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  Subjects -> CHEMISTRY (Total: 765 journals)
    - ANALYTICAL CHEMISTRY (45 journals)
    - CHEMISTRY (530 journals)
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CHEMISTRY (530 journals)                  1 2 3 4 5 6 | Last

2D Materials     Hybrid Journal  
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 32)
ACS Catalysis     Full-text available via subscription   (Followers: 23)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 13)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 7)
ACS Macro Letters     Full-text available via subscription   (Followers: 16)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 24)
ACS Nano     Full-text available via subscription   (Followers: 214)
ACS Photonics     Full-text available via subscription   (Followers: 1)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 8)
Acta Chemica Iasi     Open Access  
Acta Chimica Slovaca     Open Access   (Followers: 5)
Acta Chromatographica     Full-text available via subscription   (Followers: 9)
Acta Facultatis Medicae Naissensis     Open Access   (Followers: 1)
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 2)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 2)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 4)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 8)
Advanced Functional Materials     Hybrid Journal   (Followers: 31)
Advances in Chemical Engineering and Science     Open Access   (Followers: 21)
Advances in Chemical Science     Open Access   (Followers: 8)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 13)
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: 11)
Advances in Nanoparticles     Open Access   (Followers: 10)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 8)
Advances in Polymer Science     Hybrid Journal   (Followers: 38)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 9)
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: 1)
Afrique Science : Revue Internationale des Sciences et Technologie     Open Access  
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Alchemy     Open Access   (Followers: 2)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 4)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Applied Sciences     Open Access   (Followers: 27)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 123)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 11)
American Journal of Chemistry     Open Access   (Followers: 17)
American Journal of Plant Physiology     Open Access   (Followers: 9)
American Mineralogist     Full-text available via subscription   (Followers: 2)
Analyst     Full-text available via subscription   (Followers: 35)
Angewandte Chemie     Hybrid Journal   (Followers: 11)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 174)
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: 9)
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: 14)
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  
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 6)
Biochemistry     Full-text available via subscription   (Followers: 162)
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)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 1)
Biointerphases     Open Access  
Biomacromolecules     Full-text available via subscription   (Followers: 16)
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: 12)
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: 11)
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: 10)
Carbon     Hybrid Journal   (Followers: 34)
Catalysis for Sustainable Energy     Open Access   (Followers: 1)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 4)
Catalysis Science and Technology     Free   (Followers: 4)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 4)
Catalysts     Open Access   (Followers: 6)
Cellulose     Hybrid Journal   (Followers: 4)
Central European Journal of Chemistry     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  [2563 journals]
  • Development of inhibitors of heterotrimeric Gαi subunits
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Kathryn M. Appleton , Kevin J. Bigham , Christopher C. Lindsey , Starr Hazard , Jonel Lirjoni , Stuart Parnham , Mirko Hennig , Yuri K. Peterson
      Heterotrimeric G-proteins are the immediate downstream effectors of G-protein coupled receptors (GPCRs). Endogenous protein guanine nucleotide dissociation inhibitors (GDIs) like AGS3/4 and RGS12/14 function through GPR/Goloco GDI domains. Extensive characterization of GPR domain peptides indicate they function as selective GDIs for Gαi by competing for the GPCR and Gβγ and preventing GDP release. We modified a GPR consensus peptide by testing FGF and TAT leader sequences to make the peptide cell permeable. FGF modification inhibited GDI activity while TAT preserved GDI activity. TAT-GPR suppresses G-protein coupling to the receptor and completely blocked α2-adrenoceptor (α2AR) mediated decreases in cAMP in HEK293 cells at 100nM. We then sought to discover selective small molecule inhibitors for Gαi. Molecular docking was used to identify potential molecules that bind to and stabilize the Gαi–GDP complex by directly interacting with both Gαi and GDP. Gαi–GTP and Gαq–GDP were used as a computational counter screen and Gαq–GDP was used as a biological counter screen. Thirty-seven molecules were tested using nucleotide exchange. STD NMR assays with compound 0990, a quinazoline derivative, showed direct interaction with Gαi. Several compounds showed Gαi specific inhibition and were able to block α2AR mediated regulation of cAMP. In addition to being a pharmacologic tool, GDI inhibition of Gα subunits has the advantage of circumventing the upstream component of GPCR-related signaling in cases of overstimulation by agonists, mutations, polymorphisms, and expression-related defects often seen in disease.
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      PubDate: 2014-06-27T14:36:28Z
       
  • The design and synthesis of novel SGLT2 inhibitors: C-glycosides with
           benzyltriazolopyridinone and phenylhydantoin as the aglycone moieties
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Cheng Guo , Min Hu , Russell J. DeOrazio , Alexander Usyatinsky , Kevin Fitzpatrick , Zhenjun Zhang , Jun-Ho Maeng , Douglas B. Kitchen , Susan Tom , Michele Luche , Yuri Khmelnitsky , Andrew J. Mhyre , Peter R. Guzzo , Shuang Liu
      The sodium glucose co-transporter 2 (SGLT2) has received considerable attention in recent years as a target for the treatment of type 2 diabetes mellitus. This report describes the design, synthesis and structure–activity relationship (SAR) of C-glycosides with benzyltriazolopyridinone and phenylhydantoin as the aglycone moieties as novel SGLT2 inhibitors. Compounds 5p and 33b demonstrated high potency in inhibiting SGLT2 and high selectivity against SGLT1. The in vitro ADMET properties of these compounds will also be discussed.
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      PubDate: 2014-06-27T14:36:28Z
       
  • Design, synthesis, and characterization of novel apigenin analogues that
           suppress pancreatic stellate cell proliferation in vitro and associated
           pancreatic fibrosis in vivo
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Haijun Chen , Amy A. Mrazek , Xiaofu Wang , Chunyong Ding , Ye Ding , Laura J. Porro , Huiling Liu , Celia Chao , Mark R. Hellmich , Jia Zhou
      Accumulating evidence suggests that activated pancreatic stellate cells (PSC) play an important role in chronic pancreatitis (CP), and inhibition of the activated PSC is considered as a potential strategy for the treatment and prevention of CP. Herein, we disclose our findings that apigenin and its novel analogues suppress the proliferation and induce apoptosis in PSC, which reduce the PSC-mediated fibrosis in CP. Chemical modifications of apigenin have been directed to build a focused library of O-alkylamino-tethered apigenin derivatives at 4′-O position of the ring C with the attempt to enhance the potency and drug-like properties including aqueous solubility. A number of compounds such as 14, 16, and 24 exhibited potent antiproliferative effects as well as improved aqueous solubility. Intriguingly, apigenin, new analogues 23 and 24 displayed significant efficacy to reduce pancreatic fibrosis even at a low dose of 0.5mg/kg in our proof-of-concept study using a preclinical in vivo mouse model of CP.
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      PubDate: 2014-06-27T14:36:28Z
       
  • Design, synthesis and evaluation of novel quinazoline-2,4-dione
           derivatives as chitin synthase inhibitors and antifungal agents
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Qinggang Ji , Dan Yang , Xin Wang , Chunyan Chen , Qiao Deng , Zhiqiang Ge , Lvjiang Yuan , Xiaolan Yang , Fei Liao
      A series of novel 1-methyl-3-substituted quinazoline-2,4-dione derivatives were designed, synthesized, and characterized by 1H NMR, 13C NMR and MS spectral data. Their inhibition against chitin synthase (CHS) and antifungal activities were evaluated in vitro. Results showed compounds 5b, 5c, 5e, 5f, 5j, 5k, 5l, and 5o had strong inhibitory potency against CHS. Compound 5c, which has the highest potency among these compounds, had a half-inhibition concentration (IC50) of 0.08mmol/L, while polyoxin B as positive drug had IC50 of 0.18mmol/L. These IC50 values of compounds 5i, 5m, 5n, and 5s were greater than 0.75mmol/L, which revealed that those compounds had weak inhibition activity against CHS. Moreover, most of these compounds exhibited moderate to excellent antifungal activities. In detail, to Candida albicans, the activities of compound 5g and 5k were 8-fold stronger than that of fluconazole and 4-fold stronger than that of polyoxin B; to Aspergillus flavus, the activities of 5g, 5l and 5o were16-fold stronger than that of fluconazole and 8-fold stronger than that of polyoxin B; to Cryptococcus neoformans, the minimum-inhibition-concentration (MIC) values of compounds 5c, 5d, 5e and 5l were comparable to those of fluconazole and polyoxin B. The antifungal activities of these compounds were positively correlated to their IC50 values against CHS. Furthermore, these compounds had negligible actions to bacteria. Therefore, these compounds were promising selective antifungal agents.
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      PubDate: 2014-06-27T14:36:28Z
       
