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  Subjects -> CHEMISTRY (Total: 795 journals)
    - ANALYTICAL CHEMISTRY (47 journals)
    - CHEMISTRY (554 journals)
    - CRYSTALLOGRAPHY (22 journals)
    - ELECTROCHEMISTRY (24 journals)
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CHEMISTRY (554 journals)                  1 2 3 4 5 6 | Last

2D Materials     Hybrid Journal   (Followers: 4)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 31)
ACS Catalysis     Full-text available via subscription   (Followers: 25)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 13)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 8)
ACS Macro Letters     Full-text available via subscription   (Followers: 18)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 25)
ACS Nano     Full-text available via subscription   (Followers: 310)
ACS Photonics     Full-text available via subscription   (Followers: 6)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 8)
Acta Chemica Iasi     Open Access  
Acta Chimica Sinica     Full-text available via subscription  
Acta Chimica Slovaca     Open Access   (Followers: 6)
Acta Chromatographica     Full-text available via subscription   (Followers: 10)
Acta Facultatis Medicae Naissensis     Open Access   (Followers: 1)
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 4)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 4)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 5)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 8)
Advanced Functional Materials     Hybrid Journal   (Followers: 36)
Advances in Chemical Engineering and Science     Open Access   (Followers: 22)
Advances in Chemical Science     Open Access   (Followers: 9)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 14)
Advances in Drug Research     Full-text available via subscription   (Followers: 16)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 7)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 12)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 15)
Advances in Nanoparticles     Open Access   (Followers: 12)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 9)
Advances in Polymer Science     Hybrid Journal   (Followers: 39)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 10)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 4)
African Journal of Chemical Education     Open Access   (Followers: 1)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 4)
Afrique Science : Revue Internationale des Sciences et Technologie     Open Access   (Followers: 1)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 1)
Alchemy     Open Access   (Followers: 3)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 4)
AMB Express     Open Access  
American Journal of Applied Sciences     Open Access   (Followers: 29)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 188)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 11)
American Journal of Chemistry     Open Access   (Followers: 18)
American Journal of Plant Physiology     Open Access   (Followers: 10)
American Mineralogist     Full-text available via subscription   (Followers: 5)
Analyst     Full-text available via subscription   (Followers: 35)
Angewandte Chemie     Hybrid Journal   (Followers: 17)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 246)
Annales UMCS, Chemia     Open Access   (Followers: 2)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 1)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 2)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 4)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 10)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 11)
Anti-Infective Agents     Hybrid Journal   (Followers: 1)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 4)
Applied Spectroscopy     Full-text available via subscription   (Followers: 12)
Applied Surface Science     Hybrid Journal   (Followers: 19)
Arabian Journal of Chemistry     Full-text available via subscription   (Followers: 6)
ARKIVOC     Open Access   (Followers: 1)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 4)
Autophagy     Full-text available via subscription   (Followers: 1)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 6)
Biochemistry     Full-text available via subscription   (Followers: 235)
Biochemistry Insights     Open Access   (Followers: 4)
Biochemistry Research International     Open Access   (Followers: 4)
BioChip Journal     Hybrid Journal   (Followers: 1)
Bioinorganic Chemistry and Applications     Open Access   (Followers: 4)
Bioinspired Materials     Open Access  
Biointerface Research in Applied Chemistry     Open Access   (Followers: 1)
Biointerphases     Open Access  
Biomacromolecules     Full-text available via subscription   (Followers: 17)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 5)
Biomedical Chromatography     Hybrid Journal   (Followers: 7)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 2)
BioNanoScience     Partially Free   (Followers: 4)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 30)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 24)
Bioorganic Chemistry     Hybrid Journal   (Followers: 5)
Biopolymers     Hybrid Journal   (Followers: 14)
Biosensors     Open Access   (Followers: 3)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 1)
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 1)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 13)
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 3)
Canadian Journal of Chemistry     Full-text available via subscription   (Followers: 6)
Canadian Mineralogist     Full-text available via subscription   (Followers: 1)
Carbohydrate Research     Hybrid Journal   (Followers: 11)
Carbon     Hybrid Journal   (Followers: 54)
Catalysis for Sustainable Energy     Open Access   (Followers: 2)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 5)
Catalysis Science and Technology     Free   (Followers: 4)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 4)
Catalysts     Open Access   (Followers: 7)
Cellulose     Hybrid Journal   (Followers: 5)

        1 2 3 4 5 6 | Last

Journal Cover Bioorganic & Medicinal Chemistry
   [32 followers]  Follow    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
     ISSN (Print) 0968-0896
     Published by Elsevier Homepage  [2575 journals]
  • Editorial board
    • Abstract: Publication date: 15 December 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 24




      PubDate: 2014-12-21T03:31:50Z
       
  • Graphical contents list
    • Abstract: Publication date: 15 December 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 24




      PubDate: 2014-12-21T03:31:50Z
       
  • Synthesis and evaluation of N-acyl-substituted 1,2-benzisothiazol-3-one
           derivatives as caspase-3 inhibitors
    • Abstract: Publication date: 15 December 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 24
      Author(s): Zhenghui Li , Yang Pan , Weilong Zhong , Yunpeng Zhu , Yongle Zhao , Lixin Li , Wei Liu , Honggang Zhou , Cheng Yang
      A small molecule library of N-acyl-substituted 1,2-benzisothiazol-3-one derivatives has been synthesized and evaluated as inhibitors of caspase-3 and -7, in which some of them showed nanomolar potency against caspase-3 and -7 in vitro. Meanwhile, in 10μM concentration, both compounds 24 and 25 showed significant protection against apoptosis in camptothecin-induced Jurkat T cells system. The docking studies predicted the interactions and binding modes of the synthesized inhibitors in the caspase-3 active site.
      Graphical abstract image

      PubDate: 2014-12-21T03:31:50Z
       
  • Synthesis and pharmacological evaluation of N-benzyl substituted
           4-bromo-2,5-dimethoxyphenethylamines as 5-HT2A/2C partial agonists
    • Abstract: Publication date: Available online 17 December 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Martin Hansen , Stine Engesgaard Jacobsen , Shane Plunkett , Gudrun Eckhard Liebscher , John D. McCorvy , Hans Bräuner-Osborne , Jesper Langgaard Kristensen
      N-benzyl substitution of phenethylamine 5-HT2A receptor agonists has dramatic effects on binding affinity, receptor selectivity and agonist activity. In this paper we examine how affinity for the 5-HT2A/2C receptors are influenced by N-benzyl substitution of 4-bromo-2,5-dimethoxyphenethylamine derivatives. Special attention is given to the 2’ and 3’-position of the N-benzyl as such compounds are known to be very potent. We found that substitutions in these positions are generally well tolerated. The 2’-position was further examined using a range of substituents to probe the hydrogen bonding requirements for optimal affinity and selectivity, and it was found that small changes in the ligands in this area had a profound effect on their affinities. Furthermore, two ligands that lack a 2’-benzylsubstituent was also found to have high affinity contradicting previous held notions. Several high-affinity ligands were identified and assayed for functional activity at the 5-HT2A and 5-HT2C receptor, and they were generally found to be less efficacious agonists than previously reported N-benzyl phenethylamines.
      Graphical abstract image

      PubDate: 2014-12-21T03:31:50Z
       
  • Fluoro-substituted phenylazocarboxamides: dopaminergic behavior and
           N-arylating properties for irreversible binding
    • Abstract: Publication date: Available online 17 December 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Amelie L. Bartuschat , Tamara Schellhorn , Harald Hübner , Peter Gmeiner , Markus R. Heinrich
      Phenylazocarboxamides can serve as bioisosteres for cinnamides, which are widely occurring substructures in medicinal chemistry. Starting from our lead compound 2, the introduction of additional fluoro substituents and the exchange of the methoxyphenylpiperazine head group by an aminoindane moiety was investigated resulting in dopamine D3 receptor antagonists and agonists with K i values in the sub- and low-nanomolar range. As a potentially irreversible ligand, the 3,4,5-trifluoro substituted phenylazocarboxamide 7 was investigated for its N-arylating properties by incubation with the protected lysine analog 18 and with the L89K mutant of the dopamine D3 receptor. Whereas covalent bond formation with the lysine unit in TM2 of D3 could not be detected, substantial N-arylation of the side chain of the model compound 18 has been observed.
      Graphical abstract image

