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00:03 EDT 1st November 2014 | BioPortfolio

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Showing PubMed Articles 1–25 of 1,800+ from Journal of medicinal chemistry

Friday 21st July 1110

Structure-based Design and Development of Functionalized Mercaptoguanine Derivatives as Inhibitors of the Folate Biosynthesis Pathway Enzyme 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase from Staphylococcus aureus.

6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), an enzyme from the folate biosynthesis pathway, catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin and is a yet-to-be-drugged antimicrobial target. Building on our previous discovery that 8-mercaptoguanine (8-MG) is an inhibitor of S. aureus HPPK (SaHPPK), we have identified and characterized the binding of an S8-functionalized derivative (3). X-ray structures of both the SaHPPK/3/cofactor analog ternary and the SaH...

1109428

A class of 4-sulfamoylphenyl-ω-aminoalkyl ethers with effective carbonic anhydrase inhibitory action and antiglaucoma effects.

We report a series of 4-sulfamoylphenyl-ω-aminoalkyl ethers as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. Structure-activity relationship was drawn for the inhibition of four physiologically relevant isoforms, hCA I, II, IX and XII. Many of these compounds were highly effective, low nanomolar inhibitors of all CA isoforms, whereas several isoform-selective were also identified. X-ray crystal structures of two new sulfonamides bound to the physiologically dominant CA II isoform showed the tails of thes...

1109380

Discovery and characterization of novel selective inhibitors of carbonic anhydrase IX.

Human carbonic anhydrase IX (CA IX) is highly expressed in tumor tissues and its selective inhibition provides potential target for treatment against numerous cancers. Development of potent, highly selective inhibitors against this target remains an unmet need in anti-cancer therapeutics. A series of fluorinated benzenesulfonamides with substituents on the benzene ring were designed and synthesized. Several of these exhibited a highly potent and selective inhibition profile against CA IX. Three fluorine ato...

Wednesday 14th December 1109

Synthesis of 7-Halogenated Isatin Sulfonamides: Nonradioactive Counterparts of Caspase-3/-7 Inhibitor-based Potential Radiopharmaceuticals for Molecular Imaging of Apoptosis.

N-alkylated (S)-7-halogen-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatins were developed as a new group of non-radioactive reference compounds for future radiotracers. Inhibitor potency studies of these compounds suggest that the binding pockets readily accommodate both the 7-halogen substituents and aliphatic side chains (methyl to n-butyl) as well as some ω-fluorinated analogues (3-fluoropropyl and 4-fluorobutyl) at the isatin nitrogen. Indeed, compared to the halogen free parent compounds, some 7-hal...

Thursday 7th April 1109

Discovery and preclinical profiling of 3-4-(morpholin-4-yl)-7H-pyrrolo2,3-dpyrimidin-5-ylbenzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor.

Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD) by genome-wide association studies (GWAS). The most common LRRK2 mutation, but relatively rare in the total population, G2019S gives rise to increased kinase activity, thus LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the discovery and optimization of a novel series of potent LRRK2 inhibitors, focusing on improving kinome selectivity using a surrogate crystallography appr...

1107397

Hybrids of phenylsulfonylfuroxan and coumarin as potent antitumor agents.

Sixteen furoxan-based nitric oxide (NO) releasing coumarin derivatives (6a-c, 8a-g, 10a, 13a-b, 15 and 17a-b) were designed, synthesized and evaluated against the A549, Hela, A2780, A2780/CDDP and HUVEC cell lines. Most derivatives displayed potent anti-proliferation activities. Among them, 8b exhibited the strongest anti-proliferation activity on the four sensitive cell lines mentioned above and three drug resistant tumor cell lines A2780/CDDP, MDA-MB-231/Gem and SKOV3/CDDP with IC50 values from 14 to 53 n...

Thursday 7th August 1107

1,4-Disubstituted-1,2,3triazolyl-containing analogs of MT-II - design, synthesis, conformational analysis, and biological activity.