  • Design, synthesis and biological evaluation of hydroxy- or
           methoxy-substituted 5-benzylidene(thio) barbiturates as novel tyrosinase
           inhibitors
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Zhiyong Chen , Dachuan Cai , Dehai Mou , Qin Yan , Yifeng Sun , Wenlong Pan , Yiqian Wan , Huacan Song , Wei Yi
      Here a new class of hydroxy- or methoxy-substituted 5-benzylidene(thio)barbiturates were designed, synthesized and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were evaluated. The results showed that several compounds had more potent tyrosinase inhibitory activities than the widely used tyrosinase inhibitor kojic acid (IC50 =18.25μM). In particular, 3′,4′-dihydroxylated 1e was found to be the most potent inhibitor with IC50 value of 1.52μM. The inhibition mechanism analysis revealed that the potential compounds 1e and 2e exhibited such inhibitory effects on tyrosinase by acting as the irreversible inhibitors. Structure–activity relationships’ (SARs) analysis also suggested that further development of such compounds might be of interest.
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      PubDate: 2014-06-27T14:36:28Z
       
  • Synthesis and evaluation of 18F-labeled mitiglinide derivatives as
           positron emission tomography tracers for β-cell imaging
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Hiroyuki Kimura , Hirokazu Matsuda , Hiroyuki Fujimoto , Kenji Arimitsu , Kentaro Toyoda , Eri Mukai , Hiroshi Nakamura , Yu Ogawa , Mikako Takagi , Masahiro Ono , Nobuya Inagaki , Hideo Saji
      Measuring changes in β-cell mass in vivo during progression of diabetes mellitus is important for understanding the pathogenesis, facilitating early diagnosis, and developing novel therapeutics for this disease. However, a non-invasive method has not been developed. A novel series of mitiglinide derivatives (o-FMIT, m-FMIT and p-FMIT; FMITs) were synthesized and their binding affinity for the sulfonylurea receptor 1 (SUR1) of pancreatic islets were evaluated by inhibition studies. (+)-(S)-o-FMIT had the highest affinity of our synthesized FMITs (IC50 =1.8μM). (+)-(S)-o-[18F]FMIT was obtained with radiochemical yield of 18% by radiofluorination of racemic precursor 7, hydrolysis, and optical resolution with chiral HPLC; its radiochemical purity was >99%. In biodistribution experiments using normal mice, (+)-(S)-o-[18F]FMIT showed 1.94±0.42% ID/g of pancreatic uptake at 5min p.i., and decreases in radioactivity in the liver (located close to the pancreas) was relatively rapid. Ex vivo autoradiography experiments using pancreatic sections confirmed accumulation of (+)-(S)-o-[18F]FMIT in pancreatic β-cells. These results suggest that (+)-(S)-o-[18F]FMIT meets the basic requirements for an radiotracer, and could be a candidate positron emission tomography tracer for in vivo imaging of pancreatic β-cells.
      Graphical abstract image

      PubDate: 2014-06-27T14:36:28Z
       
  • New rhenium complexes with ciprofloxacin as useful models for
           
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Joan Lecina , Pilar Cortés , Montserrat Llagostera , Carlos Piera , Joan Suades
      Rhenium complexes with the antibiotic ciprofloxacin have been prepared to be studied as models of technetium radiopharmaceuticals. With this aim, the new rhenium complexes 1 {[ReO(Cpf)2]Cl}, 2 {[ReO(CpfH)2]Cl3} and 3 {fac-[Re(CO)3(H2O)(Cpf)]} with ciprofloxacin (CpfH=ciprofloxacin; Cpf=conjugated base of ciprofloxacin) have been synthesised and characterised by elemental analyses, IR, NMR (1H, 19F and 13C CP-MAS) spectroscopy, as well as MS measurements. All spectroscopic data are consistent with the coordination of ciprofloxacin in all these complexes through the carbonyl and the carboxylate oxygen atoms with the formation of a six member chelate ring. The study of a Tc-ciprofloxacin solution by ESI–MS reveals the presence of [TcO(Cpf)2]+ cations, which agrees with the hypothesis that complexes 1 and 2 can be seen as model rhenium complexes of this radiopharmaceutical. Antimicrobial and DNA gyrase inhibition studies performed with complexes 2 and 3 have shown a very similar behaviour between complex 2 and the free antibiotic, whereas complex 3 exhibit a lower antimicrobial activity. Based on a joint analysis of the data reported in the literature and the chemical and biological results obtained in this study, a tentative proposal to explain some aspects of the behaviour of Tc-ciprofloxacin radiopharmaceutical has been made.
      Graphical abstract image Highlights

      PubDate: 2014-06-27T14:36:28Z
       
  • SAR studies on hydropentalene derivatives—Important core units of
           biologically active tetramic acid macrolactams and ptychanolides
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Vanessa Lutz , Fabian Mannchen , Michael Krebs , Natja Park , Claudia Krüger , Aruna Raja , Florenz Sasse , Angelika Baro , Sabine Laschat
      Structurally diverse bicyclo[3.3.0]octanes were prepared and tested for their biological activity. Both the antiproliferative activity and the results of phenotypic characterization varied with the substitution patterns. Two derivatives displayed high inhibitory (IC50 ⩽3μM) activity against the L-929 cell line, but differed in their mode of action. A cluster analysis with impedance profiling data showed the two compounds in relationship to microtubule interfering compounds. In PtK2 cells treated with both derivatives a perturbing effect on the microtubular network was observed, whereas the actin cytoskeleton in incubated PtK2 cells was disturbed only by one compound. The effects on tubulin and actin polymerization could be confirmed by in vitro polymerization experiments.
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      PubDate: 2014-06-27T14:36:28Z
       
  • Anti-proliferative effect of chalcone derivatives through inactivation of
           NF-κB in human cancer cells
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Eeda Venkateswararao , Vinay K. Sharma , Jieun Yun , Youngsoo Kim , Sang-Hun Jung
      To investigate the anti-proliferative effect of NF-κB inhibitor, a series of analogs of (E)-1-(2-hydroxy-6-(isopentyloxy)phenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (5a) were prepared and evaluated for their NF-κB inhibition and anti-proliferative activity against various human cancer cell lines. Compounds (E)-1-(2-(3,3-dimethylbutoxy)-6-hydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (5e) and (E)-4-(3-(2-(3,3-dimethylbutoxy)-6-hydroxyphenyl)-3-oxoprop-1-enyl)benzenesulfonamide (5p) showed good NF-κB inhibition as well as potent anti-proliferative activity. SAR studies showed that all the compounds with potent or moderate NF-κB inhibition displayed good anti-proliferative activity. All the analogs (5b–r) maintained a good correlation between their NF-κB inhibition and anti-proliferative activity though the extent is not directly proportional to each other.
      Graphical abstract image

      PubDate: 2014-06-27T14:36:28Z
       
  • Synthesis and biological activity of new arenediyne-linked isoxazolidines
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Roberto Romeo , Michele Navarra , Salvatore V. Giofrè , Caterina Carnovale , Santa Cirmi , Giuseppe Lanza , Maria A. Chiacchio
      Arenediyne–isoxazolidine conjugates have been synthesized as a new scaffold for the development of bioactive mimics. Some of the synthesized compounds are endowed with antiproliferative activity against three human cancer cell lines. Their thermal reactivity suggests that the biological activity probably could not be linked to the Bergman cyclization.
      Graphical abstract image Highlights

      PubDate: 2014-06-27T14:36:28Z
       
  • Amino derivatives of glycyrrhetinic acid as potential inhibitors of
           cholinesterases
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Stefan Schwarz , Susana Dias Lucas , Sven Sommerwerk , René Csuk
      The development of remedies against the Alzheimer’s disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients. Drugs presently used for the treatment of AD inhibit the two ACh controlling enzymes, acetylcholinesterase as well as butyrylcholinesterase; hence, the design of selective inhibitors is called for. Glycyrrhetinic acid seems to be an interesting starting point for the development of selective inhibitors. Although its glycon, glycyrrhetinic acid is known for being an AChE activator, several derivatives, altered in position C-3 and C-30, exhibited remarkable inhibition constants in micro-molar range. Furthermore, five representative compounds were subjected to three more enzyme assays (on carbonic anhydrase II, papain and the lipase from Candida antarctica) to gain information about the selectivity of the compounds in comparison to other enzymes. In addition, photometric sulforhodamine B assays using murine embryonic fibroblasts (NiH 3T3) were performed to study the cytotoxicity of these compounds. Two derivatives, bearing either a 1,3-diaminopropyl or a 1H-benzotriazolyl residue, showed a BChE selective inhibition in the single-digit micro-molar range without being cytotoxic up to 30μM. In silico molecular docking studies on the active sites of AChE and BChE were performed to gain a molecular insight into the mode of action of these compounds and to explain the pronounced selectivity for BChE.
      Graphical abstract image