      PubDate: 2014-12-21T03:31:50Z
       
  • Synthesis and In Vitro Biological Evaluation of 2-(Phenylcarbamoyl)phenyl
           4-Substituted Benzoates
    • Abstract: Publication date: Available online 18 December 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Martin Krátký , Szilvia Bősze , Zsuzsa Baranyai , Ildikó Szabó , Jiřina Stolaříková , Georgios Paraskevopoulos , Jarmila Vinšová
      Based on the previously described antimicrobial activity of salicylanilide derivatives, we designed and synthesized novel 2-(phenylcarbamoyl)phenyl 4-substituted benzoates. The most active salicylanilides were selected for esterification by various 4-substituted benzoic acids. These compounds were evaluated in vitro against Mycobacterium tuberculosis, including multidrug-resistant strains, nontuberculous mycobacteria (M. avium and M. kansasii), and eight bacterial and fungal strains. We also investigated the cytostatic and cytotoxic actions of the esters. The minimum inhibitory concentrations (MICs) against mycobacteria ranged from 0.125 to 8 μM. Interestingly, the drug-resistant strains exhibited the highest susceptibility without any cross-resistance with established drugs. 4-Bromo-2-[4-(trifluoromethyl)phenylcarbamoyl]phenyl 4-nitrobenzoate showed the most potent inhibition with MIC values ranging from 0.25 to 2 μM. Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, were inhibited by two derivatives with MIC values of at least 0.49 μM, whereas Gram-negative bacteria and most of the tested fungi did not display any marked susceptibility. Benzoates exhibited no cytotoxicity at concentrations up to 50 μM but most caused significant cytostasis with IC50 values lower than 10 μM. Some cytotoxicity-based selectivity indexes for drug-susceptible and drug-resistant M. tuberculosis as well as Staphylococci were higher than 100. These values indicate that some of these derivatives are promising candidates for future research.
      Graphical abstract image

      PubDate: 2014-12-21T03:31:50Z
       
  • Novel agonists of benzodiazepine receptors: design, synthesis, binding
           assay and pharmacological evaluation of 1,2,4-triazolo[1,5-a]pyrimidinone
           and 3-amino-1,2,4-triazole derivatives
    • Abstract: Publication date: Available online 18 December 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Mehrdad Faizi , Sara Dabirian , Hamed Tajali , Fatemeh Ahmadi , Elham Rezaee Zavareh , Soraya Shahhosseini , Sayyed Abbas Tabatabai
      Agonists of benzodiazepine (BZD) binding site in GABA receptors are widely used in clinical practice. In spite of their benefits they have several side effects, so synthesis of new agonists of these receptors to get more specific effect and better profile of adverse drug reactions is still continued. Novel BZD agonists were designed based on the pharmacophore/receptor model of BZD binding site of GABAA receptor. Energy minima conformers of the designed compounds and estazolam, a known BZD receptor agonist, were well superimposed in conformational analysis. Docking studies revealed that the carbonyl group of the compound 4c, 3-(2-chlorobenzyl)-5-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one, was near the nitrogen moiety of triazole ring of estazolam providing the hydrogen bond acceptor in proper direction in the BDZ-binding site of GABAA receptor model (α1β2ϒ2). The designed compounds were synthesized and their in vitro affinity for the central BZD receptor was determined. Most of the novel compounds had better affinity for the BZD site of action on GABAA receptor complex than diazepam. Finally, the novel compound 4c with the best affinity in radioligand receptor binding assay (Ki=0.42 nM and IC50= 0.68 nM) was selected as candidate for in vivo evaluation. This compound showed significant hypnotic activity and weak anticonvulsant effect with no impairment on learning and memory performance in mouse. The pharmacological effects of the compound 4c were antagonized by flumazenil, a BZD antagonist, which confirms the involvement of BZD receptors in the biological effects of the novel ligand.
      Graphical abstract image

      PubDate: 2014-12-21T03:31:50Z
       
  • Discovery of triazolone derivatives as novel, potent stearoyl-CoA
           desaturase-1 (SCD1) inhibitors
    • Abstract: Publication date: Available online 18 December 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Shaoyi Sun , Zaihui Zhang , Natalia Pokrovskaia , Sultan Chowdhury , Qi Jia , Elaine Chang , Kuldip Khakh , Rainbow Kwan , David G. McLaren , Chris C. Radomski , Leslie G. Ratkay , Jianmin Fu , Natalie A. Dales , Michael D. Winther
      Stearoyl-CoA desaturase-1 (SCD1) plays an important role in lipid metabolism. Inhibition of SCD1 activity represents a potential novel approach for the treatment of metabolic diseases such as obesity, type 2 diabetes and dyslipidemia, as well as skin diseases, acne and cancer. Herein, we report the synthesis and structure–activity relationships (SAR) of a series of novel triazolone derivatives, culminating in the identification of pyrazolyltriazolone 17a, a potent SCD1 inhibitor, which reduced plasma C16:1/C16:0 triglycerides desaturation index (DI) in an acute Lewis rat model in a dose dependent manner, with an ED50 of 4.6 mg/kg. In preliminary safety studies, compound 17a did not demonstrate adverse effects related to SCD1 inhibition after repeat dosing at 100 mg/kg. Together, these data suggest that sufficient safety margins can be achieved with certain SCD1 inhibitors, thus allowing exploration of clinical utility in metabolic disease settings.
      Graphical abstract image

      PubDate: 2014-12-21T03:31:50Z
       
  • Synthesis and biological evaluation of isoindoloisoquinolinone,
           pyroloisoquinolinone and benzoquinazolinone derivatives as PolyADP-Ribose
           Polymerase-1 inhibitors
    • Abstract: Publication date: Available online 18 December 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Arumugam Suyavaran , Chitteti Ramamurthy , Ramachandran Mareeswaran , Yagna Viswa Shanthi , Jayaraman Selvakumar , Selvaraj Mangalaraj , Muthuvel Suresh Kumar , Chinnasamy Ramaraj Ramanathan , Chinnasamy Thirunavukkarasu
      A series of novel fused isoquinolinones with isoindoloisoquinolinone, pyroloisoquinolinone, and benzoquinalizinone skeletons were synthesized from corresponding phenethylimides. The isoquinolinone derivatives were evaluated for their protective effect on chicken erythrocytes subjected to oxidative damage. The effect of isoquinolinone derivatives were analysed by estimation of cell viability, antioxidant enzyme activities, DNA damage (comet assay), PARP-1 inhibition assay and molecular docking of the compounds with PARP-1 active site. The compounds CRR-271, CRR-288 and CRR-224+225 showed significant protective effect at 100 μM concentration. The PARP-1 inhibition assay revealed the IC50 values of CRR-271, CRR-288 and CRR-224+225 as <200 nM, further molecular docking studies shows higher binding energies with PARP-1 active site. Interesting findings in this study suggest that the novel isoquinolinone derivatives inhibit PARP-1 activity and protect cells against oxidative DNA damage, which could be implemented in the treatment of inflammatory diseases.
      Graphical abstract image

      PubDate: 2014-12-21T03:31:50Z
       
  • Flavonoids as noncompetitive inhibitors of Dengue virus NS2B-NS3 protease:
           inhibition kinetics and docking studies
    • Abstract: Publication date: Available online 18 December 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Lorena Ramos Freitas de Sousa , Hongmei Wu , Liliane Nebo , João Batista Fernandes , Maria Fátima das Graças Fernandes da Silva , Werner Kiefer , Manuel Kanitz , Jochen Bodem , Wibke E. Diederich , Tanja Schirmeister , Paulo Cezar Vieira
      NS2B-NS3 is a serine protease of the Dengue virus considered a key target in the search for new antiviral drugs. In this study flavonoids were found to be inhibitors of NS2B-NS3 proteases of the Dengue virus serotypes 2 and 3 with IC50 values ranging from 15 to 44 μM. Agathisflavone (1) and myricetin (4) turned out to be noncompetitive inhibitors of dengue virus serotype 2 NS2B-NS3 protease with K i values of 11 and 4.7 μM, respectively. Docking studies propose a binding mode of the flavonoids in a specific allosteric binding site of the enzyme. Analysis of biomolecular interactions of quercetin (5) with NT647-NHS-labeled Dengue virus serotype 3 NS2B-NS3 protease by microscale thermophoresis experiments, yielded a dissociation constant K D of 20 μM. Our results help to understand the mechanism of inhibition of the Dengue virus serine protease by flavonoids, which is essential for the development of improved inhibitors.
      Graphical abstract image

      PubDate: 2014-12-21T03:31:50Z
       
  • Anthranilic acid derivatives as nuclear receptor modulators –
           development of novel PPAR selective and dual PPAR/FXR ligands
    • Abstract: Publication date: Available online 18 December 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Daniel Merk , Christina Lamers , Julia Weber , Daniel Flesch , Matthias Gabler , Ewgenij Proschak , Manfred Schubert-Zsilavecz
      Nuclear receptors, especially the peroxisome proliferator activated receptors (PPARs) and the farnesoid X receptor (FXR) fulfill crucial roles in metabolic balance. Their activation offers valuable therapeutic potential which has high clinical relevance with the fibrates and glitazones as PPAR agonistic drugs. With growing knowledge about the various functions of nuclear receptors in many disorders, new selective or dual ligands of these pharmaceutical targets are however still required. Here we report the class of anthranilic acid derivatives as novel selective PPAR or dual FXR/PPAR ligands. We identified distinct molecular determinants that govern selectivity for each PPAR subtype or FXR as well as the amplitude of activation of the respective receptors. We thereby discovered several lead compounds for further optimization and developed a highly potent dual PPARα/FXR partial agonist that might have a beneficial synergistic effect on lipid homeostasis by simultaneous activation of two nuclear receptors involved in lipid metabolism.
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      PubDate: 2014-12-21T03:31:50Z
       
