitors
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Raffaella Cincinelli , Loana Musso , Lucio Merlini , Giuseppe Giannini , Loredana Vesci , Ferdinando M. Milazzo , Nives Carenini , Paola Perego , Sergio Penco , Roberto Artali , Franco Zunino , Claudio Pisano , Sabrina Dallavalle
      7-Azaindole-1-carboxamides were designed as a new class of PARP-1 inhibitors. The compounds displayed a variable pattern of target inhibition profile that, in part, paralleled the antiproliferative activity in cell lines characterized by homologous recombination defects. A selected compound (1l; ST7710AA1) showed significant in vitro target inhibition and capability to substantially bypass the multidrug resistance mediated by Pgp. In antitumor activity studies against the MX1 human breast carcinoma growth in nude mice, the compound exhibited an effect similar to that of Olaparib in terms of tumor volume inhibition when used at a lower dose than the reference compound. Treatment was well tolerated, as no deaths or significant weight losses were observed among the treated animals.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Formosusin A, a novel specific inhibitor of mammalian DNA polymerase
           β from the fungus Paecilomyces formosus
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Yoshiyuki Mizushina , Hiroe Suzuki-Fukudome , Toshifumi Takeuchi , Kenji Takemoto , Isoko Kuriyama , Hiromi Yoshida , Shinji Kamisuki , Fumio Sugawara
      Variotin (1) and three novel compounds, formosusin A (2), B (3), and C (4), were isolated from the cultures of the fungus Paecilomyces formosus, and their structures were determined by spectroscopic analyses. Compound 2 is (6Z,8E,10E)-variotin, a new cis-olefin analog of compound 1. Compound 2 selectively inhibited the activity of mammalian DNA polymerase β (pol β) in vitro, with an IC50 of 35.6μM. By contrast, compounds 1, 3, and 4 did not influence the activity of pol β. These four compounds showed no effect on the activities of other 10 mammalian pols (i.e., pols α, γ, δ, ε, η, ι, κ, λ, and μ, and terminal deoxynucleotidyl transferase). These compounds also did not inhibit the activities of fish, insect, plant, and prokaryotic pols and other DNA metabolic enzymes tested. These results suggested that compound 2 could be a selective inhibitor of mammalian pol β. The compound 2-induced inhibition of rat pol β activity was competitive and non-competitive with respect to the DNA template–primer substrate and the dNTP substrate, respectively. On the basis of these results, the relationship between the three-dimensional structure and pol β inhibitory mechanism of compound 2 is discussed.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Carbamazepine derivatives with P2X4 receptor-blocking activity
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Maoqun Tian , Aliaa Abdelrahman , Stephanie Weinhausen , Sonja Hinz , Stefanie Weyer , Stefan Dosa , Ali El-Tayeb , Christa E. Müller
      Antagonists for the P2 receptor subtype P2X4, an ATP-activated cation channel receptor, have potential as novel drugs for the treatment of neuropathic pain and other inflammatory diseases. In the present study, a series of 47 carbamazepine derivatives including 32 novel compounds were designed, synthesized, and evaluated as P2X4 receptor antagonists. Their potency to inhibit ATP-induced calcium influx in 1321N1 astrocytoma cells stably transfected with the human P2X4 receptor was determined. Additionally, species selectivity (human, rat, mouse) and receptor subtype selectivity (P2X4 vs P2X1, 2, 3, 7) were investigated for selected derivatives. The most potent compound of the present series, which exhibited an allosteric mechanism of P2X4 inhibition, was N,N-diisopropyl-5H-dibenz[b,f]azepine-5-carboxamide (34, IC50 of 3.44μM). The present study extends the so far very limited knowledge on structure–activity relationships of P2X4 receptor antagonists.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Design, synthesis and ex-vivo release studies of colon-specific
           polyphosphazene–anticancer drug conjugates
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Rajiv Sharma , Ravindra K. Rawal , Manav Malhotra , A.K. Sharma , T.R. Bhardwaj
      Colon-specific azo based polyphosphazene–anticancer drug conjugates (11–18) have been synthesized and evaluated by ex-vivo release studies. The prepared polyphosphazene drug conjugates (11–18) are stable in acidic (pH=1.2) buffer which showed that these polymer drug conjugates are protected from acidic environment which is the primary requirement of colon specific targeted drug delivery. The ex-vivo release profiles of polyphosphazene drug conjugates (11–18) have been performed in the presence as well as in the absence of rat cecal content. The results showed that more than 89% of parent drugs (methotrexate and gemcitabine) are released from polymeric backbone of polyphosphazene drug conjugates (14 and 18) having n-butanol (lipophilic moiety). The in-vitro cytotoxicity assay has also been performed which clearly indicated that these polymeric drug conjugates are active against human colorectal cancer cell lines (HT-29 and COLO 320 DM). The drug release kinetic study demonstrated that Higuchi’s equation is found to be best fitted equation which showed that release of drug from polymeric backbone as square root of time dependent process based on non-fickian diffusion. Therefore, the synthesized polyphosphazene azo based drug conjugates of methotrexate and gemcitabine are the potential candidates for colon targeted drug delivery system with minimal undesirable side effects.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Chemoenzymatic synthesis of ADP-d-glycero-β-d-manno-heptose and study
           of the substrate specificity of HldE
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Tiehai Li , Liuqing Wen , Adriel Williams , Baolin Wu , Lei Li , Jingyao Qu , Jeffrey Meisner , Zhongying Xiao , Junqiang Fang , Peng George Wang
      An efficient one-pot three enzymes strategy for chemoenzymatic synthesis of ADP-d-glycero-β-d-manno-heptose (ADP-d, d-heptose) was reported using chemically synthesized d, d-heptose-7-phosphate and the ADP-d, d-heptose biosynthetic enzymes HldE and GmhB. Moreover, the result of investigating substrate specificity of the kinase action of HldE revealed that HldE had highly restricted substrate specificity towards structurally modified heptose-7-phosphate analogs.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Synthesis and anti-rhinovirus activity of novel
           3-[2-(pyridinyl)vinyl]substituted -2H-chromenes and -4H-chromen-4-ones
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Cinzia Conti , Luca Proietti Monaco , Nicoletta Desideri
      Human rhinoviruses (HRVs) are the most common cause of viral respiratory infections and their complications. So far, no anti-viral agent has been approved for prevention or treatment of HRV infections. Pursuing our researches on small molecules with anti-rhinovirus activity, in this paper we describe the synthesis and in vitro anti-HRV 1B and 14 properties of new [2-(2H-chromen-3-yl)vinyl]pyridines and 3-[2-(pyridinyl)vinyl]-4H-chromen-4-ones. Generally, the synthesized compounds interfered with the replication of both serotypes at the micromolar or submicromolar concentrations. Preliminary results on their mechanism of action, performed on selected (E)-2-[2-(2H-chromen-3-yl)vinyl]pyridine, indicate an interference with the early step(s) of HRV 1B and 14 replication, probably at the uncoating level.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Synthesis/biological evaluation of hydroxamic acids and their prodrugs as
           inhibitors for Botulinum neurotoxin A light chain
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Hajime Seki , Sabine Pellett , Peter Šilhár , G. Neil Stowe , Beatriz Blanco , Matthew A. Lardy , Eric A. Johnson , Kim D. Janda
      Botulinum neurotoxin A (BoNT/A) is the most potent toxin known. Unfortunately, it is also a potential bioweapon in terrorism, which is without an approved therapeutic treatment once cellular intoxication takes place. Previously, we reported how hydroxamic acid prodrug carbamates increased cellular uptake, which translated to successful inhibition of this neurotoxin. Building upon this research, we detail BoNT/A protease molecular modeling studies accompanied by the construction of small library of hydroxamic acids based on 2,4-dichlorocinnamic hydroxamic acid scaffold and their carbamate prodrug derivatization along with the evaluation of these molecules in both enzymatic and cellular models.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Synthesis of novel indenoquinoxaline derivatives as potent
           α-glucosidase inhibitors
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Madiha Sahar Khan , Munawar Ali Munawar , Mohammad Ashraf , Umber Alam , Athar Ata , Abdullah Mohamed Asiri , Samina Kousar , Misbahul Ain Khan