      PubDate: 2014-06-27T14:36:28Z
       
  • Ultrapure ajulemic acid has improved CB2 selectivity with reduced CB1
           activity
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Mark A. Tepper , Robert B. Zurier , Sumner H. Burstein
      Ajulemic acid, a side-chain analog of Δ8-THC-11-oic acid, was designed as a potent therapeutic agent free of the psychotropic adverse effects typical of most cannabinoids. Subsequent studies of ajulemic acid have yielded widely divergent findings on the occurrence of these adverse effects. To help resolve these discrepancies, we have prepared highly purified ajulemic acid using a different synthetic method than previously reported in the literature and compared its cannabinoid receptor binding constants with those obtained using several other preparations from different sources. Whereas CB2 binding did not vary greatly among all of the samples, the CB1 binding showed a wide range of affinities. The highly purified product (JBT-101) reported here had the weakest affinity for CB1 while the original preparation (HU-239) showed the strongest affinity for CB1. The CB1/CB2 ratio of affinities was 12.3 for JBT-101 whereas that for HU-239 was 0.19, a 65-fold difference. Functional responses such as catalepsy and hypothermia using JBT-101 versus HU-239 displayed reduced CB1 activity in keeping with the receptor binding data. Thus, earlier conclusions on the limited therapeutic index for ajulemic acid need to be reconsidered in the light of the data now obtained using JBT-101.
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      PubDate: 2014-06-27T14:36:28Z
       
  • Editorial board
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13




      PubDate: 2014-06-27T14:36:28Z
       
  • Graphical contents list
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13




      PubDate: 2014-06-27T14:36:28Z
       
  • Synthesis and antimalarial activity of metal complexes of cross-bridged
           tetraazamacrocyclic ligands
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Timothy J. Hubin , Prince N.-A. Amoyaw , Kimberly D. Roewe , Natalie C. Simpson , Randall D. Maples , TaRynn N. Carder Freeman , Amy N. Cain , Justin G. Le , Stephen J. Archibald , Shabana I. Khan , Babu L. Tekwani , M.O. Faruk Khan
      Using transition metals such as manganese(II), iron(II), cobalt(II), nickel(II), copper(II), and zinc(II), several new metal complexes of cross-bridged tetraazamacrocyclic chelators namely, cyclen- and cyclam-analogs with benzyl groups, were synthesized and screened for in vitro antimalarial activity against chloroquine-resistant (W2) and chloroquine-sensitive (D6) strains of Plasmodium falciparum. The metal-free chelators tested showed little or no antimalarial activity. All the metal complexes of the dibenzyl cross-bridged cyclam ligand exhibited potent antimalarial activity. The Mn2+ complex of this ligand was the most potent with IC50s of 0.127 and 0.157μM against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) P. falciparum strains, respectively. In general, the dibenzyl hydrophobic ligands showed better anti-malarial activity compared to the activity of monobenzyl ligands, potentially because of their higher lipophilicity and thus better cell penetration ability. The higher antimalarial activity displayed by the manganese complex for the cyclam ligand in comparison to that of the cyclen, correlates with the larger pocket of cyclam compared to that of cyclen which produces a more stable complex with the Mn2+. Few of the Cu2+ and Fe2+ complexes also showed improvement in activity but Ni2+, Co2+ and Zn2+ complexes did not show any improvement in activity upon the metal-free ligands for anti-malarial development.
      Graphical abstract image

      PubDate: 2014-06-27T14:36:28Z
       
  • Synthesis and biological evaluation of substituted
           3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors
    • Abstract: Publication date: 15 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14
      Author(s): Nathan J. O’Brien , Martin Brzozowski , David J.D. Wilson , Leslie W. Deady , Belinda M. Abbott
      PDK1 is an important regulator of the PI3K/Akt pathway, which has been found frequently activated in a large number of human cancers. Herein we described the preparation of novel substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors. The synthesis is based around a Buchwald–Hartwig cross-coupling of various 3-bromo-6-substituted-quinolin-2(1H)-ones with three different functionalised anilines. The modular nature of the designed synthesis allowed access to a series of novel inhibitors through derivatisation of a late-stage intermediate. All compounds were screened against isolated PDK1 enzyme, with modest inhibition observed.
      Graphical abstract image

      PubDate: 2014-06-27T14:36:28Z
       
  • Interaction analysis of a ladder-shaped polycyclic ether and model
           transmembrane peptides in lipid bilayers by using Förster resonance
           energy transfer and polarized attenuated total reflection infrared
           spectroscopy
    • Abstract: Publication date: 15 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14
      Author(s): Kazuya Yamada , Haruki Kuriyama , Toshiaki Hara , Michio Murata , Raku Irie , Yanit Harntaweesup , Masayuki Satake , Seketsu Fukuzawa , Kazuo Tachibana
      Ladder-shaped polycyclic ethers (LSPs) are predicted to interact with membrane proteins; however, the underlying mechanism has not been satisfactorily elucidated. It has been hypothesized that LSPs possess non-specific affinity to α-helical segments of transmembrane proteins. To verify this hypothesis, we constructed a model LSP interaction system in a lipid bilayer. We prepared 5 types of α-helical peptides and reconstituted them in liposomes. The reconstitution and orientation of these peptides in the liposomes were examined using polarized attenuated total reflection infrared (ATR-IR) spectroscopy and gel filtration. The results revealed that 4 peptides were retained in liposomes, and 3 of them formed stable transmembrane structures. The interaction between the LSP and the peptides was investigated using Förster resonance energy transfer (FRET). In the lipid bilayer, the LSP strongly recognized the peptides that possessed aligned hydrogen donating groups with leucine caps. We propose that this leucine-capped 16-amino acid sequence is a potential LPS binding motif.
      Graphical abstract image Highlights

      PubDate: 2014-06-27T14:36:28Z
       
  • Novel synthetic route for antimalarial benzo[a]phenoxazine derivative
           SSJ-183 and two active metabolites
    • Abstract: Publication date: 15 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14
      Author(s): Yuki Mizukawa , Jian-Feng Ge , Abu Bakar Md , Isamu Itoh , Christian Scheurer , Sergio Wittlin , Reto Brun , Hiroyuki Matsuoka , Masataka Ihara
      A productive synthesis of benzo[a]phenoxazine derivative SSJ-183 (1), a promising lead for antimalarial agents, was developed using a one pot procedure. Furthermore, N-deethylated metabolite 3 and bis-N,N-deethylated metabolite 4 were synthesized by the application of the method. The metabolites 3 and 4 showed comparable and ∼2-fold increased activities against drug-sensitive and drug-resistant Plasmodium falciparum parasites.
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      PubDate: 2014-06-27T14:36:28Z
       
  • The design and discovery of water soluble
           4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as multitargeted receptor
           tyrosine kinase inhibitors and microtubule targeting antitumor agents
    • Abstract: Publication date: 15 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14
      Author(s): Xin Zhang , Sudhir Raghavan , Michael Ihnat , Jessica E. Thorpe , Bryan C. Disch , Anja Bastian , Lora C. Bailey-Downs , Nicholas F. Dybdal-Hargreaves , Cristina C. Rohena , Ernest Hamel , Susan L. Mooberry , Aleem Gangjee
      The design, synthesis and biological evaluations of fourteen 4-substituted 2,6-dimethylfuro[2,3-d]pyrimidines are reported. Four compounds (11–13, 15) inhibit vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor β (PDGFR-β), and target tubulin leading to cytotoxicity. Compound 11 has nanomolar potency, comparable to sunitinib and semaxinib, against tumor cell lines overexpressing VEGFR-2 and PDGFR-β. Further, 11 binds at the colchicine site on tubulin, depolymerizes cellular microtubules and inhibits purified tubulin assembly and overcomes both βIII-tubulin and P-glycoprotein-mediated drug resistance, and initiates mitotic arrest leading to apoptosis. In vivo, its HCl salt, 21, reduced tumor size and vascularity in xenograft and allograft murine models and was superior to docetaxel and sunitinib, without overt toxicity. Thus 21 affords potential combination chemotherapy in a single agent.
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      PubDate: 2014-06-27T14:36:28Z
       