Side chain-to-side chain cyclizations represent a strategy to select a family of bioactive conformations by reducing the entropy and enhancing the stabilization of functional ligand-induced receptor conformations. This structural manipulation contributes to increased target specificity, enhanced biological potency, improved pharmacokinetic properties, increasing functional potency, lowering metabolic susceptibility. The CuI-catalyzed azide-alkyne 1,3-dipolar Huisgen's cycloaddition, the prototypic click rea...

Tuesday 18th February 1107

A New Class of Peptidomimetics Targeting the Polo-box Domain of Polo-like kinase 1.

Recent progress in the development of peptide-derived Polo-like kinase (Plk1) polo-box domain (PBD) inhibitors has led to the synthesis of multiple peptide ligands with high binding affinity and selectivity. However, few systematic analyses have been conducted to identify key Plk1 residues and characterize their interactions with potent Plk1 peptide inhibitors. We performed systematic deletion analysis using the most potent 4j peptide and studied N-terminal capping of the minimal peptide with diverse organi...

1106432

Exploiting the Therapeutic Potential of 8-β-D-Glucopyranosylgenistein: Synthesis, Antidiabetic Activity and Molecular Interaction with Islet Amyloid Polypeptide and Amyloid β-Peptide (1-42).

8-β-D-Glucopyranosylgenistein (1), the major component of Genista tenera, was synthesized and showed an extensive therapeutical impact in the treatment of STZ-induced diabetic rats, producing normalization of fasting hyperglycemia, amelioration of excessive postprandial glucose excursions, and increasing β-cell sensitivity, insulin secretion, and circulating insulin within 7 days at a dose of 4mg/kg b.w./day. Suppression of islet amyloid polypeptide (IAPP) fibril formation by compound 1 was demonstrated b...

1104539

Targeting Dopamine D3 and Serotonin 5-HT1A and 5-HT2A Receptors for Developing Effective Antipsychotics: Synthesis, Biological Characterization, and Behavioral Studies.

Combination of dopamine D3 antagonism, serotonin 5-HT1A partial agonism and antagonism at 5-HT2A leads to a novel approach to potent atypical antipsychotics. Exploitation of the original structure-activity relationships resulted in the identification of safe and effective antipsychotics devoid of extrapyramidal symptoms liability, sedation, and catalepsy. The potential atypical antipsychotic 5bb was selected for further pharmacological investigation. The distribution of c-fos positive cells in the ventral s...

1103367

Discovery of Dual Leucine Zipper Kinase (DLK, MAP3K12) Inhibitors with Activity in Neurodegeneration Models.

Dual leucine zipper kinase (DLK, MAP3K12) was recently identified as an essential regulator of neuronal degeneration in multiple contexts. Here we describe the generation of potent and selective DLK inhibitors starting from a high-throughput screening hit. Using proposed hinge-binding interactions to infer a binding mode and specific design parameters to optimize for CNS druglike molecules, we came to focus on the di(pyridin-2-yl)amines because of their combination of desirable potency and good brain penetr...

Sunday 10th October 1103

Structure-guided development of deoxycytidine kinase inhibitors with nanomolar affinity and improved metabolic stability.

Recently, we have shown that small molecule dCK inhibitors in combination with pharmacological perturbations of de novo dNTP biosynthetic pathways could eliminate acute lymphoblastic leukemia cells in animal models. However, our previous lead compound had a short half-life in vivo. Therefore, we set out to develop dCK inhibitors with favorable pharmacokinetic properties. We delineated the sites of the inhibitor for modification, guided by crystal structures of dCK in complex with the lead compound and with ...

1102651

Understanding the Molecular Basis of Toxin Promiscuity: The Analgesic Sea Anemone Peptide APETx2 Interacts with Acid-Sensing Ion Channel 3 and hERG Channels via Overlapping Pharmacophores.

