Kooperativer Bibliotheksverbund

Berlin Brandenburg

and
and

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
Type of Medium
Language
Year
  • 1
    Language: English
    In: Journal of medicinal chemistry, 14 July 2011, Vol.54(13), pp.4490-507
    Description: Various inflammatory diseases are associated with the excessive formation of leukotrienes (LTs) and prostaglandins (PGs). Herein, we present a novel class of dual inhibitors of 5-lipoxygenase (5-LO) and microsomal prostaglandin E(2) synthase-1 (mPGES-1), key enzymes in the formation of LTs and PGE(2), respectively. On the basis of the structure of 2-[(4,6-diphenethoxypyrimidin-2-yl)thio]hexanoic acid (1), we performed a detailed SAR analysis, and mechanistic studies were carried out to elucidate the mode of 5-LO inhibition. Interestingly, the pyrimidine ring including the thioether of 1 could be replaced by a simple benzyl or a benzylidene moiety yielding a novel series of bioactive 2-benzylidene- and 2-benzylhexanoic acids exemplified by 2-(2,3-diphenethoxybenzylidene)hexanoic acid, 29 (IC(50) 5-LO = 0.8 μM; mPGES-1 = 1.1 μM). Importantly, none of the novel bioactive derivatives strongly inhibited cyclooxygenase activities. Together, we provide novel promising lead compounds for the treatment of inflammatory diseases valuable for further investigations in vivo.
    Keywords: Anti-Inflammatory Agents, Non-Steroidal -- Chemical Synthesis ; Benzene Derivatives -- Chemical Synthesis ; Caproates -- Chemical Synthesis ; Intramolecular Oxidoreductases -- Antagonists & Inhibitors ; Lipoxygenase Inhibitors -- Chemical Synthesis ; Microsomes -- Enzymology ; Pyrimidines -- Chemical Synthesis
    ISSN: 00222623
    E-ISSN: 1520-4804
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 2
    Language: English
    In: Bioorganic & Medicinal Chemistry Letters, 15 August 2014, Vol.24(16), pp.4048-4052
    Description: Peroxisome proliferator-activated receptors (PPARs) are attractive targets for the treatment of the metabolic syndrome. Especially a combination of PPARα and PPARγ agonistic activity seems worthwhile to be pursued. Herein we present the design and synthesis of a series of pirinixic acid derivatives as potent PPARα particularly dual PPARα/γ agonists with 2-((4-chloro-6-((4-(phenylamino)phenyl)amino)pyrimidin-2-yl)thio)octanoicacid having the highest potential. Our investigations based on molecular docking and structure–activity relationship (SAR) studies elucidated structural determinants affecting the potency at PPARα. A diphenylamine-scaffold seems to play a key role. Careful in silico analysis revealed an essential role for a hydrogen bond between the diphenylamine and a water cluster. We confirmed this hypothesis using a mutated PPARα LBD in our transactivation assay to disrupt the water cluster and to validate the proposed interaction.
    Keywords: Metabolic Syndrome ; Peroxisome Proliferator-Activated Receptor ; Dual Pparα/Γ Agonist ; Structure–Activity Relationship ; Site-Directed Mutagenesis ; Medicine ; Chemistry ; Anatomy & Physiology
    ISSN: 0960-894X
    E-ISSN: 1464-3405
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 3
    Language: English
    In: Archiv der Pharmazie, November 2010, Vol.343(11‐12), pp.625-630
    Description: Fatty acid mimetics such as pirinixic acid (PA) derivatives and 2‐(phenylthio)alkanoic acid derivatives are drug‐like small molecules with an interesting pharmacological profile. Previously, we have characterized PA derivatives (., ) as dual agonists of peroxisome proliferator‐activated receptors (PPARs) α and γ and as inhibitors of microsomal prostaglandin E‐synthase‐1 (mPGES‐1) and 5‐lipoxygenase (5‐LO). 2‐(Phenylthio)alkanoic acids (., ) were shown to act as highly active and selective PPARα agonists. Encouraged by these results, we would like to identify other target proteins and, thereby, further explore the pharmacological profile of these molecules. An elegant method to screen for potential interaction partners is the so‐called “protein‐fishing” approach. Requirement is coupling of a functionalized small molecule to a solid phase which is used for biological experiments. Ideally, the pharmacophore of the small molecule remains intact as far as possible. Here, we describe the successful design and synthesis of functionalized fatty acid mimetics, thus providing an eligible starting point for solid‐phase coupling and subsequent “protein‐fishing” experiments. “Protein‐fishing” experiments are an elegant method for target identification. Requirement is that the small molecules of interest are coupled to a solid phase as matrix. Pharmacophore functionalization exemplified by selected fatty acid mimetics is described.