      A series of new N-(11H-Indeno[1,2-b]quinoxalin-11-ylidene)benzohydrazide derivatives (3a–3p) were synthesized and evaluated for their α-glucosidase inhibitory activity. The synthesized compounds 3d, 3f, 3g, 3k, 3n, 3p and 4 showed significant α-glucosidase inhibitory activity as compared to acrabose, a standard drug used to treat type II diabetes. Structures of the synthesized compounds were determined by using FT-IR, 1H NMR, 13C NMR, mass spectrometry and elemental analysis techniques.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Structure–activity relationships of substituted oxyoxalamides as
           inhibitors of the human soluble epoxide hydrolase
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): In-Hae Kim , In-Hee Lee , Hisashi Nishiwaki , Bruce D. Hammock , Kosuke Nishi
      We explored both structure–activity relationships among substituted oxyoxalamides used as the primary pharmacophore of inhibitors of the human sEH and as a secondary pharmacophore to improve water solubility of inhibitors. When the oxyoxalamide function was modified with a variety of alkyls or substituted alkyls, compound 6 with a 2-adamantyl group and a benzyl group was found to be a potent sEH inhibitor, suggesting that the substituted oxyoxalamide function is a promising primary pharmacophore for the human sEH, and compound 6 can be a novel lead structure for the development of further improved oxyoxalamide or other related derivatives. In addition, introduction of substituted oxyoxalamide to inhibitors with an amide or urea primary pharmacophore produced significant improvements in inhibition potency and water solubility. In particular, the N,N,O-trimethyloxyoxalamide group in amide or urea inhibitors (26 and 31) was most effective among those tested for both inhibition and solubility. The results indicate that substituted oxyoxalamide function incorporated into amide or urea inhibitors is a useful secondary pharmacophore, and the resulting structures will be an important basis for the development of bioavailable sEH inhibitors.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Glutathione-analogous peptidyl phosphorus esters as mechanism-based
           inhibitors of γ-glutamyl transpeptidase for probing cysteinyl-glycine
           binding site
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Mado Nakajima , Bunta Watanabe , Liyou Han , Bun-ichi Shimizu , Kei Wada , Keiichi Fukuyama , Hideyuki Suzuki , Jun Hiratake
      γ-Glutamyl transpeptidase (GGT) catalyzing the cleavage of γ-glutamyl bond of glutathione and its S-conjugates is involved in a number of physiological and pathological processes through glutathione homeostasis. Defining its Cys-Gly binding site is extremely important not only in defining the physiological function of GGT, but also in designing specific and effective inhibitors for pharmaceutical purposes. Here we report the synthesis and evaluation of a series of glutathione-analogous peptidyl phosphorus esters as mechanism-based inhibitors of human and Escherichia coli GGTs to probe the structural and stereochemical preferences in the Cys-Gly binding site. Both enzymes were inhibited strongly and irreversibly by the peptidyl phosphorus esters with a good leaving group (phenoxide). Human GGT was highly selective for l-aliphatic amino acid such as l-2-aminobutyrate (l-Cys mimic) at the Cys binding site, whereas E. coli GGT significantly preferred l-Phe mimic at this site. The C-terminal Gly and a l-amino acid analogue at the Cys binding site were necessary for inhibition, suggesting that human GGT was highly selective for glutathione (γ-Glu-l-Cys-Gly), whereas E. coli GGT are not selective for glutathione, but still retained the dipeptide (l-AA-Gly) binding site. The diastereoisomers with respect to the chiral phosphorus were separated. Both GGTs were inactivated by only one of the stereoisomers with the same stereochemistry at phosphorus. The strict recognition of phosphorus stereochemistry gave insights into the stereochemical course of the catalyzed reaction. Ion-spray mass analysis of the inhibited E. coli GGT confirmed the formation of a 1:1 covalent adduct with the catalytic subunit (small subunit) with concomitant loss of phenoxide, leaving the peptidyl moiety that presumably occupies the Cys-Gly binding site. The peptidyl phosphonate inhibitors are highly useful as a ligand for X-ray structural analysis of GGT for defining hitherto unidentified Cys-Gly binding site to design specific inhibitors.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Synthesis, in vitro antimalarial activity and cytotoxicity of novel
           4-aminoquinolinyl-chalcone amides
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Frans J. Smit , David D. N’Da
      A series of 4-aminoquinolinyl-chalcone amides 11–19 were synthesized through condensation of carboxylic acid-functionalized chalcone with aminoquinolines, using 1,1′-carbonyldiimidazole as coupling agent. These compounds were screened against the chloroquine sensitive (3D7) and chloroquine resistant (W2) strains of Plasmodium falciparum. Their cytotoxicity towards the WI-38 cell line of normal human fetal lung fibroblast was determined. All compounds were found active, with IC50 values ranging between 0.04–0.5μM and 0.07–1.8μM against 3D7 and W2, respectively. They demonstrated moderate to high selective activity towards the parasitic cells in the presence of mammalian cells. However, amide 15, featuring the 1,6-diaminohexane linker, despite possessing predicted unfavourable aqueous solubility and absorption properties, was the most active of all the amides tested. It was found to be as potent as CQ against 3D7, while it displayed a two-fold higher activity than CQ against the W2 strain, with good selective antimalarial activity (SI=435) towards the parasitic cells. During this study, amide 15 was thus identified as the best drug-candidate to for further investigation as a potential drug in search for new, safe and effective antimalarial drugs.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Unsymmetrical 1,5-diaryl-3-oxo-1,4-pentadienyls and their evaluation as
           antiparasitic agents
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Zia Ud Din , Taicia Pacheco Fill , Francisco Favaro de Assis , Danielle Lazarin-Bidóia , Vanessa Kaplum , Francielle Pelegrin Garcia , Celso Vataru Nakamura , Kleber Thiago de Oliveira , Edson Rodrigues-Filho
      In this work the synthesis and antiparasitical activity of new 1,5-diaryl-3-oxo-1,4-pentadienyl derivatives are described. First, compounds 1a, 1b, 1c and 1d were prepared by acid-catalyzed aldol reaction between 2-butanone and benzaldehyde, anisaldehyde, p-N,N-dimethylaminobenzaldehyde and p-nitrobenzaldehyde. Reacting each of the methyl ketones 1a, 1b, 1c and 1d with the p-substituted benzaldehydes under basic-catalyzed aldol reaction, we further prepared compounds 2a–2p. All twenty compounds were evaluated for antiproliferative activity, particularly for promastigote of Leishmania amazonensis and epimastigote of Trypanosoma cruzi. All compounds showed good activity while nitro compounds 2i and 2k showed inhibition activity at a few μM.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Synthesis and structure-activity relationship of p-carborane-based
           non-secosteroidal vitamin D analogs
    • Abstract: Publication date: Available online 21 January 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Shinya Fujii , Atsushi Kano , Chalermkiat Songkram , Hiroyuki Masuno , Yoshiyuki Taoda , Emiko Kawachi , Tomoya Hirano , Aya Tanatani , Hiroyuki Kagechika
      1α,25-Dihydroxyvitamin D3 [1α,25(OH)2D3: 1] is a specific modulator of nuclear vitamin D receptor (VDR), and novel vitamin D analogs are therapeutic candidates for multiple clinical applications. We recently developed non-secosteroidal VDR agonists bearing a p-carborane cage (a carbon-containing boron cluster) as a hydrophobic core structure. These carborane derivatives are structurally quite different from classical secosteroidal vitamin D analogs. Here, we report systematic synthesis and activity evaluation of carborane-based non-secosteroidal vitamin D analogs. The structure-activity relationships of carborane derivatives are different from those of secosteroidal vitamin D derivatives, and in particular, the length and the substituent position of the dihydroxylated side chain are rather flexible in carborane derivatives. The structure-activity relationships presented here should be helpful in development of non-secosteroidal vitamin D analogs for clinical applications.
      Graphical abstract image Highlights Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan, Institute of Molecular and Cellular Bioscience, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan, Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Kho-Hong, Hat Yai, Songkhla 90112, Thailand, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, and Department of Chemistry, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan

      PubDate: 2014-01-23T23:23:36Z
       
  • Design and synthesis of peptide-MCA substrates for a novel assay of
           histone methyltransferases and their inhibitors
    • Abstract: Publication date: Available online 21 January 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Hongfang Chi , Yasushi Takemoto , Tienabe K. Nsiama , Tamaki Kato , Norikazu Nishino , Akihiro Ito , Minoru Yoshida
      Histone methyltransferases (HMTs) play an important role in controlling gene expression through site-specific methylation of lysines in core and linker histones within chromatin. As the typical HMTs, G9a and Set7/9 have been intensively studied that G9a is specific to the methylation at H3K9 and H3K27 and represses transcription, while Set7/9 methylates at H3K4. In this report we prepared various peptide-MCAs (4-methylcoumaryl-7-amides) related to histone tail and protein-substrates such as p53 and estrogen receptor-α. The fluorogenic substrates are applied for the assay of HMTs and an inhibitor, for example. The most sensitive and specific MCA-substrates to G9a and Set7/9 are discovered. The peptide-MCAs corresponding to the methylation sequences are promising for screening of HMT inhibitors.
      Graphical abstract image Highlights

      PubDate: 2014-01-23T23:23:36Z
       
  • Discovery of novel 6,7-disubstituted-4-phenoxyquinoline derivatives
           bearing 5-(aminomethylene)pyrimidine-2,4,6-trione moiety as c-Met kinase
           inhibitors
    • Abstract: Publication date: Available online 22 January 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Qidong Tang , Guogang Zhang , Xinming Du , Wufu Zhu , Ruijuan Li , Huafang Lin , Pengcheng Li , Maosheng Cheng , Ping Gong , Yanfang Zhao
      A series of novel quinoline derivatives bearing 5-(aminomethylene)pyrimidine-2,4,6-trione moiety were designed, synthesized, and evaluated for their c-Met kinase inhibitory activities and antiproliferative activities against 5 cancer cell lines (HT-29, H460, MKN-45, A549, and U87MG) in vitro. Most compounds showed moderate to excellent potency, with the most promising analogue 45 (c-Met half-maximal inhibitory concentration [IC50] = 1.15 nM) showing high selectivity versus 5 other tyrosine kinases, VEGFR-2, Flt-3, PDGFR-β, c-Kit, and EGFR. Structure-activity relationship studies indicated that electron-donating groups on the phenyl ring at the 3-position of pyrimidine-2,4,6-trione were required to increase the electron density on the 5-(aminomethylene)pyrimidine-2,4,6-trione moiety.
      Graphical abstract image Highlights

