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12:42 EDT 18th April 2015 | BioPortfolio

The US National Library of Medicine and National Institutes of Health manage which comprises of more than 21 million records, papers, reports for biomedical literature, including MEDLINE, life science and medical journals, articles, reviews, reports and  books.  BioPortfolio aims to publish relevant information on published papers, clinical trials and news associated with users selected topics.

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Showing PubMed Articles 1–25 of 2,000+ from Journal of medicinal chemistry

Saturday 26th November 1216

6-substituted Sulfocoumarins Are Selective Carbonic Anhdydrase IX and XII Inhibitors with Significant Cytotoxicity against Colorectal Cancer Cells.

6-Substituted sulfocoumarins bearing the carboxamido, trimethylammonium as well as the cyano and methoxy moieties with interesting inhibitory action/selectivity against the tumor associated carbonic anhydrase (CA, EC isoforms hCA IX and XII are reported. Moieties leading to best inhibition were tert-butyl-, phenyl- and 4-pyridyl-carboxamido, with KIs of 2.1 - 8.1 nM. No inhibition of the off-target hCA II and I was observed. A number of these compounds were evaluated against HT-29 colon cancer cell...


Peptide Triazole Inactivators of HIV-1 Utilize a Conserved Two-Cavity Binding Site at the Junction of the Inner and Outer Domains of Env gp120.

We used coordinated mutagenesis, synthetic design and flexible docking to investigate the structural mechanism of Env gp120 encounter by peptide triazole (PT) inactivators of HIV-1. Prior results demonstrated that the PT class of inhibitors suppresses binding at both CD4 and co-receptor sites on Env and triggers gp120 shedding, leading to cell-independent irreversible virus inactivation. In spite of these enticing anti-HIV-1 phenotypes, structural understanding of the PT-gp120 binding mechanism has been inc...

Thursday 17th November 1211

pkCSM: predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures.

Drug development has a high attrition rate, with poor pharmacokinetic and safety properties a significant hurdle. Computational approaches may help minimize these risks. We have developed a novel approach (pkCSM), which uses graph-based signatures to develop predictive models of central ADMET properties for drug development. pkCSM performs as well or better than current methods. A freely accessible web server (, which retains no information submitted to it, provides an ...


HM30181 Derivatives as Novel Potent and Selective Inhibitors of the Breast Cancer Resistance Protein (BCRP/ABCG2).

The Breast Cancer Resistance Protein (BCRP, ABCG2) belongs to the superfamily of ATP binding-cassette (ABC) proteins. In addition to other physiological functions, it transports potentially cell-damaging compounds out of the cell using the energy from ATP hydrolysis. Certain tumors overexpressing BCRP were found to become resistant against various anticancer drugs. In previous work, we found that tariquidar analogs lacking the tetrahydroisoquinoline moiety selectively inhibit BCRP. In the present study, we ...

Tuesday 9th November 1210

The Discovery of I-BRD9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition.

Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain 'reader' modules. Inhibitors of the Bromodomain and Extra Terminal domain (BET) family of bromodomains have shown profound anti-cancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe f...

Monday 26th April 1210

A Broad Anti-influenza Hybrid Small Molecule that Potently Disrupts the Polymerase Acidic Protein-Basic Protein 1 (PA-PB1) Subunits Interaction.

In continuing our efforts to identify small molecules able to disrupt PA-PB1 subunits interaction of influenza virus (Flu) RNA-dependent RNA polymerase, this paper was devoted to the optimization of a dihydrotriazolopyrimidine derivative, previously identified through a SBDD. The structure modifications performed around the bicyclic core led to the identification of compounds endowed with both the ability to disrupt PA-PB1 subunits interaction and anti-Flu activity with no cytotoxicity. Very interesting res...


Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics.

PAC-1 is an ortho-hydroxy-N¬-acylhydrazone that induces apoptosis in cancer cells by chelation of inhibitory labile zinc from procaspase-3. PAC-1 has been assessed in a wide variety of cell culture experiments and in vivo models of cancer, with promising results, and a Phase 1 clinical trial in cancer patients has been initiated (NCT02355535). For certain applications, however, the in vivo half-life of PAC-1 could be limiting. Thus, with the goal of developing a compound with enhanced metabolic stability, ...


Lathyrol Diterpenes as Modulators of P-Glycoprotein Dependent Multidrug Resistance: Structure-Activity Relationship Studies on Euphorbia factor L3 Derivatives.

Five series of 37 new acylate and epoxide derivatives (3-39) of Euphorbia factor L3, a lathyrol diterpene isolated from Euphorbia lathyris, were designed by modifying the hydroxyl moiety of C-3, C-5 or C-15. Chemoreversal effects of the acylates on multidrug resistance (MDR) were evaluated in breast cancer multidrug-resistant MCF-7/ADR cells that overexpress P-glycoprotein (P-gp). Eight derivatives exhibited greater chemoreversal ability than verapamil (VRP) against adriamycin (ADR) resistance. Compounds 19...