  • Synthesis and biological evaluation of novel chiral diazepine derivatives
           as bombesin receptor subtype-3 (BRS-3) agonists incorporating an antedrug
           approach
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Tetsuyoshi Matsufuji , Kousei Shimada , Shozo Kobayashi , Masanori Ichikawa , Asuka Kawamura , Teppei Fujimoto , Tsuyoshi Arita , Takashi Hara , Masahiro Konishi , Rie Abe-Ohya , Masanori Izumi , Yoshitaka Sogawa , Yoko Nagai , Kazuhiro Yoshida , Yasuyuki Abe , Takako Kimura , Hisashi Takahashi
      Novel compounds based on the lead BRS-3 agonists from our HTS compounds 2a and 2b have been synthesized with the focus on obtaining peripheral BRS-3 agonists. To identify potent anti-obesity compounds without adverse effects on the central nerve system, a labile carboxylic ester with an antedrug functionality was introduced onto the terminal position. Through the extensive synthetic exploration and the pharmacokinetic studies of oral administration in mice, the phenol ester 17c was selected due to the most suitable pharmacological profile. In the evaluation of food intake suppression in B6 mice, 17c showed significant in vivo efficacy and no clear adverse effect on heart rate and blood pressure change in dog iv infusion. Our study paved the way for development of anti-diabetes and obesity drugs with a safer profile.
      Graphical abstract image

      PubDate: 2014-12-21T03:31:50Z
       
  • 4(α-l-Rhamnosyloxy)-benzyl isothiocyanate, a bioactive phytochemical
           that attenuates secondary damage in an experimental model of spinal cord
           injury
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Sabrina Giacoppo , Maria Galuppo , Gina Rosalinda De Nicola , Renato Iori , Placido Bramanti , Emanuela Mazzon
      4(α-l-Rhamnosyloxy)-benzyl isothiocyanate (glucomoringin isothiocyanate; GMG-ITC) is released from the precursor 4(α-l-rhamnosyloxy)-benzyl glucosinolate (glucomoringin; GMG) by myrosinase (β-thioglucoside glucohydrolase; E.C. 3.2.1.147) catalyzed hydrolysis. GMG is an uncommon member of the glucosinolate group as it presents a unique characteristic consisting in a second glycosidic residue within the side chain. It is a typical glucosinolate found in large amounts in the seeds of Moringa oleifera Lam., the most widely distributed plant of the Moringaceae family. GMG was purified from seed-cake of M. oleifera and was hydrolyzed by myrosinase at neutral pH in order to form the corresponding GMG-ITC. This bioactive phytochemical can play a key role in counteracting the inflammatory response connected to the oxidative-related mechanisms as well as in the control of the neuronal cell death process, preserving spinal cord tissues after injury in mice. Spinal cord trauma was induced in mice by the application of vascular clips (force of 24g) for 1min., via four-level T5–T8 after laminectomy. In particular, the purpose of this study was to investigate the dynamic changes occurring in the spinal cord after ip treatment with bioactive GMG-ITC produced 15min before use from myrosinase-catalyzed hydrolysis of GMG (10mg/kg body weight+5μl Myr mouse/day). The following parameters, such as histological damage, distribution of reticular fibers in connective tissue, nuclear factor (NF)-κB translocation and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκB-α) degradation, expression of inducible Nitric Oxide Synthases (iNOS), as well as apoptosis, were evaluated. In conclusion, our results show a protective effect of bioactive GMG-ITC on the secondary damage, following spinal cord injury, through an antioxidant mechanism of neuroprotection. Therefore, the bioactive phytochemical GMG-ITC freshly produced before use by myrosinase-catalyzed hydrolysis of pure GMG, could prove to be useful in the treatment of spinal cord trauma.
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      PubDate: 2014-12-21T03:31:50Z
       
  • Ferrocenes as potential chemotherapeutic drugs: Synthesis, cytotoxic
           activity, reactive oxygen species production and micronucleus assay
    • Abstract: Publication date: Available online 18 December 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Wanda I. Pérez , Yarelys Soto , Carmen Ortíz , Jaime Matta , Enrique Meléndez
      Three new ferrocene complexes were synthesized with 4-(1H-pyrrol-1-yl)phenol group appended to one of the Cp ring. These are: 1,1’-4-(1H-pyrrol-1-yl)phenyl ferrocenedicarboxylate, (“Fc-(CO2-Ph-4-Py)2”), 1,4-(1H-pyrrol-1-yl)phenyl, 1’-carboxyl ferrocenecarboxylate (“Fc-(CO2-Ph-4-Py)CO2H”) and 4-(1H-pyrrol-1-yl)phenyl ferroceneacetylate (“Fc-CH2CO2-Ph-4-Py”). The new species were characterized by standard analytical methods. Cyclic voltammetry experiments showed that Fc-CH2CO2-Ph-4-Py has redox potential very similar to the Fc/Fc+ redox couple whereas Fc-(CO2-Ph-4-Py)2 and Fc-(CO2-Ph-4-Py)CO2H have redox potentials of over 400 mV higher than Fc/Fc+ redox couple. The in vitro studies on Fc-(CO2-Ph-4-Py)2 and Fc-(CO2-Ph-4-Py)CO2H revealed that these two compounds have moderate anti-proliferative activity on MCF-7 breast cancer cell line. In contrast Fc-CH2CO2-Ph-4-Py which displayed low anti-proliferative activity. In the HT-29 colon cancer cell line, the new species showed low anti-proliferaive activity. Cytokinesis-block micronucleus assay (CBMN) was performed on these ferrocenes and it was determined they induce micronucleus formation on binucleated cells and moderate genotoxic effects on the MCF-7 breast cancer cell line. There is a correlation between the IC50 values of the ferrocenes and the amount of micronucleus formation activity on binucleated cells and the reactive oxygen species (ROS) production on MCF-7 cell line.
      Graphical abstract image

      PubDate: 2014-12-21T03:31:50Z
       
  • Synthesis and biological evaluation of
           3-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-4-(indol-3-yl)-maleimides as
           potent, selective GSK-3β inhibitors and neuroprotective agents
    • Abstract: Publication date: Available online 19 December 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Qing Ye , Weili Mao , Yubo Zhou , Lei Xu , Qiu Li , Yuanxue Gao , Jing Wang , Chenhui Li , Yazhou Xu , Yuan Xu , Hong Liao , Luyong Zhang , Jianrong Gao , Jia Li , Tao Pang
      A series of novel 3-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-4-(indol-3-yl)-maleimides were designed, prepared and evaluated for their GSK-3β inhibitory activities. Most compounds showed high potency to GSK-3β inhibition with high selectivity. Among them, compounds 7c, 7f, 7h, 7l and 7m significantly reduced GSK-3β substrate Tau phosphorylation at Ser396 in primary neurons, showing the inhibition of cellular GSK-3β. In the in vitro neuronal injury models, compounds 7c, 7f, 7h, 7l and 7m prevented neuronal death against glutamate, oxygen-glucose deprivation and nutrient serum deprivation which are associated with cerebral ischemic stroke. In the in vivo cerebral ischemia animal model, compound 7f reduced infarct size by 15% and improved the neurological deficit following focal cerebral ischemia. These findings may provide new insights into the development of novel GSK-3β inhibitors with potential neuroprotective activity.
      Graphical abstract image

      PubDate: 2014-12-21T03:31:50Z
       
  • Natural antitubulin agents: importance of 3,4,5-trimethoxyphenyl fragment
    • Abstract: Publication date: Available online 20 December 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Arvind S. Negi , Yashvir Gautam , Sarfraz Alam , Debabrata Chanda , Suaib Luqman , Jayanta Sarkar , Feroz Khan , Rituraj Konwar
      Microtubules are polar cytoskeletal filaments assembled from head-to-tail and comprised of lateral associations of α/β-tubulin heterodimers that play key role in various cellular processes. Because of their vital role in mitosis and various other cellular processes, microtubules have been attractive targets for several disease conditions and especially for cancer. Antitubulin is the most successful class of antimitotic agents in cancer chemotherapeutics. The target recognition of antimitotic agents as a ligand is not much explored so far. However, 3,4,5-trimethoxyphenyl fragment has been much highlighted and discussed in such type of interactions. In this review, some of the most important naturally occurring antimitotic agents and their interactions with microtubules are discussed with a special emphasis on the role of 3,4,5-trimethoxyphenyl unit. At last, some emerging naturally occurring antimitotic agents have also been tabulated.
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      PubDate: 2014-12-21T03:31:50Z
       
  • Quinoline-based antimalarial hybrid compounds
    • Abstract: Publication date: Available online 19 December 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Stéphanie Vandekerckhove , Matthias D’hooghe
      Quinoline-containing compounds, such as quinine and chloroquine, have a long-standing history as potent antimalarial agents. However, the increasing resistance of the Plasmodium parasite against these drugs and the lack of licensed malaria vaccines have forced chemists to develop synthetic strategies toward novel biologically active molecules. A strategy that has attracted considerable attention in current medicinal chemistry is based on the conjugation of two biologically active molecules into one hybrid compound. Since quinolines are considered to be priviliged antimalarial building blocks, the synthesis of quinoline-containing antimalarial hybrids has been elaborated extensively in recent years. This review provides a literature overview of antimalarial hybrid molecules containing a quinoline core, covering publications between 2009 and 2014.
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      PubDate: 2014-12-21T03:31:50Z
       