      PubDate: 2014-01-23T23:23:36Z
       
  • New chiral derivatives of xanthones: Synthesis and investigation of
           enantioselectivity as inhibitors of growth of human tumor cell lines
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Carla Fernandes , Kamonporn Masawang , Maria Elizabeth Tiritan , Emília Sousa , Virgínia de Lima , Carlos Afonso , Hassan Bousbaa , Wanwisa Sudprasert , Madalena Pedro , Madalena M. Pinto
      A highly efficient and practical methodology for synthesis of new chiral derivatives of xanthones (CDXs) in enantiomerically pure form has been developed. According to this approach, thirty CDXs (3–32) were synthesized by coupling a carboxyxanthone (1) and a carboxymethoxyxanthone (2) with both enantiomers of commercially available chiral building blocks, namely six amino alcohols, one amine and one amino ester. The activation of the carboxylic acid group of the xanthonic scaffold was carried out with the coupling reagent O-(benzotriazol-1-yl)-N-N-N′-N′-tetramethyluronium tetrafluoroborate (TBTU), in the presence of a catalytic amount of TEA in anhydrous THF. The coupling reactions with the chiral blocks were performed at room temperature with short reactions times, excellent yields (ranging from 94% to 99%), and very high enantiomeric excess. The synthesized CDXs were evaluated for their effect on the in vitro growth of three human tumor cell lines, namely A375-C5 (melanoma), MCF-7 (breast adenocarcinoma), and NCI-H460 (non-small cell lung cancer). The most active compound was CDX 15 being active in all human tumor cell lines with values of GI50 of 32.15±2.03μM for A375-C5, 22.55±1.99μM for MCF-7, and 14.05±1.82μM for NCI-H460. Nevertheless, some CDXs showed cell-type selectivity. Furthermore, the growth inhibitory effects, in some cases, demonstrated to be depending on the stereochemistry of the CDXs. An interesting example was observed with the enantiomers 3 and 4, which demonstrated high enantioselectivity for MCF-7 and NCI-H460 cell lines. It can be inferred that the effects on the growth of the human tumor cell lines can be ascribed not only to the nature and positions of substituents on the xanthonic scaffold but also to the stereochemistry of the CDXs. Some considerations regarding structure–activity relationship within this class of compounds will be highlighted.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Direct synthesis of C3-mono-functionalized oxindoles from N-unprotected
           2-oxindole and their antileishmanial activity
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Angela Scala , Massimiliano Cordaro , Giovanni Grassi , Anna Piperno , Giuseppina Barberi , Antonio Cascio , Francesco Risitano
      A novel approach for the synthesis of unprecedented C3-mono-functionalized indolin-2-ones is reported, starting from 2-oxindole and chalcones. The reactions proceed regioselectively under mild conditions, without di- and tri-alkylated side products. The new compounds have been evaluated in vitro for their antiproliferative effects against the protozoan Leishmania infantum. Interestingly, they appear able to kill L. infantum promastigotes and amastigotes, without significant cytotoxic effects.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Targeting the Warburg Effect in cancer; relationships for
           2-arylpyridazinones as inhibitors of the key glycolytic enzyme
           6-phosphofructo-2-kinase/2,6-bisphosphatase 3 (PFKFB3)
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Darby G. Brooke , Ellen M. van Dam , Colin K.W. Watts , Amanda Khoury , Marie A. Dziadek , Hilary Brooks , Lisa-Jane K. Graham , Jack U. Flanagan , William A. Denny
      High-throughput screening of a small-molecule library identified a 5-triazolo-2-arylpyridazinone as a novel inhibitor of the important glycolytic enzyme 6-phosphofructo-2-kinase/2,6-bisphosphatase 3 (PFKFB3). Such inhibitors are of interest due to PFKFB3’s control of the important glycolytic pathway used by cancer cells to generate ATP. A series of analogues was synthesized to study structure-activity relationships key to enzyme inhibition. Changes to the triazolo or pyridazinone rings were not favoured, but limited-size substitutions on the aryl ring provided modest increases in potency against the enzyme. Selected analogues and literature-described inhibitors were evaluated for their ability to suppress the glycolytic pathway, as detected by a decrease in lactate production, but none of these compounds demonstrated such suppression at non-cytotoxic concentrations.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Synthesis, modelling and biological characterization of
           3-substituted-1H-indoles as ligands of GluN2B-containing
           N-methyl-d-aspartate receptors
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Rosaria Gitto , Laura De Luca , Stefania Ferro , Emilio Russo , Giovambattista De Sarro , Mariangela Chisari , Lucia Ciranna , Julio Alvarez-Builla , Ramon Alajarin , Maria Rosa Buemi , Alba Chimirri
      A three-step synthetic pathway has been employed to synthesize a small library of 2-(4-arylpiperidin-1-yl)-1-(1H-indol-3-yl)ethanone and 2-(4-arylpiperidin-1-yl)-1-(1H-indol-3-yl)ethane-1,2-dione derivatives that have been screened in [3H]ifenprodil competition binding assay. Some compounds exhibited significant binding affinity at nanomolar concentration, the most active being ligand 35 (IC50 =5.5nM). Docking experiments suggested the main interactions between 35 and GluN2B-containing NMDA receptors. Notably, the compound 35 reduced NMDA-mediated excitatory post-synaptic currents recorded in mouse hippocampal slices indicating antagonistic effects (50nM). Moreover, the compound 35 has shown antioxidant effects in a preliminary screening, thus suggesting that it might be considered prototype for future drug development of novel ‘dual target’ neuroprotective agents.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Design, Synthesis, Radiolabeling and In Vivo Evaluation of Potential
           Positron Emission Tomography (PET) Radioligands for Brain Imaging of the
           5-HT7 Receptor
    • Abstract: Publication date: Available online 23 January 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Enza Lacivita , Mauro Niso , Hanne D. Hansen , Pantaleo Di Pilato , Matthias M. Herth , Szabolcs Lehel , Anders Ettrup , Lisa Montenegro , Roberto Perrone , Francesco Berardi , Nicola A. Colabufo , Marcello Leopoldo , Gitte Moos Knudsen
      Here we describe the design, synthesis, and pharmacological evaluation of a set of compounds structurally related to the high affinity serotonin 5-HT7 receptor agonist N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (6, LP-211). Specific structural modifications were performed in order to maintain affinity for the target receptor and to improve the selectivity over 5-HT1A and adrenergic α1 receptors. The synthesized compounds have chemical features that could enable labeling with a positron emitter radioisotope (carbon-11 or fluorine-18) and lipophilicity within the range considered optimal for brain penetration and low non-specific binding. 4-[2-(4-Methoxyphenyl)phenyl]-N-(pyridin-4-ylmethyl)piperazinehexanamide (23a) and N-pyridin-4-ylmethyl-3-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]ethoxy]propanamide (26a) were radiolabelled on the methoxy group with carbon-11. PET analysis revealed that [11C]23a and [11C]26a were P-glycoprotein (P-gp) substrates and rapidly metabolized, resulting in poor brain uptake. These features were not predicted by in vitro tests.
      Graphical abstract image Highlights