  • Combination of 2-methoxy-3-phenylsulfonylaminobenzamide and
           2-aminobenzothiazole to discover novel anticancer agents
    • Abstract: Publication date: 15 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14
      Author(s): Huan Li , Xiao-Meng Wang , Juan Wang , Teng Shao , Yi-Ping Li , Qi-Bing Mei , She-Min Lu , San-Qi Zhang
      The fragment of 2-substituted-3-sulfonylaminobenzamide has been proposed to replace the fragment of 2-substituted-3-sulfonylaminopyridine in PI3K and mTOR dual inhibitors to design novel anticancer agents based on bioisostere. The combination of the fragment of 2-substituted-3-sulfonylaminobenzamide with the fragment of 2-aminobenzothiazole or 2-aminothiazolo[5,4-b]pyridine, or 2-amino[1,2,4]triazolo[1,5-a]pyridine produced the novel structures of anticancer agents. As a result, nineteen target compounds were synthesized and characterized. Their antiproliferative activities in vitro were evaluated via MTT assay against four human cancer cell lines including HCT-116, A549, MCF-7 and U-87 MG. The SAR of target compounds was preliminarily discussed. Compound 1g with potent antiproliferative activity was examined for its effect on the AKT and p-AKT473. The anticancer effect of 1g was evaluated in established nude mice HCT-116 xenograft model. The results suggested that compound 1g can block PI3K/AKT/mTOR pathway and significantly inhibit tumor growth. These findings strongly support our assumption that the fragment of benzamide can replace the pyridine ring in some PI3K and mTOR dual inhibitor to design novel anticancer agents.
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      PubDate: 2014-06-27T14:36:28Z
       
  • New coumarin derivatives: Design, synthesis and use as inhibitors of hMAO
    • Abstract: Publication date: 15 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14
      Author(s): Xu He , Yan-Yan Chen , Jing-Bo Shi , Wen-Jiang Tang , Zhi-Xiang Pan , Zhi-Qiang Dong , Bao-An Song , Jun Li , Xin-Hua Liu
      A series new 2H-chromene-3-carboxamides (4a–4i) and S-2H-chromene-3-carbothioates (5j–5t) were synthesized and evaluated as monoamine oxidase A and B inhibitors. Among them, compound 5k (IC50 =0.21μM, IC50 iproniazid =7.65μM) showed the most activity and higher MAO-B selectivity (189.2-fold vs 1-fold) with respect to the MAO-A isoform. The need to clarify at a 3D level some important molecular aspects of discussed SAR, we undertaked a number of docking simulations to better assess. The steric effect was analyzed interms of both posing and scoring by investigating the nature of the binding interactions. The docking results of active compound 5k with hMAO-B complex indicated that conserved residue ILE 199 was important for ligand binding via Sigma–Pi interaction.
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      PubDate: 2014-06-27T14:36:28Z
       
  • Design and synthesis of novel and highly-active pan-histone deacetylase
           (pan-HDAC) inhibitors
    • Abstract: Publication date: 15 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14
      Author(s): Toshihiko Tashima , Hiroaki Murata , Hidehiko Kodama
      Histone deacetylase (HDAC) inhibitions are known to elicit anticancer effects. We designed and synthesized several HDAC inhibitors. Among these compounds, compound 40 exhibited a more than 10-fold stronger inhibitory activity compared with that of suberoylanilide hydroxamic acid (SAHA) against each human HDAC isozyme in vitro (IC50 values of 40: HDAC1, 0.0038μM; HDAC2, 0.0082μM; HDAC3, 0.015μM; HDAC8, 0.0060μM; HDAC4, 0.058μM; HDAC9, 0.0052μM; HDAC6, 0.058μM). The dose of the administered HDAC inhibitors that contain hydroxamic acid as the zinc-binding group may be reduced by 40. Because the carbostyril subunit is a time-tested structural component of drugs and biologically active compounds, 40 most likely exhibits good absorption, distribution, metabolism, excretion, and toxicity (ADMET). Thus, compound 40 is expected to be a promising therapeutic agent or chemical tool for the investigation of life process.
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      PubDate: 2014-06-27T14:36:28Z
       
  • Catechol–rhodanine derivatives: Specific and promiscuous inhibitors
           of Escherichia coli deoxyxylulose phosphate reductoisomerase (DXR)
    • Abstract: Publication date: 15 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14
      Author(s): Catherine Zinglé , Denis Tritsch , Catherine Grosdemange-Billiard , Michel Rohmer
      To develop more effective inhibitors than fosmidomycin, a natural compound which inhibits the deoxyxylulose 5-phosphate reductoisomerase (DXR), the second enzyme of the MEP pathway, we designed molecules possessing on the one hand a catechol that is able to chelate the magnesium dication and on the other hand a group able to occupy the NADPH recognition site. Catechol–rhodanine derivatives (1–6) were synthesized and their potential inhibition was tested on the DXR of Escherichia coli. For the inhibitors 1 and 2, the presence of detergent in the enzymatic assays led to a dramatic decrease of the inhibition suggesting, that these compounds are rather promiscuous inhibitors. The compounds 4 and 5 kept their inhibition capacity in the presence of Triton X100 and could be considered as specific inhibitors of DXR. Compound 4 showed antimicrobial activity against Escherichia coli. The only partial protection of NADPH against the inhibition suggested that the catechol–rhodanine derivatives did not settle in the coenzyme binding site. This paper points out the necessity to include a detergent in the DXR enzymatic assays to avoid false positive when putative hydrophobic inhibitors are tested and especially when the IC50, are in the micromolar range.
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      PubDate: 2014-06-27T14:36:28Z
       
  • A novel and facile synthesis of tetra branched derivatives of
           nociceptin/orphanin FQ
    • Abstract: Publication date: 15 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14
      Author(s): Remo Guerrini , Erika Marzola , Claudio Trapella , Michela Pela’ , Stefano Molinari , Maria Camilla Cerlesi , Davide Malfacini , Anna Rizzi , Severo Salvadori , Girolamo Calo’
      Branched peptides have been found to be useful in several research fields however their synthesis and purification is complicated. Here we present a novel and facile synthesis of tetra branched derivatives of nociceptin/orphanin FQ (N/OFQ). Three N/OFQ tetra branched derivatives were prepared using novel cores (PWT1, PWT2 and PWT3) containing a maleimido moiety. [Cys18]N/OFQ-NH2 was linked to the cores via thiol-Michael reaction characterized by high yield and purity of the desired final product. In the electrically stimulated mouse vas deferens PWT-N/OFQ derivatives mimicked the inhibitory action of the natural sequence showing similar maximal effects and 3 fold higher potencies. The NOP selective antagonist SB-612111 antagonized the effects of N/OFQ and PWT derivatives with similar pK B values (8.02–8.48). In vivo after supraspinal administration PWT2-N/OFQ stimulated food intake in mice mimicking the action of N/OFQ. Compared to the natural peptide PWT2-N/OFQ was 40 fold more potent and elicited larger effects. These findings suggest that the PWT chemical strategy can be successfully applied to biologically active peptides to generate, with unprecedented high purity and yield, tetra branched derivatives displaying an in vitro pharmacological profile similar to that of the natural sequence associated, in vivo, to increased potency and effectiveness.
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      PubDate: 2014-06-27T14:36:28Z
       
  • Macrocyclic diterpenes resensitizing multidrug resistant phenotypes
    • Abstract: Publication date: 15 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14
      Author(s): Mariana A. Reis , Angela Paterna , Ricardo J. Ferreira , Hermann Lage , Maria-José U. Ferreira
      Herein, collateral sensitivity effect was exploited as a strategy to select effective compounds to overcome multidrug resistance in cancer. Thus, eleven macrocyclic diterpenes, namely jolkinol D (1), isolated from Euphorbia piscatoria, and its derivatives (2–11) were evaluated for their activity on three different Human cancer entities: gastric (EPG85-257), pancreatic (EPP85-181) and colon (HT-29) each with a variant selected for resistance to mitoxantrone (EPG85-257RN; EPP85-181RN; HT-29RN) and one to daunorubicin (EPG85-257RD; EPP85-181RD; HT-29RD). Jolkinol D (1) and most of its derivatives (2–11) exhibited significant collateral sensitivity effect towards the cell lines EPG85-257RN (associated with P-glycoprotein overexpression) and HT-29RD (altered topoisomerase II expression). The benzoyl derivative, jolkinoate L (8) demonstrated ability to target different cellular contexts with concomitant high antiproliferative activity. These compounds were previously assessed as P-glycoprotein modulators, at non-cytotoxic doses, on MDR1-mouse lymphoma cells. A regression analysis between the antiproliferative activity presented herein and the previously assessed P-glycoprotein modulatory effect showed a strong relation between the compounds that presented both high P-glycoprotein modulation and cytotoxicity.
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      PubDate: 2014-06-27T14:36:28Z
       