  • MCR synthesis of a tetracyclic tetrazole scaffold
    • Abstract: Publication date: Available online 20 December 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Pravin Patil , Kareem Khoury , Eberhardt Herdtweck , Alexander Dömling
      Scaffold diversity is key in the ongoing exercise of discovery of novel bioactive compounds using high throughput screening (HTS). Based on the Ugi tetrazole synthesis we have designed novel bi- and tri-cyclic scaffolds featuring interesting pharmacophore properties. The compounds of the scaffold (B) are synthesizable in large diversity and numbers in two steps using (hetero)phenylethylamines, HN3, oxo components and iscyanoacetaldehyde(dimethylacetale). The chemistry is amenable to parallel synthesis and is used to enhance and fill the screening decks of the European Lead factory (ELF). Here, we are reporting full experimental details, scope and limitations of the reaction, cheminformatic analysis and the 3D structures of selected compounds.
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      PubDate: 2014-12-21T03:31:50Z
       
  • Bayesian models trained with HTS data for predicting β-haematin
           inhibition and in vitro antimalarial activity
    • Abstract: Publication date: Available online 20 December 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Kathryn J. Wicht , Jill M. Combrinck , Peter J. Smith , Timothy J. Egan
      A large quantity of high throughput screening (HTS) data for antimalarial activity has become available in recent years. This includes both phenotypic and target-based activity. Realising the maximum value of these data remains a challenge. In this respect, methods that allow such data to be used for virtual screening maximise efficiency and reduce costs. In this study both in vitro antimalarial activity and inhibitory data for β-haematin formation, largely obtained from publically available sources, has been used to develop Bayesian models for inhibitors of β-haematin formation and in vitro antimalarial activity. These models were used to screen two in silico compound libraries. In the first, the 1510 U.S. Food and Drug Administration approved drugs available on PubChem were ranked from highest to lowest Bayesian score based on a training set of β-haematin inhibiting compounds active against P. falciparum that did not include any of the clinical antimalarials or close analogues. The six known clinical antimalarials that inhibit β-haematin formation were ranked in the top 2.1% of compounds. Furthermore, the in vitro antimalarial hit-rate for this prioritised set of compounds was found to be 81% in the case of the subset where activity data are available in PubChem. In the second, a library of about 5,000 commercially available compounds (AldrichCPR) was virtually screened for ability to inhibit β-haematin formation and then for in vitro antimalarial activity. A selection of 34 compounds was purchased and tested, of which 24 were predicted to be β-haematin inhibitors. The hit rate for inhibition of β-haematin formation was found to be 25% and a third of these were active against P. falciparum, corresponding to enrichments estimated at about 25- and 140-fold relative to random screening, respectively.
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      PubDate: 2014-12-21T03:31:50Z
       
  • Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS
           3CL protease inhibitors
    • Abstract: Publication date: Available online 20 December 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Yasuhiro Shimamoto , Yasunao Hattori , Kazuya Kobayashi , Kenta Teruya , Akira Sanjoh , Atsushi Nakagawa , Eiki Yamashita , Kenichi Akaji
      The design and evaluation of a novel decahydroisoquinolin scaffold as an inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CLpro) are described. Focusing on hydrophobic interactions at the S2 site, the decahydroisoquinolin scaffold was designed by connecting the P2 site cyclohexyl group of the substrate-based inhibitor to the main-chain at the α−nitrogen atom of the P2 position via a methylene linker. Starting from a cyclohexene enantiomer obtained by salt resolution, trans-decahydroisoquinolin derivatives were synthesized. All decahydroisoquinolin inhibitors synthesized showed moderate but clear inhibitory activities for SARS 3CLpro, which confirmed the fused ring structure of the decahydroisoquinolin functions as a novel scaffold for SARS 3CLpro inhibitor. X-ray crystallographic analyses of the SARS 3CLpro in a complex with the decahydroisoquinolin inhibitor revealed the expected interactions at the S1 and S2 sites, as well as additional interactions at the N-substituent of the inhibitor.
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      PubDate: 2014-12-21T03:31:50Z
       
  • Identification of the dioxygenase-generated intermediate formed during
           biosynthesis of the dihydropyrrole moiety common to anthramycin and
           sibiromycin
    • Abstract: Publication date: Available online 20 December 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Shalini Saha , Wei Li , Barbara Gerratana , Steven E. Rokita
      A description of pyrrolo[1,4]benzodiazepine (PBD) biosynthesis is a prerequisite for engineering production of analogs with enhanced antitumor activity. Predicted dioxygenases Orf12 and SibV associated with dihydropyrrole biosynthesis in PBDs anthramycin and sibiromycin, respectively, were expressed and purified for activity studies. UV-visible spectroscopy revealed that these enzymes catalyze the regiospecific 2,3-extradiol dioxygenation of L-3,4-dihydroxyphenylalanine (L-DOPA) to form L-2,3-secodopa (λmax = 368 nm). 1H NMR spectroscopy indicates that L-2,3-secodopa cyclizes into the α-keto acid tautomer of L-4-(2-oxo-3-butenoic-acid)-4,5-dihydropyrrole-2-carboxylic acid (λmax = 414 nm). Thus, the dioxygenases arekey for establishing thescaffold of the dihydropyrrole moiety. Kinetic studies suggest the dioxygenase product is relatively labile and is likely consumed rapidly by subsequent biosynthetic steps. The enzymatic product and dimeric state of these dioxygenases are conserved in dioxygenases involved in dihydropyrrole or pyrrolidine biosynthesiswithin both PBD and non-PBD pathways.
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      PubDate: 2014-12-21T03:31:50Z
       
  • Identification of a novel glycan processing enzyme with exo-acting
           β-allosidase activity in the Golgi apparatus using a new platform for
           the synthesis of fluorescent substrates
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Wataru Hakamata , Kazuki Miura , Takako Hirano , Toshiyuki Nishio
      The majority of eukaryotic proteins undergo post-translational modifications (PTMs) involving the attachment of complex glycans, predominantly through N-glycosylation and O-glycosylation. PTMs play important roles in virtually all cellular processes, and aberrant regulation of protein glycosylation and glycan processing has been implicated in various diseases. However, glycan processing on proteins in various cellular contexts has not been visualized. We had previously developed a quinone methide cleavage (QMC) platform for enhanced substrate design. This platform was applied here to screen for novel glycan-processing enzymes. We designed and synthesized fluorescent substrates with β-allopyranoside residues using the QMC platform. When applied in cell-based assays, the fluorescent substrates allowed rapid and clear visualization of β-allosidase activity in the Golgi apparatus of human cultured cells. The QMC platform will likely find broad applications in visualizing the activities of glycan processing enzymes in living cells and in studying PTMs.
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      PubDate: 2014-12-21T03:31:50Z
       
  • Retraction notice to “3-Benzhydryl-4-piperidones as novel
           neurokinin-1 receptor antagonists and their efficient synthesis”
           [Bioorg. Med. Chem. 19 (2011) 5175–5182]
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Junya Shirai , Minoru Nakamura , Naoki Tarui , Tadatoshi Hashimoto , Yoshinori Ikeura



      PubDate: 2014-12-21T03:31:50Z
       
  • Synthesis of aminoalkyl-substituted aurone derivatives as
           acetylcholinesterase inhibitors
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Young Hun Lee , Min Cheol Shin , Yong Don Yun , Seo Young Shin , Jong Min Kim , Jeong Moo Seo , Nam-Jung Kim , Jong Hoon Ryu , Yong Sup Lee
      Alzheimer’s disease (AD), a progressive and neurodegenerative disorder of the brain, is the most common cause of dementia among elderly people. To date, the successful therapeutic strategy to treat AD is maintaining the levels of acetylcholine by inhibiting acetylcholinesterase (AChE). In the present study, aurone derivatives were designed and synthesized as AChE inhibitors based on the lead structure of sulfuretin. Of those synthesized, compound 10d showed ca. 1700-fold and 6-fold higher AChE inhibitory activity than sulfuretin and galantamine, respectively. This compound also ameliorated scopolamine-induced memory deficit in mice when administered orally at the dose of 1 and 2mg/kg.
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      PubDate: 2014-12-21T03:31:50Z
       