      PubDate: 2014-01-23T23:23:36Z
       
  • Structure–activity relationship studies on acremomannolipin A, the
           potent calcium signal modulator with a novel glycolipid structure 2: Role
           of the alditol side chain stereochemistry
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Nozomi Tsutsui , Genzoh Tanabe , Genki Gotoh , Nao Morita , Naohisa Nomura , Ayako Kita , Reiko Sugiura , Osamu Muraoka
      Five alditol analogs 1b–1f of a novel glycolipid acremomannolipin A (1a), the potential Ca2+ signal modulator isolated from Acremonium strictum, were synthesized by employing a stereoselective β-mannosylation of appropriately protected mannose with five hexitols with different stereochemistry, and their potential on modulating Ca2+ signaling were evaluated. All these analogs were more potent compared to the original compound 1a, and proved that mannitol stereochemistry of 1a was not critical for the potent calcium signal modulating.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Inhibition of tyrosinase activity by polyphenol compounds from Flemingia
           philippinensis roots
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Yan Wang , Marcus J. Curtis-Long , Byong Won Lee , Heung Joo Yuk , Dae Wook Kim , Xue Fei Tan , Ki Hun Park
      Flemingia philippinensis is used as a foodstuff or medicinal plant in the tropical regions of China. The methanol (95%) extract of the roots of this plant showed potent tyrosinase inhibition (80% inhibition at 30μg/ml). Activity-guided isolation yielded six polyphenols that inhibited both the monophenolase (IC50 =1.01–18.4μM) and diphenolase (IC50 =5.22–84.1μM) actions of tyrosinase. Compounds 1–6 emerged to be three new polyphenols and three known flavanones, flemichin D, lupinifolin and khonklonginol H. The new compounds (1–3) were identified as dihydrochalcones which we named fleminchalcones (A–C), respectively. The most potent inhibitor, dihydrochalcone (3) showed significant inhibitions against both the monophenolase (IC50 =1.28μM) and diphenolase (IC50 =5.22μM) activities of tyrosinase. Flavanone (4) possessing a resorcinol group also inhibited monophenolase (IC50 =1.79μM) and diphenolase (IC50 =7.48μM) significantly. In kinetic studies, all isolated compounds behaved as competitive inhibitors. Fleminchalcone A was found to have simple reversible slow-binding inhibition against monophenolase.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Synthesis, biological evaluation and molecular docking studies of
           benzyloxyacetohydroxamic acids as LpxC inhibitors
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Marina Szermerski , Jelena Melesina , Kanin Wichapong , Marius Löppenberg , Joachim Jose , Wolfgang Sippl , Ralph Holl
      The inhibition of the UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) represents a promising strategy to combat infections caused by multidrug-resistant Gram-negative bacteria. In order to elucidate the functional groups being important for the inhibition of LpxC, the structure of our previously reported hydroxamic acid 4 should be systematically varied. Therefore, a series of benzyloxyacetohydroxamic acids was prepared, of which the diphenylacetylene derivatives 28 (K i =95nM) and 21 (K i =66nM) were the most potent inhibitors of Escherichia coli LpxC. These compounds could be synthesized in a stereoselective manner employing a Sharpless asymmetric dihydroxylation and a Sonogashira coupling in the key steps. The obtained structure–activity relationships could be rationalized by molecular docking studies.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Synthesis and biological evaluation of novel oxadiazole derivatives: A new
           class of thymidine phosphorylase inhibitors as potential anti-tumor agents
           
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Sohail Anjum Shahzad , Muhammad Yar , Marek Bajda , Bushra Jadoon , Zulfiqar Ali Khan , Syed Ali Raza Naqvi , Ahson Jabbar Shaikh , Khizar Hayat , Adeem Mahmmod , Nasir Mahmood , Sławomir Filipek
      Based on the fact that the thymidine phosphorylase inhibitors are considered potential anti-tumor agents, a range of novel oxadiazole derivatives 3a–3u was designed and synthesized by a simple and facile synthetic route. The biological assay revealed that majority of compounds displayed modest inhibitory activity against thymidine phosphorylase at low micromolar concentrations (IC50 173.23±3.04 to 14.40±2.45μM). In the current study the most active compounds were 3h and 3q with IC50 values 14.40±2.45 and 17.60±1.07μM, respectively. Molecular docking studies were performed on the most active compounds (3h, 3k, 3o–3q) to show their binding mode.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Editorial board
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3




      PubDate: 2014-01-23T23:23:36Z
       
  • Graphical contents list
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3




      PubDate: 2014-01-23T23:23:36Z
       
  • Synthesis of quercetin glycosides and their melanogenesis stimulatory
           activity in B16 melanoma cells
    • Abstract: Publication date: 1 February 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 3
      Author(s): Kosei Yamauchi , Tohru Mitsunaga , Irmanida Batubara
      4′-O-β-d-Glucopyranosyl-quercetin-3-O-β-d-glucopyranosyl-(1→4)-β-d-glucopyra-noside (3) was isolated from Helminthostachys zeylanica root extract as a melanogenesis acceleration compound and was synthesized using rutin as the starting material. Related compounds were also synthesized to understand the structure–activity relationships in melanin biosynthesis. Melanogenesis activities of the glycosides were determined by measuring intracellular melanin content in B16 melanoma cells. Among the synthesized quercetin glycosides, quercetin-3-O-β-d-glucopyranoside (1), quercetin-3-O-β-d-glucopyranosyl-(1→4)-β-d-glucopyranoside (2), and 3 showed more potent intracellular melanogenesis acceleration activities than theophyline used as positive control in a dose-dependent manner with no cytotoxic effect.
      Graphical abstract image