  • Tyrosinase-catalyzed hydroxylation of hydroquinone, a depigmenting agent,
           to hydroxyhydroquinone: A kinetic study
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): María del Mar García-Molina , Jose Luis Muñoz Muñoz , Francisco Martinez-Ortiz , José Rodriguez Martinez , Pedro Antonio García-Ruiz , José Neptuno Rodriguez-López , Francisco García-Cánovas
      Hydroquinone (HQ) is used as a depigmenting agent. In this work we demonstrate that tyrosinase hydroxylates HQ to 2-hydroxyhydroquinone (HHQ). Oxy-tyrosinase hydroxylates HQ to HHQ forming the complex met-tyrosinase-HHQ, which can evolve in two different ways, forming deoxy-tyrosinase and p-hydroxy-o-quinone, which rapidly isomerizes to 2-hydroxy-p-benzoquinone or on the other way generating met-tyrosinase and HHQ. In the latter case, HHQ is rapidly oxidized by oxygen to generate 2-hydroxy-p-benzoquinone, and therefore, it cannot close the enzyme catalytic cycle for the lack of reductant (HHQ). However, in the presence of hydrogen peroxide, met-tyrosinase (inactive on hydroquinone) is transformed into oxy-tyrosinase, which is active on HQ. Similarly, in the presence of ascorbic acid, HQ is transformed into 2-hydroxy-p-benzoquinone by the action of tyrosinase; however, in this case, ascorbic acid reduces met-tyrosinase to deoxy-tyrosinase, which after binding to oxygen, originates oxy-tyrosinase. This enzymatic form is now capable of reacting with HQ to generate p-hydroxy-o-quinone, which rapidly isomerizes to 2-hydroxy-p-benzoquinone. The formation of HHQ during the action of tyrosinase on HQ is demonstrated by means of high performance liquid chromatography mass spectrometry (HPLC–MS) by using hydrogen peroxide and high ascorbic acid concentrations. We propose a kinetic mechanism for the tyrosinase oxidation of HQ which allows us the kinetic characterization of the process. A possible explanation of the cytotoxic effect of HQ is discussed.
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      PubDate: 2014-06-27T14:36:28Z
       
  • Structure-based efforts to optimize a non-β-lactam inhibitor of AmpC
           β-lactamase
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Jenna M. Hendershot , Uma J. Mishra , Robert P. Smart , William Schroeder , Rachel A. Powers
      β-Lactams are the most widely prescribed class of antibiotics, yet their efficacy is threatened by expression of β-lactamase enzymes, which hydrolyze the defining lactam ring of these antibiotics. To overcome resistance due to β-lactamases, inhibitors that do not resemble β-lactams are needed. A novel, non-β-lactam inhibitor for the class C β-lactamase AmpC (3-[(4-chloroanilino)sulfonyl]thiophene-2-carboxylic acid; K i 26μM) was previously identified. Based on this lead, a series of compounds with the potential to interact with residues at the edge of the active site were synthesized and tested for inhibition of AmpC. The length of the carbon chain spacer was extended by 1, 2, 3, and 4 carbons between the integral thiophene ring and the benzene ring (compounds 4, 5, 6, and 7). Compounds 4 and 6 showed minimal improvement over the lead compound (K i 18 and 19μM, respectively), and compound 5 inhibited to the same extent as the lead. The X-ray crystal structures of AmpC in complexes with compounds 4, 5, and 6 were determined. The complexes provide insight into the structural reasons for the observed inhibition, and inform future optimization efforts in this series.
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      PubDate: 2014-06-27T14:36:28Z
       
  • Synthesized quercetin derivatives stimulate melanogenesis in B16 melanoma
           cells by influencing the expression of melanin biosynthesis proteins MITF
           and p38 MAPK
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Kosei Yamauchi , Tohru Mitsunaga , Mizuho Inagaki , Tohru Suzuki
      In order to understand the effect of structure–activity relationships on melanogenesis using B16 melanoma cells, 19 quercetin derivatives were synthesized. Among the synthesized compounds, 3-O-methylquercetin (11) and 3′,4′,7-O-trimethylquercetin (14) increased melanin content more potently than the positive control theophylline, while exhibiting low cytotoxicity. Compound 11 exhibited less melanogenesis-stimulating activity than compound 14. However, 11 increased the expression of tyrosinase and tyrosinase-related protein 1 (TRP-1) to a greater extent than 14, thereby suggesting that melanogenesis in melanoma cells does not depend solely on the expression of the enzymes catalyzing melanin biosynthesis. Furthermore, 14 also stimulated the expression of the microphthalmia-associated transcription factor (MITF) and p-p38 mitogen activated protein kinase (MAPK), while they were not increased by 11. These results suggest that 11 may enhance the expression of tyrosinase and TRP-1 by regulating the proteasomal degradation of melanogenic enzymes and/or by activating other transcriptional factors regulating enzyme expression.
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      PubDate: 2014-06-27T14:36:28Z
       
  • Preparation, anticholinesterase activity and molecular docking of new
           lupane derivatives
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): María Julia Castro , Victoria Richmond , Carmen Romero , Marta S. Maier , Ana Estévez-Braun , Ángel G. Ravelo , María Belén Faraoni , Ana Paula Murray
      A set of twenty one lupane derivatives (2–22) was prepared from the natural triterpenoid calenduladiol (1) by transformations on the hydroxyl groups at C-3 and C-16, and also on the isopropenyl moiety. The derivatives were tested for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and some structure–activity relationships were outlined with the aid of enzyme kinetic studies and docking modelization. The most active compound resulted to be 3,16,30-trioxolup-20(29)-ene (22), with an IC50 value of 21.5μM for butyrylcholinesterase, which revealed a selective inhibitor profile towards this enzyme.
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      PubDate: 2014-06-27T14:36:28Z
       
  • Design and synthesis of fluorescent probes for GPR54
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Masato Kaneda , Ryosuke Misu , Hiroaki Ohno , Akira Hirasawa , Nahoko Ieda , Yoshihisa Uenoyama , Hiroko Tsukamura , Kei-ichiro Maeda , Shinya Oishi , Nobutaka Fujii
      Kisspeptins are neuropeptides that induce the secretion of gonadotropin-releasing hormone via the activation of the cognate receptor, G-protein coupled receptor 54 (GPR54). The kisspeptin–GPR54 axis is associated with the onset of puberty and the maintenance of the reproductive system. In this study, several fluorescent probes have been designed and synthesized for rat GPR54 through the modification of the N-terminus of rat kisspeptins to allow for the visualization of the expression and localization of kisspeptin receptor(s) in living cells and native tissues. The tetramethylrhodamine (TMR) and rhodamine green (RG)-labeled kisspeptins exhibited good binding and agonistic activities towards GPR54, and the results of the application studies demonstrated that these fluorescent probes could be used effectively for the detection of GPR54 receptors in flow cytometry and confocal microscopy experiments.
      Graphical abstract image Highlights

      PubDate: 2014-06-27T14:36:28Z
       
  • Carbonic anhydrase inhibitors: Synthesis, molecular docking, cytotoxic and
           inhibition of the human carbonic anhydrase isoforms I, II, IX, XII with
           novel benzenesulfonamides incorporating pyrrole, pyrrolopyrimidine and
           fused pyrrolopyrimidine moieties
    • Abstract: Publication date: 15 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14
      Author(s): Mostafa M. Ghorab , Mansour S. Alsaid , Mariangela Ceruso , Yassin M. Nissan , Claudiu T. Supuran
      A series of novel pyrroles, pyrrolopyrimidines, pyrazolopyrrolopyrimidine, triazolopyrrolopyrimidines, tetrazolopyrrolopyrimidine, triazinopyrrolopyrimidines and pyrrolopyrimidotriazepines bearing the biologically active benzenesulfonamide moiety were synthesized by using pyrrole-o-amino-carbonitrile as key intermediate. All the synthesized compounds were evaluated for their in vitro carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects against the human (h) isoforms hCA I, II, IX and XII. Among the tested derivatives, compounds 16, 18 and 20–24 showed potent activity as inhibitors for the tumor associated transmembrane isoforms (hCA IX and XII) in the nanomolar and subnanomolar range, with high selectivity. All compounds underwent cytotoxic activity assays on human breast cancer cell line (MCF-7) showing effective activity, comparable to that of the clinically used drug doxorubicin.
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      PubDate: 2014-06-27T14:36:28Z
       