Activation of the γ-Aminobutyric Acid Type B (GABAB) Receptor by Agonists and Positive Allosteric Modulators.

Since the discovery of the GABAB agonist and muscle relaxant, baclofen, there have been substantial advancements in the development of compounds that activate the GABAB receptor as agonists or positive allosteric modulators. For the agonists, most of the existing structure-activity data applies to understanding the role of substituents on the backbone of GABA as well as replacing the carboxylic acid and amine groups. In the cases of the positive allosteric modulators, the allosteric binding site(s) and stru...


Structure-Related Mode-of-Action Differences of Anticancer Organoruthenium Complexes with β-Diketonates.

A series of organoruthenium(II) chlorido complexes with fluorinated O,O-ligands [(η6-p-cymene)Ru(F3C-acac-Ar)Cl] (1a-6a) and their respective 1,3,5-triaza-7-phosphaadamantane (pta) derivatives [(η6-p-cymene)Ru(F3C-acac-Ar)pta]PF6 (1b-6b) were synthesized and fully characterized in both solution and solid state. All complexes were inactive against non-malignant keratinocytes but displayed variable activity against cancer cell models (ovarian, osteosarcoma). Compounds with a ligand containing the 4-chloroph...


ent-Kaurane Diterpenoids from Chinese Liverworts and Their Antitumor Activities through Michael Addition as in-situ Detected by a Florescence Probe.

It is generally accepted that the origin of the cytotoxicity of ent-kaurane diterpenoids was due to the reactive oxygen species (ROS) formation and the alpha,beta-unsaturated carbonyl was a pivotal moiety. Herein we demonstrated the isolation of 32 new and 12 known ent-kaurane diterpenoids from two Chinese liverworts. These compounds and three semi-synthesized derivatives were screened against human cancer cell lines. It is revealed that their anticancer activities were caused by ROS formation through Micha...


β-d-2'-C-Methyl-2,6-diaminopurine Ribonucleoside Phosphoramidates are Potent and Selective Inhibitors of Hepatitis C Virus (HCV) and Are Bioconverted Intracellularly to Bioactive 2,6-Diaminopurine and Guanosine 5'-Triphosphate Forms.

The conversion of selected β-d-2,6-diaminopurine nucleosides (DAPNs) to their phosphoramidate prodrug (PD) substantially blocks the conversion to the G-analog allowing for the generation of two bioactive nucleoside triphosphates (NTPs) in human hepatocytes. A variety of 2'-C-methyl DAPN-PDs were prepared and evaluated for inhibition of HCV viral replication in Huh-7 cells, cytotoxicity in various cell lines, and cellular pharmacology in both Huh-7 and primary human liver cells. The DAPN-PDs were pan-genoty...

Sunday 7th September 1208

Correction to Imidazol-1-ylethylindazole Voltage-Gated Sodium Channel Ligands Are Neuroprotective during Optic Neuritis in a Mouse Model of Multiple Sclerosis.

Wednesday 12th March 1208

Poly(amidoamine) dendrimers with carbonic anhydrase inhibitory activity and antiglaucoma action.

Four generations of poly(amidoamine) (PAMAM) dendrimers decorated with benzenesulfonamide moieties were prepared by derivatizing the amino groups of the dendrimer with 4-carboxy-benzenesulfonamide functionalities. Compounds incorporating 4, 8, 16 and 32 sulfonamide moieties were thus obtained which showed an increasing carbonic anhydrase (CA, EC inhibitory action with the increase of the number of sulfamoyl groups in the dendrimer. Best inhibitory activity (in the low nanomolar - subnanomolar range...


Structure-based design of potent and selective inhibitors of the metabolic kinase PFKFB3.

A weak screening hit with adverse physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. Select examples demonstrated exposure in animals following oral dosing and may serve as useful probes to understand the emerging biology of this metabolic target.


Tetrahydroindazoles as Interleukin-2 Inducible T-Cell Kinase Inhibitors. Part II. Second Generation Analogs with Enhanced Potency, Selectivity, and Pharmacodynamic Modulation in Vivo.

The medicinal chemistry community has directed considerable efforts toward the discovery of selective inhibitors of interleukin-2 inducible T-cell kinase (ITK) given its role in T-cell signaling downstream of the T-cell receptor (TCR), and the implications of this target for inflammatory disorders such as asthma. We have previously disclosed a structure- and property-guided lead optimization effort which resulted in the discovery of a new series of tetrahydroindazole-containing selective ITK inhibitors. Her...


Discovery of Tricyclic Indoles That Potently Inhibit Mcl-1 Using Fragment-Based Methods and Structure-Based Design.

Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 family of proteins that is overexpressed and amplified in many cancers. Overexpression of Mcl-1 allows cancer cells to evade apoptosis and contributes to the resistance of cancer cells to be effectively treated with various chemotherapies. From an NMR-based screen of a large fragment library, several distinct chemical scaffolds that bind to Mcl-1 were discovered. Here, we describe the discovery of potent tricyclic 2-indole carboxylic a...


Short hydrophobic peptides with cyclic constraints are potent glucagon-like peptide-1 receptor (GLP-1R) agonists.