      PubDate: 2014-01-23T23:23:36Z
       
  • Enhancing the pharmacodynamic profile of a class of selective COX-2
           inhibiting nitric oxide donors
    • Abstract: Publication date: 15 January 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 2
      Author(s): Mariangela Biava , Claudio Battilocchio , Giovanna Poce , Salvatore Alfonso , Sara Consalvi , Angela Di Capua , Vincenzo Calderone , Alma Martelli , Lara Testai , Lidia Sautebin , Antonietta Rossi , Carla Ghelardini , Lorenzo Di Cesare Mannelli , Antonio Giordani , Stefano Persiani , Milena Colovic , Melania Dovizio , Paola Patrignani , Maurizio Anzini
      We report herein the development, synthesis, physicochemical and pharmacological characterization of a novel class of pharmacodynamic hybrids that selectively inhibit cyclooxygenase-2 (COX-2) isoform and present suitable nitric oxide releasing properties. The replacement of the ester moiety with the amide group gave access to in vivo more stable and active derivatives that highlighted outstanding pharmacological properties. In particular, the glycine derivative proved to be extremely active in suppressing hyperalgesia and edema.
      Graphical abstract image

      PubDate: 2014-01-12T00:04:34Z
       
  • Structural studies, homology modeling and molecular docking of novel
           non-competitive antagonists of GluK1/GluK2 receptors
    • Abstract: Publication date: 15 January 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 2
      Author(s): Agnieszka A. Kaczor , Zbigniew Karczmarzyk , Andrzej Fruziński , Kalevi Pihlaja , Jari Sinkkonen , Kirsti Wiinämaki , Christiane Kronbach , Klaus Unverferth , Antti Poso , Dariusz Matosiuk
      Non-competitive ligands of kainate receptors have focused significant attention as medicinal compounds because they seem to be better tolerated than competitive antagonists and uncompetitive blocker of these receptors. Here we present structural studies (X-ray structure determination, NMR and MS spectra) of novel indole-derived non-competitive antagonists of GluK1/GluK2 receptors, homology models of GluK1 and GluK2 receptors based on novel AMPA receptor template as well as molecular docking of ligands to their molecular targets. We find that the allosteric site is in the receptor transduction domain, in one receptor subunit, not between the two subunits as it was indicated by our earlier studies.
      Graphical abstract image

      PubDate: 2014-01-12T00:04:34Z
       
  • Preclinical evaluation of a CXCR4-specific 68Ga-labelled TN14003
           derivative for cancer PET imaging
    • Abstract: Publication date: 15 January 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 2
      Author(s): Guillaume P.C. George , Elizabeth Stevens , Ola Åberg , Quang-Dé Nguyen , Federica Pisaneschi , Alan C. Spivey , Eric O. Aboagye
      Molecular imaging is an ideal platform for non-invasive detection and assessment of cancer. In recent years, the targeted imaging of CXCR4, a chemokine receptor that has been associated with tumour metastasis, has become an area of intensive research. In our pursuit of a CXCR4-specific radiotracer, we designed and synthesised a novel derivative of the CXCR4 peptidic antagonist TN14003, CCIC16, which is amenable to radiolabelling by chelation with a range of PET and SPECT radiometals, such as 68Ga, 64Cu and 111In as well as 18F (Al18F). Potent in vitro binding affinity and inhibition of signalling-dependent cell migration by unlabelled CCIC16 were confirmed by a threefold uptake in CXCR4-over-expressing cells compared to their isogenic counterparts. Furthermore, in vivo experiments demonstrated the favourable pharmacokinetic properties of the 68Ga-labelled tracer 68 Ga–CCIC16, along with its CXCR4-specific accumulation in tissues with desirable contrast (tumour-to-muscle ratio: 9.5). The specificity of our tracer was confirmed by blocking experiments. Taking into account the attractive intrinsic PET imaging properties of 68Ga, the comprehensive preclinical evaluation presented here suggests that 68 Ga–CCIC16 is a promising PET tracer for the specific imaging of CXCR4-expressing tumours.
      Graphical abstract image

      PubDate: 2014-01-12T00:04:34Z
       
  • Honokiol trimers and dimers via biotransformation catalyzed by Momordica
           charantia peroxidase: Novel and potent α-glucosidase inhibitors
    • Abstract: Publication date: 15 January 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 2
      Author(s): Ye He , Xiao-Bing Wang , Bo-Yi Fan , Ling-Yi Kong
      Ten honokiol oligomers (1–10), including four novel trimers (1–4) and four novel dimers (5–8), were obtained by means of biotransformation of honokiol catalyzed by Momordica charantia peroxidase (MCP) for the first time. Their structures were established on the basis of spectroscopic methods. The biological results demonstrated that most of the oligomers were capable of inhibiting α-glucosidase with significant abilities, which were one to two orders of magnitude more potent than the substrate, honokiol. In particular, compound 2, the honokiol trimer, displayed the greatest inhibitory activity against α-glucosidase with an IC50 value of 1.38μM. Kinetic and CD studies indicated that 2 inhibited α-glucosidase in a reversible, mixed-type manner and caused conformational changes in the secondary structure of the enzyme protein. These findings suggested that 2 might be exploited as a promising drug candidate for the treatment of diabetes.
      Graphical abstract image

      PubDate: 2014-01-12T00:04:34Z
       
  • Synthesis and antiproliferative activity of conformationally restricted
           1,2,3-triazole analogues of combretastatins in the sea urchin embryo model
           and against human cancer cell lines
    • Abstract: Publication date: 15 January 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 2
      Author(s): Dmitry V. Demchuk , Alexander V. Samet , Natalia B. Chernysheva , Vladimir I. Ushkarov , Galina A. Stashina , Leonid D. Konyushkin , Mikhail M. Raihstat , Sergei I. Firgang , Alex A. Philchenkov , Michael P. Zavelevich , Ludmila M. Kuiava , Vasyl F. Chekhun , Dmitry Yu. Blokhin , Alex S. Kiselyov , Marina N. Semenova , Victor V. Semenov
      A series of 1,5-diaryl- and 4,5-diaryl-1,2,3-triazole derivatives of combretastatin A4 were synthesized and evaluated as antimitotic microtubule destabilizing agents using the sea urchin embryo model. Structure–activity relationship studies identified compounds substituted with 3,4,5-trimethoxyphenyl and 3,4-methylenedioxy-5-methoxyphenyl ring A and 4-methoxyphenyl ring B as potent antiproliferative agents with high cytotoxicity against a panel of human cancer cell lines including multi-drug resistant cells. 4,5-Diaryl-1,2,3-triazoles (C–C geometry) were found to be considerably more active than the respective 1,5-diaryl-1,2,3-triazoles (N–C geometry). Compound 10ad′ induced G2/M cell cycle arrest and apoptosis in human T-leukemia Jurkat cells via caspase 2/3/9 activation and downregulation of the antiapoptotic protein XIAP. A mitotic catastrophe has been evaluated as another possible cell death mode.
      Graphical abstract image