  • Combination of cyclohexane and piperazine based κ-opioid receptor
           agonists: Synthesis and pharmacological evaluation of
           trans,trans-configured perhydroquinoxalines
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Christian Bourgeois , Elena Werfel , Dirk Schepmann , Bernhard Wünsch
      Desymmetrization of the pseudochiral (2r)-configured cyclohexane-1,2,3-triamines 8 with dimethyl oxalate led to racemic aminoquinoxaline-2,3-diones 9. Selective introduction of the κ pharmacophoric structural elements pyrrolidine and 3,4-dichlorophenylacetamide with a two-carbon distance afforded conformationally restricted κ agonists 13–15 based on the quinoxaline ring system. In competitive radioligand receptor binding studies the benzylamine 13b, the secondary amine 14b, and the carbamate 15 displayed high κ receptor affinity. The K i value of the lead compound derived methoxycarbonyl derivative 15 is 9.7nM. However, the κ affinity of 15 is exceeded by 13b and 14b with a basic functional group instead of the methoxycarbonyl group in 1-position of the quinoxaline system. The chlorine atoms of the dichlorophenylacetyl residue are essential, since the corresponding phenylacetyl analogs show considerably reduced κ affinity. The potent κ ligands 13b, 14b and 15 are selective over the related μ- and δ-opioid receptors, σ1, σ2 and NMDA receptors. In the [35S]GTPγS-binding assay 13b behaved as partial agonist with lower activity than U-69,593.
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      PubDate: 2014-06-27T14:36:28Z
       
  • 4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein
           tyrosine phosphatase 1B
    • Abstract: Publication date: 15 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14
      Author(s): Ying Zhi , Li-Xin Gao , Yi Jin , Chun-Lan Tang , Jing-Ya Li , Jia Li , Ya-Qiu Long
      Protein tyrosine phosphatase 1B is a negative regulator in the insulin and leptin signaling pathways, and has emerged as an attractive target for the treatment of type 2 diabetes and obesity. However, the essential pharmacophore of charged phosphotyrosine or its mimetic confer low selectivity and poor cell permeability. Starting from our previously reported aryl diketoacid-based PTP1B inhibitors, a drug-like scaffold of 4-quinolone-3-carboxylic acid was introduced for the first time as a novel surrogate of phosphotyrosine. An optimal combination of hydrophobic groups installed at C-6, N-1 and C-3 positions of the quinolone motif afforded potent PTP1B inhibitors with low micromolar IC50 values. These 4-quinolone-3-carboxylate based PTP1B inhibitors displayed a 2–10 fold selectivity over a panel of PTP’s. Furthermore, the bidentate inhibitors of 4-quinolone-3-carboxylic acids conjugated with aryl diketoacid or salicylic acid were cell permeable and enhanced insulin signaling in CHO/hIR cells. The kinetic studies and molecular modeling suggest that the 4-quinolone-3-carboxylates act as competitive inhibitors by binding to the PTP1B active site in the WPD loop closed conformation. Taken together, our study shows that the 4-quinolone-3-carboxylic acid derivatives exhibit improved pharmacological properties over previously described PTB1B inhibitors and warrant further preclinical studies.
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      PubDate: 2014-06-27T14:36:28Z
       
  • Synthesis and evaluation of (E)-2-(acrylamido)cyclohex-1-enecarboxylic
           acid derivatives as HCA1, HCA2, and HCA3 receptor agonists
    • Abstract: Publication date: 15 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14
      Author(s): Olga Bobileva , Rasma Bokaldere , Vija Gailite , Ilze Kaula , Martins Ikaunieks , Gunars Duburs , Ramona Petrovska , Ilona Mandrika , Janis Klovins , Einars Loza
      2-(3-(Naphthalen-2-yl)propanamido)cyclohex-1-enecarboxylic acid and its 6-hydroxynaphthalen-2-yl analogue are well-known hydroxyl-carboxylic acid (HCA) receptor HCA2 agonists. A series of novel aryl derivatives of 2-amidocyclohex-1-ene carboxylic acid that contained rigidity elements, such as an E-double bond, triple bond, and trans or cis-substituted cyclopropane rings, instead of the saturated ethane linker in the amide part of the molecules were designed and synthesized, and the derivatives’ potency for the activation of HCA1, HCA2, and HCA3 receptors by 3′–5′-cyclic adenosine monophosphate (cAMP) assay were evaluated. The SAR studies revealed that the rigidifying of appropriate molecules enabled modulation of the potency and selectivity of the HCA2 receptor activation.
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      PubDate: 2014-06-27T14:36:28Z
       
  • Photo-triggered molecular release based on auto-degradable
           polymer-containing organic–inorganic hybrids
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Hiroshi Okada , Kazuo Tanaka , Wataru Ohashi , Yoshiki Chujo
      The photo-triggered molecular release from the organic–inorganic polymer hybrids is presented in this manuscript. Initially, the preparation of the auto-degradable polymer is explained with the photo-cleavable group at the end of the polymer main-chain. The silica-based dye-loaded hybrids containing these polymers were fabricated. It was found that by UV irradiation, the end capping was removed, and then the auto-degradation occurs through the polymer main-chain. Finally, the molecular release of the loaded dyes was accomplished in various media by the UV irradiation. In particular, it was shown that both of hydrophobic and hydrophilic dyes can be applied in this system.
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      PubDate: 2014-06-27T14:36:28Z
       
  • Discovery of novel oxindole derivatives as potent α-glucosidase
           inhibitors
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Momin Khan , Muhammad Yousaf , Abdul Wadood , Muhammad Junaid , Muhammad Ashraf , Umber Alam , Muhammad Ali , Muhammad Arshad , Zahid Hussain , Khalid Mohammed Khan
      A series of 6-chloro-3-oxindole derivatives 1–25 were synthesized in high yields by the reaction of 6-chlorooxindole with different aromatic aldehydes in the presence of piperidine. All the synthesized compounds were isolated with E configuration. The structures were confirmed using spectroscopic techniques, including 1H NMR and EIMS. These compounds showed varying degree of yeast α-glucosidase inhibition and seven were found as potent inhibitors of the enzyme. Compounds 2, 3, 4, 5, 6, 23, and 25 exhibited IC50 values 2.71±0.007, 11.41±0.005, 37.93±0.002, 15.19±0.004, 24.71±0.007, 17.33±0.001, and 14.2±0.002μM, respectively, as compared to standard acarbose (IC50, 38.25±0.12μM). Docking studies helped to find interactions between the enzyme and the active compounds. As a result of this study, oxindoles have been discovered as a new class of α-glucosidase inhibitors which have not been reported earlier.
      Graphical abstract image Highlights A series of 6-chloro-3-oxindole derivatives 1–25 were synthesized and screened for their α-glucosidase inhibition activity in vitro. In addition, molecular docking studies were also carried out using the MOE-Dock program to predict their structure–activity relationship.

      PubDate: 2014-06-27T14:36:28Z
       
  • Synthesis of a novel legumain-cleavable colchicine prodrug with
           cell-specific toxicity
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Robert Løvsletten Smith , Ove Alexander Høgmoen Åstrand , Luan Minh Nguyen , Tina Elvestrand , Gunnar Hagelin , Rigmor Solberg , Harald Thidemann Johansen , Pål Rongved
      Conventional chemotherapy has undesirable toxic side-effects to healthy tissues due to low cell selectivity of cytotoxic drugs. One approach to increase the specificity of a cytotoxic drug is to make a less toxic prodrug which becomes activated at the tumour site. The cysteine protease legumain have remarkable restricted substrate specificity and is the only known mammalian asparaginyl (Asn) endopeptidase. Over-expression of legumain is reported in cancers and unstable atherosclerotic plaques, and utilizing legumain is a promising approach to activate prodrugs. In this study we have synthesized the legumain-cleavable peptide sequence N-Boc-Ala-Ala-Asn-Val-OH. The peptide was subsequently conjugated to deacetyl colchicine during three steps to produce Suc-Ala-Ala-Asn-Val-colchicine (prodrug) with >90% chemical purity. Several cell lines with different expressions and activities of legumain were used to evaluate the general toxicity, specificity and efficacy of the microtubule inhibitor colchicine, valyl colchicine and the legumain-cleavable colchicine prodrug. The prodrug was more toxic to the colorectal cancer HCT116 cells (expressing both the 36kDa active and 56kDa proform of legumain) than SW620 cells (only expressing the 56kDa prolegumain) indicating a relationship between toxicity of the prodrug and activity of legumain in the cells. Also, in monoclonal legumain over-expressing HEK293 cells the prodrug toxicity was higher compared to native HEK293 cells. Furthermore, co-administration of the prodrug either with the potent legumain inhibitor cystatin E/M or the endocytosis inhibitor Dyngo-4a inhibited cell death, indicating that the prodrug toxicity was dependent on both asparaginyl endopeptidase activity and endocytosis. This colchicine prodrug adds to a legumain-activated prodrug strategy approach and could possibly be of use both in targeted anticancer and anti-inflammatory therapy.
      Graphical abstract image