  • Design, synthesis and biological activity of a novel Rutin analogue with
           improved lipid soluble properties
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Anna Baldisserotto , Silvia Vertuani , Alessia Bino , Daniela De Lucia , Ilaria Lampronti , Roberta Milani , Roberto Gambari , Stefano Manfredini
      Recent interest in flavonoids has increased greatly due to their biological and pharmacological activities. Flavonoids, consist of a large group of low molecular weight polyphenolic substances, naturally occurring in fruits, vegetables, tea, and wine, and are an integral part of the human diet. Rutin is a common dietary flavonoid that is widely consumed worldwide from plant-derived beverages and foods as traditional and folk medicine remedy as well. Rutin exhibit important pharmacological activities, including anti-oxidation, anti-inflammation, anti-diabetic, anti-adipogenic, neuroprotective and hormone therapy. Here, we present the synthesis, antimicrobial, antiproliferative and pro-apoptotic effect on human leukemic K562 cells of compound R2, a new semi-synthetic derivative of Rutin as compared to Rutin itself. The new derivative was also included in finished topical formulations to evaluate a potential application to the dermatology field in view of the antioxidant/antimicrobial/antiinflammatory properties. Stability studies were performed by HPLC; PCL assay and ORAC tests were used to determine the antioxidant activity. R2 presented an antioxidant activity very close to that of the parent Rutin while bearing much better lipophilic character. Regarding antiproliferative effects on the human K562 cell line, R2 was found to be more effective than parent Rutin. Preliminary experiments demonstrated that R2 inhibits NF-kB activity and promotes cellular apoptosis.
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      PubDate: 2014-12-21T03:31:50Z
       
  • Ether modifications to
           1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine (SA4503):
           Effects on binding affinity and selectivity for sigma receptors and
           monoamine transporters
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Rong Xu , Sarah A. Lord , Ryan M. Peterson , Emily A. Fergason-Cantrell , John R. Lever , Susan Z. Lever
      Two series of novel ether analogs of the sigma (σ) receptor ligand 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine (SA4503) have been prepared. In one series, the alkyl portion of the 4-methoxy group was replaced with allyl, propyl, bromoethyl, benzyl, phenethyl, and phenylpropyl moieties. In the second series, the 3,4-dimethoxy was replaced with cyclic methylenedioxy, ethylenedioxy and propylenedioxy groups. These ligands, along with 4-O-des-methyl SA4503, were evaluated for σ1 and σ2 receptor affinity, and compared to SA4503 and several known ether analogs. SA4503 and a subset of ether analogs were also evaluated for dopamine transporter (DAT) and serotonin transporter (SERT) affinity. The highest σ1 receptor affinities, K i values of 1.75–4.63nM, were observed for 4-O-des-methyl SA4503, SA4503 and the methylenedioxy analog. As steric bulk increased, σ1 receptor affinity decreased, but only to a point. Allyl, propyl and bromoethyl substitutions gave σ1 receptor K i values in the 20–30nM range, while bulkier analogs having phenylalkyl, and Z- and E-iodoallyl, ether substitutions showed higher σ1 affinities, with K i values in the 13–21nM range. Most ligands studied exhibited comparable σ1 and σ2 affinities, resulting in little to no subtype selectivity. SA4503, the fluoroethyl analog and the methylenedioxy congener showed modest six- to fourteen-fold selectivity for σ1 sites. DAT and SERT interactions proved much more sensitive than σ receptor interactions to these structural modifications. For example, the benzyl congener (σ1 K i =20.8nM; σ2 K i =16.4nM) showed over 100-fold higher DAT affinity (K i =121nM) and 6-fold higher SERT affinity (K i =128nM) than the parent SA4503 (DAT K i =12650nM; SERT K i =760nM). Thus, ether modifications to the SA4503 scaffold can provide polyfunctional ligands having a broader spectrum of possible pharmacological actions.
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      PubDate: 2014-12-21T03:31:50Z
       
  • Synthesis of prenylated quinolinecarboxylic acid derivatives and their
           anti-obesity activities
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Haruhisa Kikuchi , Toshiyuki Suzuki , Masato Ogura , Miwako K. Homma , Yoshimi Homma , Yoshiteru Oshima
      Mitochondrial uncoupling is one of the therapeutic strategies used to control energy metabolism in various metabolic diseases and in obesity. Ppc-1 (1), a prenylated quinolinecarboxylic acid isolated from cellular slime molds, shows uncoupling activity in vitro and anti-obesity activity in vivo. In this study, we synthesized Ppc-1 (1) and its derivatives, and revealed the structure–activity relationship of uncoupling activities. The triprenylated compound 18 showed mitochondrial uncoupling activity that was more potent than that of Ppc-1 (1). Compound 18 also suppressed weight gain in mice without undesired effects such as lesions on tissues. These results indicate that compound 18 could be used as a seed compound for new anti-obesity drugs.
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      PubDate: 2014-12-21T03:31:50Z
       
  • Antidepressant- and anxiolytic-like activity of
           7-phenylpiperazinylalkyl-1,3-dimethyl-purine-2,6-dione derivatives with
           diversified 5-HT1A receptor functional profile
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Anna Partyka , Grażyna Chłoń-Rzepa , Anna Wasik , Magdalena Jastrzębska-Więsek , Adam Bucki , Marcin Kołaczkowski , Grzegorz Satała , Andrzej J. Bojarski , Anna Wesołowska
      Continuing our earlier study in a group of purine-2,6-dione derivatives of long chain arylpiperazines (LCAPs), a series of 8-unsubstituted 7-phenylpiperazin-4-yl-alkyl (4–14) and 7-tetrahydroisoquinolinyl-alkyl (15–17) analogues were synthesized and their serotonin 5-HT1A, 5-HT2A, 5-HT6, 5-HT7 and dopamine D2 receptor affinities were determined. The study allowed us to identify some potent 5-HT1A receptor ligands with additional moderate affinity for 5-HT2A, 5-HT7 and dopamine D2 receptors. Compounds 9, 12, 13 and 14, with the highest 5HT1A receptor affinity, were selected for further functional in vivo studies and behavioural evaluation of antidepressant- and antianxiety-like activity. Compounds 9, 12 and 13 showed features of agonists of pre- and/or post-synaptic 5-HT1A receptors, whereas 14 was classified as an antagonist of postsynaptic sites. Moreover, derivatives 9 and 14 acted as antagonists of 5-HT2A receptors. In behavioural studies, compounds 9 and 13 showed antidepressant-like activity in the mouse forced swim test, and their effects were similar or stronger than those of imipramine. Compounds 9, 12 and 14 displayed potential anxiolytic-like properties in the mouse four-plate test, similar or even greater than those of the reference anxiolytic drug, diazepam.
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      PubDate: 2014-12-21T03:31:50Z
       
  • Modified 2,4-diaminopyrimidine-based dihydrofolate reductase inhibitors as
           potential drug scaffolds against Bacillus anthracis
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Baskar Nammalwar , Christina R. Bourne , Nancy Wakeham , Philip C. Bourne , Esther W. Barrow , N. Prasad Muddala , Richard A. Bunce , K. Darrell Berlin , William W. Barrow
      The current Letter describes the synthesis and biological evaluation of dihydrophthalazine-appended 2,4-diaminopyrimidine (DAP) inhibitors (1) oxidized at the methylene bridge linking the DAP ring to the central aromatic ring and (2) modified at the central ring ether groups. Structures 4a–b incorporating an oxidized methylene bridge showed a decrease in activity, while slightly larger alkyl groups (CH2CH3 vs CH3) on the central ring oxygen atoms (R2 and R3) had a minimal impact on the inhibition. Comparison of the potency data for previously reported RAB1 and BN-53 with the most potent of the new derivatives (19b and 20a–b) showed similar values for inhibition of cellular growth and direct enzymatic inhibition (MICs 0.5–2μg/mL). Compounds 29–34 with larger ester and ether groups containing substituted aromatic rings at R3 exhibited slightly reduced activity (MICs 2–16μg/mL). One explanation for this attenuated activity could be encroachment of the extended R3 into the neighboring NADPH co-factor. These results indicate that modest additions to the central ring oxygen atoms are well tolerated, while larger modifications have the potential to act as dual-site inhibitors of dihydrofolate reductase (DHFR).
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      PubDate: 2014-12-21T03:31:50Z
       