Cyclic constraints are incorporated here into an 11-residue analogue of the N-terminus of glucagon-like peptide-1 (GLP-1) to investigate effects of structure on agonist activity. Cyclization through linking side chains of residues 2 and 5 or 5 and 9 produced agonists at nM concentrations in a cAMP assay. 2D-NMR and CD spectra revealed an N-terminal β-turn and a C-terminal helix that differentially influenced affinity and agonist potency. These structures can inform development of small molecule agonists of...


Design and synthesis of antitumour Heck coupled Sclareol analogues: Modulation of BH3 family members by SS-12 in autophagy and apoptotic cell death.

Sclareol, a promising anticancer labdane diterpene, was isolated from Salvia sclarea. Keeping the basic stereochemistry rich framework of the molecule intact, the synthesis of novel sclareol analogues was designed using Palladium (II) catalyzed oxidative Heck coupling reaction for structure activity relationship (SAR). Both sclareol and its derivatives showed an interesting cytotoxicity profile with SS-12 as the most potent analogue having IC50 of 0.082 µM against PC-3 cells. It was found that SS-12 is com...


Evaluation of 3-ethyl-3-(phenylpiperazinylbutyl)oxindoles as PET Ligands for the Serotonin 5-HT7 Receptor - Synthesis, Pharmacology, Radiolabeling and in vivo Brain Imaging in Pigs.

We have investigated several oxindole derivatives in the pursuit of a 5-HT7 PET ligand. Herein the synthesis, chiral separation and pharmacological profiling of two possible PET candidates towards a wide selection of CNS-targets are detailed. Subsequent 11C-labeling and in vivo evaluation in Danish land race pigs showed that both ligands displayed high brain uptake. However, neither of the radioligands could be displaced by the 5-HT7-selective inverse agonist SB-269970.


Synthesis and Evaluation of Fluorinated Fingolimod (FTY720) Analogues for Sphingosine-1-Phosphate Receptor Molecular Imaging by Positron Emission Tomography.

Sphingosine-1-phosphate (S1P) is a lysophospholipid that evokes a variety of biological responses via stimulation of a set of cognate G-protein coupled receptors (GPCRs) named S1P1 to S1P5. S1P and its receptors (S1PRs) play important roles in the immune, cardiovascular and central nervous systems and have also been implicated in carcinogenesis. Recently, the S1P analogue Fingolimod (FTY720) has been approved for the treatment of patients with relapsing multiple sclerosis. This work presents the synthesis o...

Thursday 5th December 1202

Nicotinic Acid Adenine Dinucleotide Phosphate Analogs Substituted on the Nicotinic Acid and Adenine Ribosides. Effects on Receptor-Mediated Ca(2+) release.

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a Ca(2+) releasing intracellular second messenger in both mammals and echinoderms. We report that large functionalized substituents introduced at the nicotinic acid 5-position are recognized by the sea urchin receptor, albeit with a 20-500 fold loss in agonist potency. 5-(3-Azidopropyl)-NAADP was shown to release Ca(2+) with an EC50 of 31 μM and to compete with NAADP for receptor binding with an IC50 of 56 nM. Attachment of charged groups to the nico...

Tuesday 11th June 1202

Identification of Novel ROS Inducers, Quinone Derivatives Tethered with Long Hydrocarbon Chains.

We performed the first synthesis of the 17-carbon chain-tethered quinone moiety 22 (SAN5201) of Irisferin A, a natural product exhibiting an anti-cancer activity, and its derivatives. We found that 22 is a potent ROS inducer and cytotoxic agent. Compound 25 (SAN7401), hydroquinone form of 22, more profoundly released intracellular ROS and induced apoptosis (EC50 = ca. 1.3-2.6 uM) in cancer cell lines including A549 and HCT-116. Compared with a well-known ROS inducer piperlongumine, 22 and 25 showed stronger...


Identifying Medication Targets for Psychostimulant Addiction: Unraveling the Dopamine D3 Receptor Hypothesis.

The dopamine D3 receptor (D3R) is a target for developing medications to treat substance use disorders. D3R-selective compounds with high affinity and varying efficacies have been discovered, providing critical research tools for cell-based studies that have been translated to in vivo models of drug abuse. D3R antagonists and partial agonists have shown especially promising results in rodent models of relapse-like behavior, including stress-, drug-, and cue-induced reinstatement of drug seeking. However, to...

Tuesday 26th June 1201

DUPA Conjugation of a Cytotoxic Indenoisoquinoline Topoisomerase I Inhibitor for Selective Prostate Cancer Cell Targeting.

Prostate-specific membrane antigen (PSMA) is overexpressed in most prostate cancer cells while being present at low or undetectable levels in normal cells. This difference provides an opportunity to selectively deliver cytotoxic drugs to prostate cancer cells while sparing normal cells that lack PSMA, thus improving potencies and reducing toxicities. PSMA has high affinity for 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid (DUPA) (Ki = 8 nM). After binding to a DUPA-drug conjugate, PSMA internalizes, un...

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