      PubDate: 2014-06-27T14:36:28Z
       
  • Inhibition by active site directed covalent modification of human
           glyoxalase I
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Ronald J. Holewinski , Donald J. Creighton
      The glyoxalase pathway is responsible for conversion of cytotoxic methylglyoxal (MG) to d-lactate. MG toxicity arises from its ability to form advanced glycation end products (AGEs) on proteins, lipids and DNA. Studies have shown that inhibitors of glyoxalase I (GLO1), the first enzyme of this pathway, have chemotherapeutic effects both in vitro and in vivo, presumably by increasing intracellular MG concentrations leading to apoptosis and cell death. Here, we present the first molecular inhibitor, 4-bromoacetoxy-1-(S-glutathionyl)-acetoxy butane (4BAB), able to covalently bind to the free sulfhydryl group of Cys60 in the hydrophobic binding pocket adjacent to the enzyme active site and partially inactivate the enzyme. Our data suggests that partial inactivation of homodimeric GLO1 is due to the modification at only one of the enzymatic active sites. Although this molecule may have limited use pharmacologically, it may serve as an important template for the development of new GLO1 inhibitors that may combine this strategy with ones already reported for high affinity GLO1 inhibitors, potentially improving potency and specificity.
      Graphical abstract image

      PubDate: 2014-06-27T14:36:28Z
       
  • Synthesis of triterpenoid triazine derivatives from allobetulone and
           betulonic acid with biological activities
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Thuc Dinh Ngoc , Nico Moons , Youngju Kim , Wim De Borggraeve , Anastassiya Mashentseva , Graciela Andrei , Robert Snoeck , Jan Balzarini , Wim Dehaen
      The synthetic transformation and modification of natural products with the aim to improve the biological properties is an area of current interest. The triterpenoids betulin and betulinic acid are very abundant in nature and now are commercially available. In our study, starting from betulin and betulinic acid, we obtained allobetulone and betulonic acid in a few synthetic steps. The ketone function at the A-ring was used as the starting point for the synthesis of a series of 1,2,4-triazine-fused triterpenoids. The alkylation and Liebeskind–Srogl coupling were used for further substitution of 1,2,4-triazines, and the intramolecular hetero Diels–Alder reaction leads to interesting fused thienopyridine derivatives. All new compounds were tested for their cytostatic activities against murine leukemia L1210, human cervix carcinoma HeLa and human lymphoblast CEM tumor cells. The results show that some triterpenoid triazine betulonic acid derivatives have a promising cytostatic activity in vitro and could be used as potential leads for the development of new type of anti-cancer agents. Several compounds were also endowed with anti-HCMV activity in the low micromolar range.
      Graphical abstract image

      PubDate: 2014-06-27T14:36:28Z
       
  • Identification and characterization of a new reversible MAGL inhibitor
    • Abstract: Publication date: 1 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
      Author(s): Tiziano Tuccinardi , Carlotta Granchi , Flavio Rizzolio , Isabella Caligiuri , Vittoria Battistello , Giuseppe Toffoli , Filippo Minutolo , Marco Macchia , Adriano Martinelli
      Monoacylglycerol lipase is a serine hydrolase that play a major role in the degradation of 2-arachidonoylglycerol, an endocannabinoid neurotransmitter implicated in several physiological processes. Recent studies have shown the possible role of MAGL inhibitors as anti-inflammatory, anti-nociceptive and anti-cancer agents. The use of irreversible MAGL inhibitors determined an unwanted chronic MAGL inactivation, which acquires a functional antagonism function of the endocannabinoid system. However, the application of reversible MAGL inhibitors has not yet been explored, mainly due to the scarcity of known compounds possessing efficient reversible inhibitory activities. In this study we reported the first virtual screening analysis for the identification of reversible MAGL inhibitors. Among the screened compounds, the (4-(4-chlorobenzoyl)piperidin-1-yl)(4-methoxyphenyl)methanone (CL6a) is a promising reversible MAGL inhibitor lead (K i =8.6μM), which may be used for the future development of a new class of MAGL inhibitors. Furthermore, the results demonstrate the validity of the methodologies that we followed, encouraging additional screenings of other commercial databases.
      Graphical abstract image

      PubDate: 2014-06-27T14:36:28Z
       
  • Design, synthesis and biological evaluation of novel
           6,7-disubstituted-4-phenoxyquinoline derivatives bearing
           4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties as c-Met kinase
           inhibitors
    • Abstract: Publication date: 15 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14
      Author(s): Zijian Liu , Rui Wang , Ruiming Guo , Jinxing Hu , Ruijuan Li , Yanfang Zhao , Ping Gong
      A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against H460, MKN-45, HT-29 and MDA-MB-231 cancer cell lines in vitro. Most compounds displayed good to excellent potency against four tested cancer cell lines as compared with foretinib. The SAR analyses indicated that compounds with halogen groups, especially fluoro groups at 4-position on the phenyl ring (moiety B) were more effective than those with nitro groups or methoxy groups. In this study, a promising compound 33 (c-Met IC50 =1.63nM) was identified, which showed the most potent antitumor activities with IC50 values of 0.055μM, 0.071μM, 0.13μM, and 0.43μM against H460, MKN-45, HT-29 and MDA-MB-231 cell lines, respectively.
      Graphical abstract image

      PubDate: 2014-06-27T14:36:28Z
       
  • Design, synthesis, antiviral and cytostatic activity of
           ω-(1H-1,2,3-triazol-1-yl)(polyhydroxy)alkylphosphonates as acyclic
           nucleotide analogues
    • Abstract: Publication date: 15 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14
      Author(s): Iwona E. Głowacka , Jan Balzarini , Graciela Andrei , Robert Snoeck , Dominique Schols , Dorota G. Piotrowska
      The efficient synthesis of a new series of polyhydroxylated dibenzyl ω-(1H-1,2,3-triazol-1-yl)alkylphosphonates as acyclic nucleotide analogues is described starting from dibenzyl ω-azido(polyhydroxy)alkylphosphonates and selected alkynes under microwave irradiation. Selected O,O-dibenzylphosphonate acyclonucleotides were transformed into the respective phosphonic acids. All compounds were evaluated in vitro for activity against a broad variety of DNA and RNA viruses and for cytostatic activity against murine leukemia L1210, human T-lymphocyte CEM and human cervix carcinoma HeLa cells. Compound (1S,2S)-16b exhibited antiviral activity against Influenza A H3N2 subtype (EC50 =20μM—visual CPE score; EC50 =18μM—MTS method; MCC >100μM, CC50 >100μM) in Madin Darby canine kidney cell cultures (MDCK), and (1S,2S)-16k was active against vesicular stomatitis virus and respiratory syncytial virus in HeLa cells (EC50 =9 and 12μM, respectively). Moreover, compound (1R,2S)-16l showed activity against both herpes simplex viruses (HSV-1, HSV-2) in HEL cell cultures (EC50 =2.9 and 4μM, respectively) and feline herpes virus in CRFK cells (EC50 =4μM) but at the same time it exhibited cytotoxicity toward uninfected cell (MCC⩾4μM). Several other compounds have been found to inhibit proliferation of L1210, CEM as well as HeLa cells with IC50 in the 4–50μM range. Among them compounds (1S,2S)- and (1R,2S)-16l were the most active (IC50 in the 4–7μM range).
      Graphical abstract image Highlights Compound (1S,2S)-16b exhibited antiviral activity against Influenza A H3N2 subtype (EC50 =20μM—visual CPE score; EC50 =18μM—MTS method; MCC >100μM, CC50 >100μM) in Madin Darby canine kidney cell cultures (MDCK), and (1S,2S)-16k against vesicular stomatitis virus and respiratory syncytial virus in HeLa cells (EC50 =9 and 12μM, respectively). Moreover, (1R,2S)-16l showed activity against both herpes simplex viruses (HSV-1, HSV-2) in HEL cell cultures (EC50 =2.9 and 4μM, respectively) and feline herpes virus in CRFK cells (EC50 =4μM) but at the same time it exhibited cytotoxicity toward uninfected cell (MCC⩾4μM). Several compounds (1S,2S)-16i–l and (1R,2S)-16f–l inhibited proliferation of L1210, CEM as well as HeLa cells with IC50’s in the 4–50μM range.