The sea anemone peptide APETx2 is a potent and selective blocker of acid-sensing ion channel 3 (ASIC3). APETx2 is analgesic in a variety of rodent pain models, but lack of knowledge about its pharmacophore and binding site on ASIC3 has impeded development of improved analogs. Here we present a detailed structure-activity relationship study of APETx2. Determination of a high-resolution structure of APETx2 combined with scanning mutagenesis revealed a cluster of aromatic and basic residues that mediate its in...

Thursday 23rd October 1101

Membrane Active Phenylalnine Conjugated Lipophilic Norspermidine Derivatives with Selective Antibacterial Activity.

Natural and synthetic membrane active antibacterial agents offer hope as potential solutions to the problem of bacterial resistance as the membrane-active nature imparts low propensity for the development of resistance. In this report norspermidine based antibacterial molecules were developed which displayed excellent antibacterial activity against various wild-type bacteria (Gram-positive and Gram-negative) and drug-resistant bacteria (methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enter...

1100493

Radiosynthesis and Evaluation of an (18)F-Labeled Positron Emission Tomography (PET) Radioligand for Metabotropic Glutamate Receptor Subtype 4 (mGlu4).

Four 4-phthalimide derivatives of N-(3-chlorophenyl)-2-picolinamide were synthesized as potential ligands for the PET imaging of mGlu4 in the brain. Of these compounds, N-(3-chloro-4-(4-fluoro-1,3-dioxo-isoindolin-2-yl)phenyl)-2-picolinamide (3, KALB001) exhibited improved binding affinity (IC50 = 5.1 nM) compared with ML128 (1) and was subsequently labeled with (18)F. When finally formulated in 0.1 M citrate buffer (pH4) with 10% ethanol, the specific activity of [(18)F]3 at the end of synthesis (EOS) was ...

1100416

Characterization of Selective Exosite-Binding Inhibitors of Matrix Metalloproteinase 13 That Prevent Articular Cartilage Degradation In Vitro.

Matrix metalloproteinase 13 (MMP-13) has been shown to be the main collagenase responsible for degradation of articular cartilage during osteoarthritis (OA) and therefore represents a target for drug development. As a result of high-throughput screening (HTS) and structure-activity relationship (SAR) studies, we identified a novel, highly selective class of MMP-13 inhibitors (compounds 1 (Q), 2 (Q1), and 3 (Q2)). Mechanistic characterization revealed a noncompetitive nature of these inhibitors with binding ...

1096777

Second-Generation Antibacterial Benzimidazole Ureas: Discovery of A Preclinical Candidate with Reduced Metabolic Liability.

ABSTRACT Compound 3 is a potent aminobenzimidazole urea with broad-spectrum Gram-positive antibacterial activity resulting from dual inhibition of bacterial gyrase (GyrB) and topoisomerase IV (ParE), and demonstrates efficacy in rodent models of bacterial infection. Preclinical in vitro and in vivo studies showed that compound 3 covalently labels liver proteins, presumably via formation of a reactive metabolite, and hence presented a potential safety liability. The urea moiety in compound 3 was identified a...

1096567

11H-Pyrido3',2':4,5pyrrolo3,2-ccinnoline and pyrido3',2':4,5pyrrolo1,2-c1,2,3 benzotriazine: two new ring systems with antitumor activity.

Derivatives of new ring systems 11H-pyrido[3',2':4,5]pyrrolo[3,2-c]cinnoline and pyrido[3',2':4,5]pyrrolo[1,2-c][1,2,3]benzotriazine were prepared from the key intermediates 2-(1H-pyrrolo[2,3-b]pyridin-2-yl)anilines in excellent yields (94-99%) and screened by the National Cancer Institute (NCI, Bethesda, USA), on about 60 human tumor cell lines derived from nine cancer cell types. Tested compounds exhibited antiproliferative activity against all the human cell lines showing comparable MG_MID range 0.74-1.1...

Tuesday 13th July 1096

Loratadine and analogs: Discovery and preliminary SAR of inhibitors of the amino acid transporter B0AT2.