    Keywords: Fatty Acid Mimetics ; Functional Groups ; Pirinixic Acid ; Protein Fishing ; Solid‐Phase Coupling
    ISSN: 0365-6233
    E-ISSN: 1521-4184
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 4
    Language: English
    In: Journal of Chromatography A, 2010, Vol.1217(7), pp.1033-1040
    Description: Chiral α-arylthiocarboxylic acids with different substitution patterns, representing new pirinixic acid derivatives with dual PPARα/γ agonistic activities, have been separated into enantiomers on -butylcarbamoylquinine and quinidine based chiral anion-exchangers and amylose tris(3,5-dimethylphenylcarbamate) coated silica on analytical and preparative scale. Absolute configurations of individual enantiomers were assigned chromatographically via elution orders on the chiral anion-exchangers and were confirmed by stereoselective syntheses via Ewans auxiliaries that have lead to enantiomeric products with known absolute configurations. The results of both methods were in full agreement. Moreover, the receptor stereoselectivity in PPARα transactivation activities was consistent within the test set of structurally related compounds. Limited correlation (between elution order and substitution) was observed within the set of α-arylthiocarboxylic acids on the amylose tris(3,5-dimethylphenylcarbamate) based chiral stationary phase (CSP), in particular the elution order changed with remote substitution. This clearly demonstrates the risks of chromatographic absolute configuration assignments by prediction from one structural analog to another one, especially with CSPs such as polysaccharide CSPs that are recognized for their broad applicability due to multiple binding and chiral recognition modes. It is therefore of utmost importance that such chromatographic absolute configuration predictions by extrapolation to structural analogs are combined with orthogonal methods for verification of the results.
    Keywords: Chiral Stationary Phase ; Chiral Anion-Exchanger ; Quinine and Quinidine Carbamates ; Polysaccharide ; Amylose Tris(3,5-Dimethylphenylcarbamate) ; Chiral Separation ; Hplc ; Pirinixic Acid Derivatives ; 2-Aryloxyalkanoic Acids ; 2-Arylthioalkanoic Acids ; Enantioselective Synthesis ; Peroxisome Proliferator Activated Receptors (Ppar) ; Chemistry
    ISSN: 0021-9673
    E-ISSN: 18733778
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 5
    Language: English
    In: Journal of medicinal chemistry, 24 June 2010, Vol.53(12), pp.4691-700
    Description: We present a novel class of dual modulators of gamma-secretase and peroxisome proliferator-activated receptor gamma (PPARgamma) based on the structure of 2-(bis(phenethoxy)pyrimidine-2-ylthio)hexanoic acid 8 (IC(50)(Abeta42) = 22.8 microM, EC(50)(PPARgamma) = 8.3 microM). The modulation of both targets with approved drugs (i.e., amyloid-beta 42 (Abeta42)-lowering NSAIDs for gamma-secretase and glitazones for PPARgamma) has demonstrated beneficial effects in in vitro and in vivo models of Alzheimer's disease (AD). However, although NSAIDs and PPARgamma agonists share similar structural features, no druglike compounds with dual activities as gamma-secretase modulators (GSMs) and PPARgamma agonists have been designed so far. On the basis of our initial lead structure 8, we present the structure-activity relationships (SARs) of broad structural variations. A significant improvement was reached by the introduction of p-trifluoromethyl substituents at the phenyl residues yielding compound 16 (IC(50)(Abeta42) = 6.0 microM, EC(50)(PPARgamma) = 11.0 microM) and the replacement of the two phenyl residues of 8 by cyclohexyl yielding compound 22 (IC(50)(Abeta42) = 5.1 microM, EC(50)(PPARgamma) = 6.6 microM).
    Keywords: Amyloid Precursor Protein Secretases -- Metabolism ; Caproates -- Chemical Synthesis ; Ppar Gamma -- Agonists ; Pyrimidines -- Chemical Synthesis
    ISSN: 00222623
    E-ISSN: 1520-4804
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 6
    Language: English
    In: Oncotarget, 08 March 2016, Vol.7(10), pp.11664-76
    Description: Pirinixic acid derivatives, a new class of drug candidates for a range of diseases, interfere with targets including PPARα, PPARγ, 5-lipoxygenase (5-LO), and microsomal prostaglandin and E2 synthase-1 (mPGES1). Since 5-LO, mPGES1, PPARα, and PPARγ represent potential anti-cancer drug targets, we here investigated the effects of 39 pirinixic acid derivatives on prostate cancer (PC-3) and neuroblastoma (UKF-NB-3) cell viability and, subsequently, the effects of selected compounds on drug-resistant neuroblastoma cells. Few compounds affected cancer cell viability in low micromolar concentrations but there was no correlation between the anti-cancer effects and the effects on 5-LO, mPGES1, PPARα, or PPARγ. Most strikingly, pirinixic acid derivatives interfered with drug transport by the ATP-binding cassette (ABC) transporter ABCB1 in a drug-specific fashion. LP117, the compound that exerted the strongest effect on ABCB1, interfered in the investigated concentrations of up to 2μM with the ABCB1-mediated transport of vincristine, vinorelbine, actinomycin D, paclitaxel, and calcein-AM but not of doxorubicin, rhodamine 123, or JC-1. In silico docking studies identified differences in the interaction profiles of the investigated ABCB1 substrates with the known ABCB1 binding sites that may explain the substrate-specific effects of LP117. Thus, pirinixic acid derivatives may offer potential as drug-specific modulators of ABCB1-mediated drug transport.