  • A dual inhibitor of matrix metalloproteinases and a disintegrin and
           metalloproteinases, [18F]FB-ML5, as a molecular probe for non-invasive
           MMP/ADAM-targeted imaging
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Nathalie Matusiak , Riccardo Castelli , Adriaan W. Tuin , Herman S. Overkleeft , Rosalina Wisastra , Frank J. Dekker , Laurette M. Prély , Rainer P.M. Bischoff , Aren van Waarde , Rudi A.J.O. Dierckx , Philip H. Elsinga
      Background Numerous clinical studies have shown a correlation between increased matrix metalloproteinase (MMP)/a disintegrin and metalloproteinase (ADAM) activity and poor outcome of cancer. Various MMP inhibitors (MMPIs) have been developed for therapeutic purposes in oncology. In addition, molecular imaging of MMP/ADAM levels in vivo would allow the diagnosis of tumors. We selected the dual inhibitor of MMPs and ADAMs, ML5, which is a hydroxamate-based inhibitor with affinities for many MMPs and ADAMs. ML5 was radiolabelled with 18F and the newly obtained radiolabelled inhibitor was evaluated in vitro and in vivo. Materials and methods ML5 was radiolabelled by direct acylation with N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB) for PET (positron emission tomography). The resulting radiotracer [18F]FB-ML5 was evaluated in vitro in human bronchial epithelium 16HBE cells and breast cancer MCF-7 cells. The non-radioactive probe FB-ML5 and native ML5 were tested in a fluorogenic inhibition assay against MMP-2, -9, -12 and ADAM-17. The in vivo kinetics of [18F]FB-ML5 were examined in a HT1080 tumor-bearing mouse model. Specificity of probe binding was examined by co-injection of 0 or 2.5mg/kg ML5. Results ML5 and FB-ML5 showed high affinity for MMP-2, -9, -12 and ADAM-17; indeed IC50 values were respectively 7.4±2.0, 19.5±2.8, 2.0±0.2 and 5.7±2.2nM and 12.5±3.1, 31.5±13.7, 138.0±10.9 and 24.7±2.8nM. Radiochemical yield of HPLC-purified [18F]FB-ML5 was 13–16% (corrected for decay). Cellular binding of [18F]FB-ML5 was reduced by 36.6% and 27.5% in MCF-7 and 16HBE cells, respectively, after co-incubation with 10μM of ML5. In microPET scans, HT1080 tumors exhibited a low and homogeneous uptake of the tracer. Tumors of mice injected with [18F]FB-ML5 showed a SUVmean of 0.145±0.064 (n =6) which decreased to 0.041±0.027 (n =6) after target blocking (p <0.05). Ex vivo biodistribution showed a rapid excretion through the kidneys and the liver. Metabolite assays indicated that the parent tracer represented 23.2±7.3% (n =2) of total radioactivity in plasma, at 90min post injection (p.i.). Conclusion The nanomolar affinity MMP/ADAM inhibitor ML5 was successfully labelled with 18F. [18F]FB-ML5 demonstrated rather low binding in ADAM-17 overexpressing cell lines. [18F]FB-ML5 uptake showed significant reduction in the HT1080 tumor in vivo after co-injection of ML5. [18F]FB-ML5 may be suitable for the visualization/quantification of diseases overexpressing simultaneously MMPs and ADAMs.
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      PubDate: 2014-12-21T03:31:50Z
       
  • Discovery of 2-[2-(5-nitrofuran-2-yl)vinyl]quinoline derivatives as a
           novel type of antimetastatic agents
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Chih-Hua Tseng , Cherng-Chyi Tzeng , Chien-Chih Chiu , Chih-Yao Hsu , Chon-Kit Chou , Yeh-Long Chen
      A number of 2-furanylvinylquinoline derivatives were synthesized and evaluated for antiproliferative activities against the growth of four cancer cell lines including non-small cell lung cancer (A549 and H1299), breast cancer (MCF-7 and MDA-MB-231) and normal diploid embryonic lung cell line (MRC-5). Among them, (E)-6-methoxy-3-(4-methoxyphenyl)-2-[2-(5-nitrofuran-2-yl)vinyl]quinoline (10c) was found low cytotoxic in all cancer cells and normal cell. The aim of this study was to investigate the anti-invasive and anti-metastatic activity of compound 10c in H1299 human lung cancer cells. In this study, compound 10c inhibited the migration and invasion of cells in a concentration-dependent manner by wound healing assay and transwell invasion assay. Furthermore, the inhibition of both phosphorylation of Akt and ERK by compound 10c may be critical for cell migration and this may result in the down-regulation of several factors associated with cellular migration, including β-catenin transcription factor, Bcl-2 and COX-2. Interestingly, the treatment of compound 10c did not affect the expression level but reduced the activities of the MMP-2 and -9. The phosphorylation level of stress-activated kinase p38 was significantly increased following compound 10c treatment. To sum up, compound 10c had potential to suppress the migration and invasion of H1299 cancer cells in vitro and it could serve as a promising drug for the treatment of cancer metastasis.
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      PubDate: 2014-12-21T03:31:50Z
       
  • Synthesis and biological evaluation of pyridinone analogues as novel
           potent HIV-1 NNRTIs
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Yuanyuan Cao , Yu Zhang , Shaotong Wu , Quanzhi Yang , Xuefeng Sun , Jianxiong Zhao , Fen Pei , Ying Guo , Chao Tian , Zhili Zhang , Haining Wang , Liying Ma , Junyi Liu , Xiaowei Wang
      A novel 2-pyridinone scaffold was rationally designed and synthesized based on the active anti-HIV agent 1 (LAM-trans) via an efficient method. The biological results revealed that some target compounds inhibited HIV-1 reverse transcriptase in the lower micromolar concentration range (IC50 0.089–0.68μm). Notably, the most promising compound 25b exhibited extremely potent inhibitory activity against HIV-1 replication with an EC50 value of 0.0563μM and the viral selectivity index amounted to 3466.8. Molecular modeling studies were performed, and some SARs were rationalized.
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      PubDate: 2014-12-21T03:31:50Z
       
  • Design and synthesis of novel 2,4-diaryl-5H-indeno[1,2-b]pyridine
           derivatives, and their evaluation of topoisomerase inhibitory activity and
           cytotoxicity
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Tara Man Kadayat , Chanmi Park , Kyu-Yeon Jun , Til Bahadur Thapa Magar , Ganesh Bist , Han Young Yoo , Youngjoo Kwon , Eung-Seok Lee
      For the development of potential anticancer agents, we designed and synthesized 30 new 2,4-diaryl-5H-indeno[1,2-b]pyridine derivatives containing aryl moiety such as furyl, thienyl, pyridyl, and phenyl at 2- and 4-position of 5H-indeno[1,2-b]pyridine. They were evaluated for topoisomerase I and II inhibitory activity, and cytotoxicity against several human cancer cell lines. Among prepared 30 compounds, 7, 8, 9, 10, 12, 14, 16, 19, 20, 22, and 23 with 2- or 3-furyl and/or 2- or 3-thienyl either at 2- or 4-position of central pyridine showed the significant or moderate topoisomerase II inhibitory activity. Compounds 7, 8, 11, 12, 13, and 22 with 2-furyl, 2-thienyl or 3-thienyl at 2-position of central pyridine showed the significant or moderate topoisomerase I inhibitory activity. Especially, compound 12 with strong topoisomerase II inhibitory activity at 100μM and 20μM, and moderate topoisomerase I inhibitory activity displayed strong cytotoxicity against several human cancer cell lines.
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      PubDate: 2014-12-21T03:31:50Z
       
  • Synthesis and antimycobacterial evaluation of
           5-alkylamino-N-phenylpyrazine-2-carboxamides
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Jan Zitko , Barbora Servusová , Alena Janoutová , Pavla Paterová , Jana Mandíková , Vladimír Garaj , Marcela Vejsová , Jan Marek , Martin Doležal
      Substitution of chlorine in 5-chloro-N-phenylpyrazine-2-carboxamide (1) with simple n-alkylamines yielded a series of 5-alkylamino-N-phenylpyrazine-2-carboxamides (propylamino to octylamino derivatives), which possessed similar or increased activity against Mycobacterium tuberculosis H37Rv compared to parent 5-chloro derivative (1), with MIC ranging from 2.5 to 12.2μM. 5-Butylamino to 5-heptylamino derivatives exerted similar activity also against Mycobacterium kansasii. Importantly, the substitution led also to significant decrease of in vitro cytotoxicity in HepG2 cell line. 5-Heptylamino-N-phenylpyrazine-2-carboxamide (1e) exerted MIC=2.5μM (M. tbc) and IC50 >250μM (HepG2). Further modification of alkylamino chain with terminal methoxy or hydroxy group lead to compounds with decreased or none activity, the decrease was proportional to the decrease of lipophilicity. 5-(2-Phenylethylamino) and 5-(3-phenylpropylamino) derivatives were also of decreased activity. On contrary to alkylamino derivatives derived from 1, alkylamino derivatives derived from 5-chloro-N-2-chlorophenylpyrazine-2-carboxamide (2) possessed substantially decreased or none activity. None of the prepared compounds was active against Mycobacterium avium.
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      PubDate: 2014-12-21T03:31:50Z
       
  • Norbornane-based nucleoside and nucleotide analogues locked in North
           conformation
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Milan Dejmek , Michal Šála , Hubert Hřebabecký , Martin Dračínský , Eliška Procházková , Dominika Chalupská , Martin Klíma , Pavla Plačková , Miroslav Hájek , Graciela Andrei , Lieve Naesens , Pieter Leyssen , Johan Neyts , Jan Balzarini , Evzen Boura , Radim Nencka
      We report on the synthesis of novel conformationally locked nucleoside and nucleotide derivatives, which are structurally closely related to clinically used antivirals such as didanosine and abacavir. As a suitable conformationally rigid substitute of the sugar/pseudosugar ring allowing a permanent stabilization of the nucleoside in North conformation we employed bicyclo[2.2.1]heptane (norbornane) substituted in the bridgehead position with a hydroxymethyl group and in the C-3 position with a nucleobase. Prepared nucleoside derivatives were also converted into appropriate phosphoramidate prodrugs (ProTides) in order to increase delivery of the compounds in the cells. All target compounds were evaluated in a broad antiviral and cytostatic assay panel.
      Graphical abstract image