      PubDate: 2014-01-12T00:04:34Z
       
  • Synthesis and biological evaluation of nitric oxide-donating analogues of
           sulindac for prostate cancer treatment
    • Abstract: Publication date: 15 January 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 2
      Author(s): Andrew Nortcliffe , Alexander G. Ekstrom , James R. Black , James A. Ross , Fouad K. Habib , Nigel P. Botting , David O’Hagan
      A series of analogues of the non-steroidal anti-inflammatory drug (NSAID) sulindac 1 were synthesised tethered to nitric oxide (NO) donating functional groups. Sulindac shows antiproliterative effects against immortal PC3 cell lines. It was previously demonstrated that the effect can be enhanced when tethered to NO releasing groups such as nitrate esters, furoxans and sydnonimines. To explore this approach further, a total of fifty-six sulindac–NO analogues were prepared and they were evaluated as NO-releasing cytotoxic agents against prostate cancer (PCa) cell lines. Compounds 1k and 1n exhibited significant cytotoxic with IC50 values of 6.1±4.1 and 12.1±3.2μM, respectively, coupled with observed nitric oxide release.
      Graphical abstract image

      PubDate: 2014-01-12T00:04:34Z
       
  • Salicylanilide diethyl phosphates: Synthesis, antimicrobial activity and
           cytotoxicity
    • Abstract: Publication date: 15 January 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 2
      Author(s): Jarmila Vinšová , Ján Kozic , Martin Krátký , Jiřina Stolaříková , Jana Mandíková , František Trejtnar , Vladimír Buchta
      A series of 27 salicylanilide diethyl phosphates was prepared as a part of our on-going search for new antimicrobial active drugs. All compounds exhibited in vitro activity against Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium strains, with minimum inhibitory concentration (MIC) values of 0.5–62.5μmol/L. Selected salicylanilide diethyl phosphates also inhibit multidrug-resistant tuberculous strains at the concentration of 1μmol/L. Salicylanilide diethyl phosphates also exhibited mostly the activity against Gram-positive bacteria (MICs ⩾1.95μmol/L), whereas their antifungal activity is significantly lower. The IC50 values for Hep G2 cells were within the range of 1.56–33.82μmol/L, but there is no direct correlation with MICs for mycobacteria.
      Graphical abstract image

      PubDate: 2014-01-12T00:04:34Z
       
  • Near-infrared-fluorescence imaging of lymph nodes by using liposomally
           formulated indocyanine green derivatives
    • Abstract: Publication date: 15 January 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 2
      Author(s): Taro Toyota , Hiromichi Fujito , Akiko Suganami , Tomoki Ouchi , Aki Ooishi , Akira Aoki , Kazutaka Onoue , Yutaka Muraki , Tomoyuki Madono , Masanori Fujinami , Yutaka Tamura , Hideki Hayashi
      Liposomally formulated indocyanine green (LP-ICG) has drawn much attention as a highly sensitive near-infrared (NIR)-fluorescence probe for tumors or lymph nodes in vivo. We synthesized ICG derivatives tagged with alkyl chains (ICG-Cn), and we examined NIR-fluorescence imaging for lymph nodes in the lower extremities of mice by using liposomally formulated ICG-Cn (LP-ICG-Cn) as well as conventional liposomally formulated ICG (LP-ICG) and ICG. Analysis with a noninvasive preclinical NIR-fluorescence imaging system revealed that LP-ICG-Cn accumulates in only the popliteal lymph node 1h after injection into the footpad, whereas LP-ICG and ICG accumulate in the popliteal lymph node and other organs like the liver. This result indicates that LP-ICG-Cn is a useful NIR-fluorescence probe for noninvasive in vivo bioimaging, especially for the sentinel lymph node.
      Graphical abstract image

      PubDate: 2014-01-12T00:04:34Z
       
  • Synthesis and evaluation of novel benzimidazole derivatives as sirtuin
           inhibitors with antitumor activities
    • Abstract: Publication date: 15 January 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 2
      Author(s): Yeong Keng Yoon , Mohamed Ashraf Ali , Ang Chee Wei , Tan Soo Choon , Hasnah Osman , Keykavous Parang , Amir Nasrolahi Shirazi
      A total of 15 novel benzimidazole derivatives were designed, synthesized and evaluated for their SIRT1 and SIRT2 inhibitory activity. All compounds showed better inhibition on SIRT2 as compared to SIRT1. Among these, compound 5j displayed the best inhibitory activity for SIRT1 (IC50 =58.43μM) as well as for SIRT2 (IC50 =45.12μM). Cell cytotoxicity assays also showed that compound 5j possesses good antitumor activity against two different cancer cell lines derived from breast cancer (MCF-7 and MDA-MB-468). A simple structure–activity-relationship (SAR) study of the newly synthesized benzimidazole derivatives was also discussed.
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      PubDate: 2014-01-12T00:04:34Z
       
  • Identifying novel targets in renal cell carcinoma: Design and synthesis of
           affinity chromatography reagents
    • Abstract: Publication date: 15 January 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 2
      Author(s): Muriel Bonnet , Jack U. Flanagan , Denise A. Chan , Amato J. Giaccia , Michael P. Hay
      Two novel scaffolds, 4-pyridylanilinothiazoles (PAT) and 3-pyridylphenylsulfonyl benzamides (PPB), previously identified as selective cytotoxins for von Hippel–Lindau-deficient Renal Carcinoma cells, were used as templates to prepare affinity chromatography reagents to aid the identification of the molecular targets of these two classes. Structure–activity data and computational models were used to predict possible points of attachment for linker chains. In the PAT class, Click coupling of long chain azides with 2- and 3-pyridylanilinothiazoleacetylenes gave triazole-linked pyridylanilinothiazoles which did not retain the VHL-dependent selectivity of parent analogues. For the PPB class, Sonagashira coupling of 4-iodo-(3-pyridylphenylsulfonyl)benzamide with a propargyl hexaethylene glycol carbamate gave an acetylene which was reduced to the corresponding alkyl 3-pyridylphenylsulfonylbenzamide. This reagent retained the VHL-dependent selectivity of the parent analogues and was successfully utilized as an affinity reagent.
      Graphical abstract image