    Keywords: Abcb1 ; Cancer ; Drug Resistance ; Pirinixic Acid ; Pirinixic Acid Derivative ; Pyrimidines -- Pharmacology
    E-ISSN: 1949-2553
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 7
    Language: English
    In: QSAR & Combinatorial Science, May 2009, Vol.28(5), pp.576-586
    Description: Pirinixic acid is a moderate agonist of both the alpha and the gamma subtype of the peroxisome proliferator activated receptor (PPAR). Previously, we have shown that α‐alkyl substitution leads to balanced low micromolar‐active dual agonists of PPARα and PPARγ. Taking α‐hexyl pirinixic acid as a new scaffold, we further optimized PPAR activity by enlargement of the lipophilic backbone by substituting the 2,3‐dimethylphenyl with biphenylic moieties. Such a substitution pattern had only minor impact on PPARγ activity but further increased PPARα activity leading to nanomolar activities. Supporting docking studies proposed that the ()‐enantiomer should fit the PPARα ligand‐binding pocket better and thus be more active than the ()‐enantiomer. Single enantiomers of selected active analogues were then prepared by enantio‐selective synthesis and enantio‐selective preparative HPLC, respectively. Biological data for the distinct enantiomers fully corroborated the docking experiments and substantiate a stereochemical impact on PPAR activation.
    Keywords: Chirality ; Medicinal Chemistry ; Drug Design ; Molecular Modeling ; Structure‐Activity Relationships ; Ppar
    ISSN: 1611-020X
    E-ISSN: 1611-0218
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 8
    Description: Zugl.: Diplomarbeit.
    Keywords: Klein- Und Mittelbetrieb. Personalentwicklung.
    Source: Networked Digital Library of Theses and Dissertations
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 9
    Language: English
    In: European Archives of Psychiatry and Clinical Neuroscience, 2007, Vol.257(4), pp.222-229
    Description: The efficacy of a deficit oriented add-on therapy with free amino acids in depressive patients treated with the antidepressant Remeron® was evaluated. About 40 in-patients were investigated by a randomised double-blind placebo-controlled study during 4 weeks. Plasma levels of 20 amino acids and measures of depression, suicidal behaviour and aggression were surveyed on admission and after a 4 weeks’ therapy with Remeron® plus an individualized amino acid mixture or placebo. The preparation of the amino acid mixture was based on an aminogram and consisted of essential amino acids plus vitamins and trace elements as co-factors for the amino acid metabolism. Patients of the experimental group showed a significantly better improvement of depression and a higher responder rate than those of the placebo group. The results suggest that oral application of a deficit oriented amino acid mixture can improve the therapeutic outcome of an antidepressant. Furthermore, lacking side effects of the amino acids resulting also in a better patient compliance may improve the benefit/risk ratio.
    Keywords: major depression ; add-on-therapy ; aminogram ; individualized amino acid preparation
    ISSN: 0940-1334
    E-ISSN: 1433-8491
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 10
    Language: English
    In: Nucleic acids research, 2014, Vol.42(16), pp.10579-95
    Description: The WHO has recently classified Neisseria gonorrhoeae as a super-bacterium due to the rapid spread of antibiotic resistant derivatives and an overall dramatic increase in infection incidences. Genome sequencing has identified potential genes, however, little is known about the transcriptional organization and the presence of non-coding RNAs in gonococci. We performed RNA sequencing to define the transcriptome and the transcriptional start sites of all gonococcal genes and operons. Numerous new transcripts including 253 potentially non-coding RNAs transcribed from intergenic regions or antisense to coding genes were identified. Strikingly, strong antisense transcription was detected for the phase-variable opa genes coding for a family of adhesins and invasins in pathogenic Neisseria, that may have regulatory functions. Based on the defined transcriptional start sites, promoter motifs were identified. We further generated and sequenced a high density Tn5 transposon library to predict a core of 827 gonococcal essential genes, 133 of which have no known function. Our combined RNA-Seq and Tn-Seq approach establishes a detailed map of gonococcal genes and defines the first core set of essential gonococcal genes.
    Keywords: Genes, Bacterial ; Transcriptome ; Neisseria Gonorrhoeae -- Genetics
    ISSN: 03051048
    E-ISSN: 1362-4962
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. Further information can be found on the KOBV privacy pages