      PubDate: 2014-12-21T03:31:50Z
       
  • Synthesis and biological evaluation of phenoxyacetic acid derivatives as
           novel free fatty acid receptor 1 agonists
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Xuekun Wang , Tianxiao Zhao , Baowei Yang , Zheng Li , Jian Cui , Yuxuan Dai , Qianqian Qiu , Hao Qiang , Wenlong Huang , Hai Qian
      Free fatty acid receptor 1 (FFA1) is a new potential drug target for the treatment of type 2 diabetes because of its role in amplifying glucose-stimulated insulin secretion in pancreatic β-cell. In the present studies, we identified phenoxyacetic acid derivative (18b) as a potent FFA1 agonist (EC50 =62.3nM) based on the structure of phenylpropanoic acid derivative 4p. Moreover, compound 18b could significantly improve oral glucose tolerance in ICR mice and dose-dependently reduced glucose levels in type 2 diabetic C57BL/6 mice without observation of hypoglycemic side effect. Additionally, compound 18b exhibited acceptable PK profiles. In summary, compound 18b with ideal PK profiles exhibited good activity in vitro and in vivo, and might be a promising drug candidate for the treatment of diabetes mellitus.
      Graphical abstract image

      PubDate: 2014-12-21T03:31:50Z
       
  • Clofazimine analogs with antileishmanial and antiplasmodial activity
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Anna Barteselli , Manolo Casagrande , Nicoletta Basilico , Silvia Parapini , Chiara M. Rusconi , Michele Tonelli , Vito Boido , Donatella Taramelli , Fabio Sparatore , Anna Sparatore
      A set of novel riminophenazine derivatives has been synthesized and evaluated for in vitro activity against chloroquine–sensitive (CQ-S) and chloroquine–resistant (CQ-R) strains of Plasmodium falciparum and against different species of Leishmania promastigotes. Most of the new compounds inhibited the growth of Leishmania promastigotes as well as CQ-S and CQ-R strains of P. falciparum with IC50 in submicromolar range, resulting in the best cases 1–2 orders of magnitude more potent than the parent compound clofazimine.
      Graphical abstract image

      PubDate: 2014-12-21T03:31:50Z
       
  • 1,2,4-Triazolo[1,5-a]quinoxaline derivatives and their simplified
           analogues as adenosine A3 receptor antagonists. Synthesis,
           structure–affinity relationships and molecular modeling studies
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Daniela Catarzi , Flavia Varano , Daniela Poli , Lucia Squarcialupi , Marco Betti , Letizia Trincavelli , Claudia Martini , Diego Dal Ben , Ajiroghene Thomas , Rosaria Volpini , Vittoria Colotta
      The 1,2,4-triazolo[1,5-a]quinoxaline (TQX) scaffold was extensively investigated in our previously reported studies and recently, our attention was focused at position 5 of the tricyclic nucleus where different acyl and carboxylate moieties were introduced (compounds 2–15). This study produced some interesting compounds endowed with good hA3 receptor affinity and selectivity. In addition, to find new insights about the structural requirements for hA3 receptor–ligand interaction, the tricyclic TQX ring was destroyed yielding some 1,2,4-triazole derivatives (compounds 16–23). These simplified compounds, though maintaining the crucial structural requirements for adenosine receptor–ligand interaction, have a very low hA3 adenosine receptor affinity, the only exception being compound 23 (1-[3-(4-methoxyphenyl)-1-phenyl-1H-1,2,4-triazol-5-yl]-3-phenylurea) endowed with a K i value in the micro-molar range and high hA3 selectivity versus both hA1 and hA2A AR subtypes. Evaluation of the side products obtained in the herein reported synthetic pathways led to the identification of some new triazolo[1,5-a]quinoxalines as hA3AR antagonists (compounds 24–27). These derivatives, though lacking the classical structural requirements for the anchoring at the hA3 receptor site, show high hA3 affinity and in some case selectivity versus hA1 and hA2A subtypes. Molecular docking of the herein reported tricyclic and simplified derivatives was carried out to depict their hypothetical binding mode to our model of hA3 receptor.


      PubDate: 2014-12-21T03:31:50Z
       
  • Editorial board
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1




      PubDate: 2014-12-21T03:31:50Z
       
  • Graphical contents list
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1




      PubDate: 2014-12-21T03:31:50Z
       
  • Bioactive metabolites from Chaetomium aureum: Structure elucidation and
           inhibition of the Hsp90 machine chaperoning activity
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Fatima Zahra Kabbaj , Su Lu , My El Abbés Faouzi , Bouchra Meddah , Peter Proksch , Yahya Cherrah , Hans-Josef Altenbach , Amal H. Aly , Ahmed Chadli , Abdessamad Debbab
      Chemical investigation of the EtOAc extract of the fungus Chaetomium aureum, an endophyte of the Moroccan medicinal plant Thymelaea lythroides, afforded one new resorcinol derivative named chaetorcinol, together with five known metabolites. The structures of the isolated compounds were determined on the basis of one- and two-dimensional NMR spectroscopy and high-resolution mass spectrometry as well as by comparison with the literature. All compounds were tested for their activity towards the Hsp90 chaperoning machine in vitro using the progesterone receptor (PR) and rabbit reticulocyte lysate (RRL). Among the isolated compounds, only sclerotiorin efficiently inhibited the Hsp90 machine chaperoning activity. However, sclerotiorin showed no cytotoxic effect on breast cancer Hs578T, MDA-MB-231 and prostate cancer LNCaP cell lines. Interestingly, deacetylation of sclerotiorin increased its cytotoxicity toward the tested cell lines over a period of 48h.
      Graphical abstract image

      PubDate: 2014-12-21T03:31:50Z
       
  • Synthesis of novel 10-hydroxycamptothecin derivatives utilizing topotecan
           hydrochloride as ortho-quinonemethide precursor
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Hanyi Tan , Guolin Wang , Jiajun Li , Guangrong Meng , Zhenfeng Liu , Mengjie Dong , Yubin Li , Dianwen Ju , Qian Zhang
      A series of 9-(alkylthiomethyl)-10-hydroxycamptothecins and pyrano-fused camptothecin derivatives were synthesized via the reaction of topotecan hydrochloride with various thiols and alkyl vinyl ethers respectively. In the reactions, topotecan hydrochloride was utilized as ortho-quinonemethide (o-QM) precursor. The configuration of 19 was determined by 1H NMR and NOESY spectra as syn-isomers, suggesting that the cycloaddition of topotecan with alkyl vinyl ethers could undergo a hetero Diels–Alder reaction. All the synthesized compounds were screened on cancer cell lines HepG2, KB, HCT-8 and SGC7901. Some compounds were selected to assess their inhibitory activity against Topo I via Topo I mediated DNA cleavage assays. The results showed that among those tested 9-(alkylthiomethyl)-10-hydroxycamptothecins, the compounds with bulkier hydrophobic side chains at 9-position have better bioactivities. As well as all pyrano-fused camptothecins possess antiproliferative activity against the tested cancer cell lines. Docking studies suggested that there are more interactions between the novel analogues and the binding site of Topo I.
      Graphical abstract image

      PubDate: 2014-12-21T03:31:50Z
       
  • Design, syntheses and evaluation of 4-oxo-5-cyano thiouracils as SecA
           inhibitors
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Arpana S. Chaudhary , Jinshan Jin , Weixuan Chen , Phang C. Tai , Binghe Wang
      Protein translocation is essential for bacterial survival and the most important translocation mechanism is the secretion (Sec) pathway in which SecA is a central core driving force. Thus targeting SecA is a promising strategy for developing novel antibacterial therapeutics. Herein, we report the syntheses and evaluation of a series of nearly 60 4-oxo-5-cyano thiouracil derivatives based upon our previously reported core pyrimidine structure. Introduction of polar group such as –N3 and linker groups such as –CH2–O– enhanced the potency several fold. Apart from being potential antibacterial agents, these inhibitors can be indispensable tools for biologists to probe the mechanism of protein translocation via the SecA machinery in bacteria.
      Graphical abstract image

      PubDate: 2014-12-21T03:31:50Z
       
  • Synthesis, biological evaluation and 3D-QSAR study of novel
           4,5-dihydro-1H-pyrazole thiazole derivatives as BRAFV600E inhibitors
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Meng-Yue Zhao , Yong Yin , Xiao-Wei Yu , Chetan B. Sangani , Shu-Fu Wang , Ai-Min Lu , Li-Fang Yang , Peng-Cheng Lv , Ming-Guo Jiang , Hai-Liang Zhu
      Many reports implied that the BRAF serine/threonine kinase was mutated in various types of human tumors, which were related with cell growth, survival and differentiation. To provide new therapeutic opportunities, a series of novel 4,5-dihydro-1H-pyrazole derivatives (6a–10d) containing thiazole moiety as potential V600E mutant BRAF kinase (BRAFV600E) inhibitors were designed and synthesized. All compounds were evaluated in vitro for anticancer activities against WM266.4 human melanoma cell line and breast cancer MCF-7 cell line. Compound 10d displayed the most potential antiproliferative activity with an IC50 value of 0.12μM against cell line WM266.4 and 0.16μM against MCF-7 with positive control Sorafenib. Results of the inhibitory activity against BRAFV600E revealed that compound 10d was bearing the best bioactivity with IC50 of 0.05μM as well. On the basis of the result of flow cytometry, with the dose of compound 10d increasing, more and more cancer cell gradually encountered apoptosis or died, which indicated the compound 10d could induce remarkable apoptosis of MCF-7 and WM266.4 cells in a dose dependent manner. Furthermore, docking simulation of inhibitor analogues and 3D-QSAR modeling provided potential binding model and further knowledge of pharmacophore.
      Graphical abstract image