B0AT2, encoded by the SLC6A15 gene, is a transporter for neutral amino acids that has recently been implicated in mood and metabolic disorders. It is predominantly expressed in the brain but little is otherwise known about its function. In order to identify inhibitors for this transporter we screened a library of different 3133 bioactive compounds. Loratadine, a clinically used histamine H1 receptor antagonist, was identified as a selective inhibitor of B0AT2 with an IC50 of 4 µM while being less active or...

Wednesday 11th February 1096

Targeting Nucleus DNA with a Cyclometalated Dipyridophenazine Ruthenium(II) Complex.

Recently, coordinatively saturated and substitutionally inert Ru(II) complexes have been investigated as anticancer agents.. Herein a cyclometalated Ru(II) complex, [Ru(bpy)(phpy)(dppz)]+, was found to be rapidly taken up by cancer cells, and nearly 90% of the complex accumulated in the nuclei of cancer cells after 2 h incubation. The anticancer activity of this complex was screened against a panel of cancer cell lines. Remarkably, it exhibit-ted IC50 values that were an order of magnitude lower than cispla...

1095871

Discovery of Novel, Dual Mechanism ERK Inhibitors by Affinity Selection Screening of an Inactive Kinase.

An affinity-based mass spectrometry screening technology was used to identify novel binders to both non-phosphorylated and phosphorylated ERK2. Screening of inactive ERK2 identified a pyrrolidine analogue 1 that bound to both non-phosphorylated and phosphorylated ERK2, and inhibited ERK2 kinase activity. Chemical optimization identified compound 4 as a novel, potent, and highly selective ERK1,2 inhibitor which demonstrated not only inhibition of phosphorylation of ERK substrate p90RSK but also demonstrated ...

1095739

Inhibitory Activities of Propolis and its Promising Component, Caffeic Acid Phenethyl Ester, against Amyloidogenesis of Human Transthyretin.

Transthyretin (TTR) is a homo-tetrameric serum protein associated with amyloidoses such as familial amyloid polyneuropathy and senile systemic amyloidosis. The amyloid fibril formation of TTR can be inhibited through stabilization of the TTR tetramer by the binding of small molecules. In this study, we examined the inhibitory potency of caffeic acid phenethyl ester (CAPE) and its derivatives. Thioflavin T assay showed that CAPE suppressed the amyloid fibril formation of TTR. Comparative analysis of the inhi...

1095598

Biased multicomponent reactions to develop novel bromodomain inhibitors.

BET bromodomain inhibition has contributed new insights into gene regulation and emerged as a promising therapeutic strategy in cancer. Structural analogy of early methyl-triazolo BET inhibitors has prompted a need for structurally dissimilar ligands as probes of bromodomain function. Using fluorous-tagged multicomponent reactions we developed a focused chemical library of bromodomain inhibitors around a 3,5-dimethylisoxazole biasing element with micromolar biochemical IC50. Iterative synthesis and biochemi...

1095497

Coordination of hydroxyquinolines to a ruthenium bis-dimethyl-phenanthroline scaffold radically improves potency for potential as antineoplastic agents.

A series of ruthenium coordination complexes containing hydroxyqinoline ligands were synthesized that exhibited radically improved potencies up to 85-fold greater than clioquinol, a known cytotoxic compound. The complexes were also >100-fold more potent than clioquinol in a tumor spheroid model, with values similar to currently used chemotherapeutics for the treatment of solid tumors. Cytotoxicity occurs through rapid processes that induce apoptosis, but appear to be mediated by cell-cycle independent mecha...

Sunday 31st August 1095

Fragment-based screening of the bromodomain of ATAD2.

Cellular and genetic evidence suggest that inhibition of ATAD2 could be a useful strategy to treat several types of cancer. To discover small molecule inhibitors of the bromodomain of ATAD2, we used a fragment-based approach. Fragment hits were identified using NMR spectroscopy, and ATAD2 was crystallized with three of the hits identified in the fragment screen.


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