      PubDate: 2014-06-27T14:36:28Z
       
  • Novel 3-arylfuran-2(5H)-one-fluoroquinolone hybrid: Design, synthesis and
           evaluation as antibacterial agent
    • Abstract: Publication date: 15 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14
      Author(s): Xu-Dong Wang , Wei Wei , Peng-Fei Wang , Yun-Tao Tang , Rui-Cheng Deng , Biao Li , Sha-Sha Zhou , Jing-Wen Zhang , Lei Zhang , Zhu-Ping Xiao , Hui Ouyang , Hai-Liang Zhu
      3-Arylfuran-2(5H)-one, a novel antibacterial pharmacophore targeting tyrosyl-tRNA synthetase (TyrRS), was hybridized with the clinically used fluoroquinolones to give a series of novel multi-target antimicrobial agents. Thus, twenty seven 3-arylfuran-2(5H)-one-fluoroquinolone hybrids were synthesized and evaluated for their antimicrobial activities. Some of the hybrids exhibited merits from both parents, displaying a broad spectrum of activity against resistant strains including both Gram-negative and Gram-positive bacteria. The most potent compound (11) in antibacterial assay shows MIC50 of 0.11μg/mL against Multiple drug resistant Escherichia coli, being about 51-fold more potent than ciprofloxacin. The enzyme assays reveal that 11 is a potent multi-target inhibitor with IC50 of 1.15±0.07μM against DNA gyrase and 0.12±0.04μM against TyrRS, respectively. Its excellent inhibitory activities against isolated enzymes and intact cells strongly suggest that 11 deserves to further research as a novel antibiotic.
      Graphical abstract image

      PubDate: 2014-06-27T14:36:28Z
       
  • Antiplasmodial activity of new 4-aminoquinoline derivatives against
           chloroquine resistant strain
    • Abstract: Publication date: 15 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14
      Author(s): Manish Sinha , Vasanth R. Dola , Pooja Agarwal , Kumkum Srivastava , Wahajul Haq , Sunil K. Puri , Seturam B. Katti
      Emergence and spread of multidrug resistant strains of Plasmodium falciparum has severely limited the antimalarial chemotherapeutic options. In order to overcome the obstacle, a set of new side-chain modified 4-aminoquinolines were synthesized and screened against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of P. falciparum. The key feature of the designed molecules is the use of methylpiperazine linked α, β3- and γ-amino acids to generate novel side chain modified 4-aminoquinoline analogues. Among the evaluated compounds, 20c and 30 were found more potent than CQ against K1 and displayed a four-fold and a three-fold higher activity respectively, with a good selectivity index (SI=5846 and 11,350). All synthesized compounds had resistance index between 1.06 and >14.13 as against 47.2 for chloroquine. Biophysical studies suggested that this series of compounds act on heme polymerization target.
      Graphical abstract image

      PubDate: 2014-06-27T14:36:28Z
       
  • Structure–activity relationship study of non-steroidal NPC1L1
           ligands identified through cell-based assay using pharmacological
           chaperone effect as a readout
    • Abstract: Publication date: 15 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14
      Author(s): Fumika Karaki , Kenji Ohgane , Hiromitsu Fukuda , Masahiko Nakamura , Kosuke Dodo , Yuichi Hashimoto
      Niemann-Pick type C1-like 1 (NPC1L1) is an intestinal cholesterol transporter that is known to be the target of the cholesterol absorption inhibitor ezetimibe. We previously discovered steroidal NPC1L1 ligands by using a novel cell-based assay that employs pharmacological chaperone effect as a readout. Those steroid derivatives bound to a site different from both the sterol-binding domain and the ezetimibe-binding site, implying that they may be a novel class of NPC1L1 inhibitors with a distinct mode of action. As an extension of that work, we aimed here to find non-steroidal NPC1L1 ligands, which may be better candidates for clinical application than steroidal ligands, by using the same assay to screen our focused library of ligands for liver X receptor (LXR), a nuclear receptor that recognizes oxysterols as endogenous ligands. Here we describe identification of a novel class of NPC1L1 ligands with a ring-fused quinolinone scaffold, and an analysis of the structure–activity relationships of their derivatives as NPC1L1 ligands.
      Graphical abstract image

      PubDate: 2014-06-27T14:36:28Z
       
  • Synthesis of truncated analogues of preptin-(1–16), and
           investigation of their ability to stimulate osteoblast proliferation
    • Abstract: Publication date: 15 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14
      Author(s): Renata Kowalczyk , Sung H. Yang , Margaret A. Brimble , Karen E. Callon , Maureen Watson , Young-Eun Park , Jillian Cornish
      Preptin, a 34-amino acid residue peptide hormone is co-secreted with insulin from the β-pancreatic cells and is active in fuel metabolism. We have previously established that a shorter fragment of preptin, namely preptin-(1–16), stimulates bone growth by proliferation and increasing the survival rate of osteoblasts. This was demonstrated in both in vitro and in vivo models. These findings suggest that preptin-(1–16) could play an important role in the anabolic therapy of osteoporosis. However, due to the large size of the peptide it is not an ideal therapeutic agent. The aim of this study was to identify the shortest preptin analogue that retains or even increases the bone anabolic activity as compared to the parent preptin-(1–16) peptide. Truncations were made in a methodical manner from both the N-terminus and the C-terminus of the peptide, and the effect of these deletions on the resulting biological activity was assessed. In order to improve the enzymatic stability of the shortest yet active analogue identified, ruthenium-catalysed ring closing metathesis was used to generate a macrocyclic peptide using allylglycine residues as handles for ring formation. We have successfully identified a short 8-amino acid preptin (1–8) fragment that retains an anabolic effect on the proliferation of primary rat osteoblasts and enhances bone nodule formation. Preptin (1–8) is a useful lead compound for the development of orally active therapeutics for the treatment of osteoporosis.
      Graphical abstract image

      PubDate: 2014-06-27T14:36:28Z
       
  • Editorial board
    • Abstract: Publication date: 15 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14




      PubDate: 2014-06-27T14:36:28Z
       
  • Graphical contents list
    • Abstract: Publication date: 15 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14




      PubDate: 2014-06-27T14:36:28Z
       
  • Triglyceride-lowering agents
    • Abstract: Publication date: 15 July 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14
      Author(s): Nariman F. Salakhutdinov , Sergey S. Laev
      This review is the first attempt at systematization of the literature data on the structures and activities of triglyceride-lowering agents which used in medical practice or are in development. The effects and mechanisms of action of statins, squalene synthase inhibitors, fibrates, PPARα and PPARα/γ agonists, nicotinic acid, omega-3 fatty acids and some other molecular targets were considered. Unfortunately, to date, harmless and effective triglyceride-lowering drug still does not exist and there is still need for development of better triglyceride-lowering agents.
      Graphical abstract image

      PubDate: 2014-06-27T14:36:28Z
       
  • Sulfur, selenium and tellurium pseudopeptides: synthesis and biological
           evaluation
    • Abstract: Publication date: Available online 21 May 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Saad Shaaban , Florenz Sasse , Torsten Burkholz , Claus Jacob
      A new series of sulfur, selenium and tellurium peptidomimetic compounds was prepared employing the Passerini and Ugi isocyanide based multicomponent reactions (IMCRs). These reactions were clearly superior to conventional methods traditionally used for organoselenium and organotellurium synthesis, such as classical nucleophilic substitution and coupling methods. From the biological point of view, these compounds are of considerable interest because of suspected anticancer and antimicrobial activities. While the sulfur and selenium containing compounds generally did not show either anticancer or antimicrobial activities, their tellurium based counterparts frequently exhibited antimicrobial activity and were also cytotoxic. Some of the compounds synthesized even showed selective activity against certain cancer cells in cell culture. These compounds induced a cell cycle delay in the G0/G1 phase. At closer inspection, the ER and the actin cytoskeleton appeared to be the primary cellular targets of these tellurium compounds, in line with some of our previous studies. As most of these peptidomimetic compounds also comply with Lipinski’s Rule of Five, they promise good bioavailability, which needs to be studied as part of future investigations.
      Graphical abstract image Highlights

      PubDate: 2014-05-26T21:49:48Z
       
 
 
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