      PubDate: 2014-12-21T03:31:50Z
       
  • Bioactive constituents from the green alga Caulerpa racemosa
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Peng Yang , Ding-Quan Liu , Tong-Jun Liang , Jia Li , Hai-Yan Zhang , Ai-Hong Liu , Yue-Wei Guo , Shui-Chun Mao
      Three diterpenoids, including a pair of epimers, racemobutenolids A and B (1 and 2), and 4′,5′-dehydrodiodictyonema A (3), an α-tocopheroid, α-tocoxylenoxy (8), and an 28-oxostigmastane steroid, (23E)-3β-hydroxy-stigmasta-5,23-dien-28-one (11), together with 12 known compounds, were isolated from the green alga Caulerpa racemosa. The structures of the new compounds were elucidated by detailed analysis of spectroscopic data, and by comparison with data for related known compounds. The epimers (1 and 2) are two unusual diterpenoid lactones bearing a β-methyl-γ-substituted butenolide moiety, and 3 and 8 represent the first naturally occurring natural products with a hematinic acid ester group and 3,5-dimethylphenoxy functionality, respectively. The enzyme inhibitory activities of the isolated compounds were evaluated in vitro against PTP1B and related PTPs (TCPTP, CDC25B, LAR, SHP-1, and SHP-2). Compounds 3, 5, 6, and 9–14 exhibited different levels of PTP1B inhibitory activities with IC50 values ranging from 2.30 to 50.02μM. Of these compounds, 3, 9, and 11 showed the most potent inhibitory activities towards PTP1B with IC50 values of 2.30, 3.85, and 3.80μM, respectively. More importantly, the potent PTP1B inhibitors 3, 9, and 11 also displayed high selectivity over the highly homologous TCPTP and other PTPs. Also, the neuroprotective effects of the isolates against Aβ25-35-induced cell damage in SH-SY5Y cells were investigated. Compounds 10, 11, and 14 exhibited significant neuroprotective effects against Aβ25-35-induced SH-SY5Y cell damage with 11.31–15.98% increases in cell viability at 10μM. In addition, the cytotoxic activities of the isolated compounds were tested against the human cancer cell lines A-549 and HL-60.
      Graphical abstract image

      PubDate: 2014-12-21T03:31:50Z
       
  • Synthesis and hybridization property of a boat-shaped pyranosyl nucleic
           acid containing an exocyclic methylene group in the sugar moiety
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Kazuto Mori , Tetsuya Kodama , Satoshi Obika
      A boat-shaped pyranosyl nucleic acid (BsNA) having an exocyclic methylene group in the sugar moiety was synthesized to investigate the possibility that the axial H3′ of original BsNA is the cause of its duplex destabilization. The synthesized BsNA analog was chemically stable against various nucleophiles. From the thermal stability of duplex oligonucleotides including the BsNA analog, it was found that the duplex-forming ability can be sensitive to the size of functional groups at the 3′-position.
      Graphical abstract image

      PubDate: 2014-12-21T03:31:50Z
       
  • Synthesis, structural characterization and effect on human granulocyte
           intracellular cAMP levels of abscisic acid analogs
    • Abstract: Publication date: 1 January 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 1
      Author(s): Marta Bellotti , Annalisa Salis , Alessia Grozio , Gianluca Damonte , Tiziana Vigliarolo , Andrea Galatini , Elena Zocchi , Umberto Benatti , Enrico Millo
      The phytohormone abscisic acid (ABA), in addition to regulating physiological functions in plants, is also produced and released by several mammalian cell types, including human granulocytes, where it stimulates innate immune functions via an increase of the intracellular cAMP concentration ([cAMP]i). We synthesized several ABA analogs and evaluated the structure–activity relationship, by the systematical modification of selected regions of these analogs. The resulting molecules were tested for their ability to inhibit the ABA-induced increase of [cAMP]i in human granulocytes. The analogs with modified configurations at C-2′ and C-3′ abrogated the ABA-induced increase of the [cAMP]i and also inhibited several pro-inflammatory effects induced by exogenous ABA on granulocytes and monocytes. Accordingly, these analogs could be suitable as novel putative anti-inflammatory compounds.
      Graphical abstract image

      PubDate: 2014-12-21T03:31:50Z
       
  • Design, synthesis, anticancer activity and docking studies of novel
           4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives as
           mTOR inhibitors
    • Abstract: Publication date: 15 December 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 24
      Author(s): Wufu Zhu , Chengyu Sun , Shan Xu , Chunjiang Wu , Jielian Wu , Mengze Xu , He Zhao , Le Chen , Weipeng Zeng , Pengwu Zheng
      A series of 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives (7a–q, 10a–q) were designed, synthesized and their chemical structures were confirmed by 1H NMR, 13C NMR, MS and HRMS spectrum. All the compounds were evaluated for the inhibitory activity against mTOR kinase at 10μM level. Five selected compounds (7b, 7e, 7h, 10b and 10e) were further evaluated for the inhibitory activity against PI3Kα at 10μM level, and the IC50 values against mTOR kinase and two cancer cell lines. Twelve of the target compounds exhibited moderate antitumor activities. The most promising compound 7e showed strong antitumor activities against mTOR kinase, H460 and PC-3 cell lines with IC50 values of 0.80±0.15μM, 7.43±1.45μM and 11.90±0.94μM, which were 1.28 to 1.71-fold more active than BMCL-200908069-1 (1.37±0.07μM, 9.52±0.29μM, 16.27±0.54μM), respectively. Structure–activity relationships (SARs) and docking studies indicated that the thiopyrano[4,3-d]pyrimidine scaffolds exerted little effect on antitumor activities of target compounds. Substitutions of aryl group at C-4 position had a significant impact on the antitumor activities, and 4-OH substitution produced the best potency.
      Graphical abstract image

      PubDate: 2014-12-21T03:31:50Z
       
  • Synthesis of 2-anilinopyridine dimers as microtubule targeting and
           apoptosis inducing agents
    • Abstract: Publication date: 15 December 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 24
      Author(s): Ahmed Kamal , S.M. Ali Hussaini , V. Lakshma Nayak , M. Shaheer Malik , M. Lakshmi Sucharitha , Thokhir Basha Shaik , Md. Ashraf , Chandrakant Bagul
      A series of 2-anilinopyridine dimers have been synthesized and evaluated for their anticancer potential. Most of the compounds have showed significant growth inhibition of the cell lines tested and compound 4d was most effective amongst the series displaying a GI50 of 0.99μM specifically against the prostate cancer cell line (DU145). Studies to understand the mechanism of action of 4d indicates that it disrupts microtubule dynamics by inhibiting tubulin polymerization thereby arresting the cell cycle in G2/M phase. Competitive colchicine binding assay suggests that 4d binds into colchicine binding site of the tubulin. Further from some detailed biological studies like mitochondrial membrane potential, caspase-3 assay, DNA fragmentation analysis and Annexin V-FITC assay it is evident that 4d induces apoptosis. Molecular modeling studies provide an insight into the binding modes of 4d with colchicine binding site of tubulin and the data obtained correlates with the antiproliferative activity.
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      PubDate: 2014-12-21T03:31:50Z
       
  • Ligand-based virtual screening identifies a family of selective
           cannabinoid receptor 2 agonists
    • Abstract: Publication date: Available online 8 November 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Matteo Gianella-Borradori , Ivy Christou , Carole J.R. Bataille , Rebecca L. Cross , Graham M. Wynne , David R. Greaves , Angela J. Russell
      The cannabinoid receptor 2 (CB2R) has been linked with the regulation of inflammation, and selective receptor activation has been proposed as a target for the treatment of a range of inflammatory diseases such as atherosclerosis and arthritis. In order to identify selective CB2R agonists with appropriate physicochemical and ADME properties for future evaluation in vivo, we first performed a ligand-based virtual screen. Subsequent medicinal chemistry optimisation studies led to the identification of a new class of selective CB2R agonists. Several examples showed high levels of activity (EC50 <200nM) and binding affinity (K i <200nM) for the CB2R, and no detectable activity at the CB1R. The most promising example, DIAS2, also showed favourable in vitro metabolic stability and absorption properties along with a clean selectivity profile when evaluated against a panel of GPCRs and kinases.
      Graphical abstract image

      PubDate: 2014-12-17T10:50:33Z
       
 
 
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