      PubDate: 2014-01-12T00:04:34Z
       
  • Discovery of novel N-(5-(arylcarbonyl)thiazol-2-yl)amides and
           N-(5-(arylcarbonyl)thiophen-2-yl)amides as potent RORγt inhibitors
    • Abstract: Publication date: 15 January 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 2
      Author(s): Yonghui Wang , Wei Cai , Guifeng Zhang , Ting Yang , Qian Liu , Yaobang Cheng , Ling Zhou , Yingli Ma , Ziqiang Cheng , Sijie Lu , Yong-Gang Zhao , Wei Zhang , Zhijun Xiang , Shuai Wang , Liuqing Yang , Qianqian Wu , Lisa A. Orband-Miller , Yan Xu , Jing Zhang , Ruina Gao , Melanie Huxdorf , Jia-Ning Xiang , Zhong Zhong , John D. Elliott , Stewart Leung , Xichen Lin
      Novel series of N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides were discovered as potent retinoic acid receptor-related orphan receptor-gamma-t (RORγt) inhibitors. SAR studies of the RORγt HTS hit 6a led to identification of thiazole ketone amide 8h and thiophene ketone amide 9g with high binding affinity and inhibitory activity of Th17 cell differentiation. Compound 8h showed in vivo efficacy in both mouse experimental autoimmune encephalomyelitis (EAE) and collagen induced arthritis (CIA) models via oral administration.
      Graphical abstract image

      PubDate: 2014-01-12T00:04:34Z
       
  • Tocopheramine succinate and tocopheryl succinate: Mechanism of
           mitochondrial inhibition and superoxide radical production
    • Abstract: Publication date: 15 January 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 2
      Author(s): Julia Gruber , Katrin Staniek , Christopher Krewenka , Rudolf Moldzio , Anjan Patel , Stefan Böhmdorfer , Thomas Rosenau , Lars Gille
      Tocopherols (TOH) are lipophilic antioxidants which require the phenolic OH group for their redox activity. In contrast, non-redox active esters of α-TOH with succinate (α-TOS) were shown to possess proapoptotic activity in cancer cells. It was suggested that this activity is mediated via mitochondrial inhibition with subsequent O 2 - production triggering apoptosis and that the modification of the linker between the succinate and the lipophilic chroman may modulate this activity. However, the specific mechanism and the influence of the linker are not clear yet on the level of the mitochondrial respiratory chain. Therefore, this study systematically compared the effects of α-TOH acetate (α-TOA), α-TOS and α-tocopheramine succinate (α-TNS) in cells and submitochondrial particles (SMP). The results showed that not all cancer cell lines are highly sensitive to α-TOS and α-TNS. In HeLa cells α-TNS did more effectively reduce cell viability than α-TOS. The complex I activity of SMP was little affected by α-TNS and α-TOS while the complex II activity was much more inhibited (IC50 =42±8μM α-TOS, 106±8μM α-TNS, respectively) than by α-TOA (IC50 >1000μM). Also the complex III activity was inhibited by α-TNS (IC50 =137±6μM) and α-TOS (IC50 =315±23μM). Oxygen consumption of NADH- or succinate-respiring SMP, involving the whole electron transfer machinery, was dose-dependently decreased by α-TOS and α-TNS, but only marginal effects were observed in the presence of α-TOA. In contrast to the similar inhibition pattern of α-TOS and α-TNS, only α-TOS triggered O 2 - formation in succinate- and NADH-respiring SMP. Inhibitor studies excluded complex I as O 2 - source and suggested an involvement of complex III in O 2 - production. In cancer cells only α-TOS was reproducibly able to increase O 2 - levels above the background level but neither α-TNS nor α-TOA. Furthermore, the stability of α-TNS in liver homogenates was significantly lower than that of α-TOS. In conclusion, this suggests that α-TNS although it has a structure similar to α-TOS is not acting via the same mechanism and that for α-TOS not only complex II but also complex III interactions are involved.
      Graphical abstract image

      PubDate: 2014-01-12T00:04:34Z
       
  • Editorial board
    • Abstract: Publication date: 15 January 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 2




      PubDate: 2014-01-12T00:04:34Z
       
  • Graphical contents list
    • Abstract: Publication date: 15 January 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 2




      PubDate: 2014-01-12T00:04:34Z
       
  • Retinoic acid signaling pathways in development and diseases
    • Abstract: Publication date: 15 January 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 2
      Author(s): Bhaskar C. Das , Pritam Thapa , Radha Karki , Sasmita Das , Sweta Mahapatra , Ting-Chun Liu , Ingrid Torregroza , Darren P. Wallace , Suman Kambhampati , Peter Van Veldhuizen , Amit Verma , Swapan K. Ray , Todd Evans
      Retinoids comprise a group of compounds each composed of three basic parts: a trimethylated cyclohexene ring that is a bulky hydrophobic group, a conjugated tetraene side chain that functions as a linker unit, and a polar carbon–oxygen functional group. Biochemical conversion of carotenoid or other retinoids to retinoic acid (RA) is essential for normal regulation of a wide range of biological processes including development, differentiation, proliferation, and apoptosis. Retinoids regulate various physiological outputs by binding to nuclear receptors called retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which themselves are DNA-binding transcriptional regulators. The functional response of RA and their receptors are modulated by a host of coactivators and corepressors. Retinoids are essential in the development and function of several organ systems; however, deregulated retinoid signaling can contribute to serious diseases. Several natural and synthetic retinoids are in clinical use or undergoing trials for treating specific diseases including cancer. In this review, we provide a broad overview on the importance of retinoids in development and various diseases, highlighting various retinoids in the drug discovery process, ranging all the way from retinoid chemistry to clinical uses and imaging.
      Graphical abstract image

      PubDate: 2014-01-12T00:04:34Z
       
 
 
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