Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Discovery, synthesis and biochemical profiling of purine-2,6-dione derivatives as inhibitors of the human poly(A)-selective ribonuclease Caf1.

ABSTRACT: Eukaryotic mRNA contains a 3' poly(A) tail, which plays important roles in the regulation of mRNA stability and translation. Well-characterized enzymes involved in the shortening of the poly(A) tail include the multi-subunit Ccr4-Not deadenylase, which contains the Caf1 (Pop2) and Ccr4 catalytic components, and poly(A)-specific ribonuclease (PARN). Two Mg(2+) ions present in the active sites of these ribonucleases are required for RNA cleavage. Here, we report the discovery, synthesis and biochemical profiling of purine-2,6-dione derivatives as (sub)micromolar inhibitors of Caf1.

SUBMITTER: Jadhav GP

PROVIDER: S-EPMC4577731 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Discovery, synthesis and biochemical profiling of purine-2,6-dione derivatives as inhibitors of the human poly(A)-selective ribonuclease Caf1.

Jadhav Gopal P GP Kaur Ishwinder I Maryati Maryati M Airhihen Blessing B Fischer Peter M PM Winkler G Sebastiaan GS

Bioorganic & medicinal chemistry letters 20150806 19

Eukaryotic mRNA contains a 3' poly(A) tail, which plays important roles in the regulation of mRNA stability and translation. Well-characterized enzymes involved in the shortening of the poly(A) tail include the multi-subunit Ccr4-Not deadenylase, which contains the Caf1 (Pop2) and Ccr4 catalytic components, and poly(A)-specific ribonuclease (PARN). Two Mg(2+) ions present in the active sites of these ribonucleases are required for RNA cleavage. Here, we report the discovery, synthesis and bioche ...[more]

PMID: 26299350

Similar Datasets

Aqua-(trifluoro-methane-sulfonato)-bis-(1,3,7-trimethyl-purine-2,6-dione)silver(I).

Project description:In the title compound, [Ag(CF(3)SO(3))(C(8)H(10)N(4)O(2))(2)(H(2)O)], the Ag(I) atom is coordinated by two caffeine N atoms and, at longer distances, two O atoms of a coordinated water mol-ecule and the trifluoro-methane-sulfonate anion, resulting in an AgN(2)O(2) seesaw geometry. The caffeine mol-ecules are roughly coplanar [dihedral angle = 5.81 (5)°]. In the crystal, mol-ecules self-assemble into a linear supra-molecular chain along the c axis via O-H⋯O hydrogen bonds involving the coordinated water moledcule and carbonyl O atoms. The packing is consolidated by weak C-H⋯O inter-actions.

| S-EPMC2983140 | biostudies-literature

8-(2-Hy-droxy-phen-yl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione.

Project description:The title compound, C(13)H(12)N(4)O(3), is an imidazole derivative featuring an annealed purine ring system. The benzimidazole-inspired moiety is essentially planar (r.m.s. of all fitted non-H atoms = 0.0205 Å). An intra-molecular O-H⋯N hydrogen bond occurs. In the crystal, inter-molecular N-H⋯O and C-H⋯O hydrogen bonds are observed, which connect the mol-ecules into chains along [110]. The shortest centroid-centroid distance between two aromatic systems is 3.7771 (11) Å.

| S-EPMC3200978 | biostudies-literature

Monoclinic polymorph of 3,7-dimethyl-1-(5-oxohex-yl)-3,7-dihydro-1H-purine-2,6-dione.

Project description:The structure of the title compound, pentoxifylline, C(13)H(18)N(4)O(3), has been previously characterized as a triclinic polymorph [Pavelčík et al. (1989 ▶). Acta Cryst. C45, 836-837]. We have discovered the monoclinic form. There are no strong hydrogen bonds in the crystal structure, rather, moderate C-H⋯O hydrogen bonds are present, which serve to stabilize the three-dimensional architecture.

| S-EPMC3247589 | biostudies-literature

7-(1,3-Dioxolan-2-ylmeth-yl)-1,3-di-methyl-purine-2,6(1H,3H)-dione trichloro-acetic acid solvate.

Project description:In the title compound, C(11)H(14)N(4)O(4)·C(2)HCl(3)O(2), the dioxolane ring adopts an envelope conformation. Doxophylline [7-(1,3-dioxolan-2-yl-meth-yl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione] and trichloro-acetic acid mol-ecules are linked by O-H⋯N and C-H⋯O hydrogen bonds.

| S-EPMC2915388 | biostudies-literature

Diphenyl purine derivatives as peripherally selective cannabinoid receptor 1 antagonists.

Project description:Cannabinoid receptor 1 (CB1) antagonists are potentially useful for the treatment of several diseases. However, clinical development of several CB1 antagonists was halted due to central nervous system (CNS)-related side effects including depression and suicidal ideation in some users. Recently, studies have indicated that selective regulation of CB1 receptors in the periphery is a viable strategy for treating several important disorders. Past efforts to develop peripherally selective antagonists of CB1 have largely targeted rimonabant, an inverse agonist of CB1. Reported here are our efforts toward developing a peripherally selective CB1 antagonist based on the otenabant scaffold. Even though otenabant penetrates the CNS, it is unique among CB1 antagonists that have been clinically tested because it has properties that are normally associated with peripherally selective compounds. Our efforts have resulted in an orally absorbed compound that is a potent and selective CB1 antagonist with limited penetration into the CNS.

| S-EPMC4492447 | biostudies-literature

Evaluation of analgesic and anti-inflammatory activity of purine-2,6-dione-based TRPA1 antagonists with PDE4/7 inhibitory activity.

Project description:BackgroundTo verify the validity of the proposed pain treatment approach, which is based on concomitant blocking of the Transient Receptor Potential Ankyrin 1 (TRPA1) channel and phosphodiesterases (PDEs) 4B/7A activity, we continued our pharmacological studies on 8-alkoxypurine-2,6-diones selected based on previous in vitro screening.MethodsDerivatives 17, 31, and 36 were pharmacologically evaluated in vivo using the formalin test and oxaliplatin-induced neuropathic pain: the von Frey and the cold plate tests, and in the carrageenan-induced edema model. Compound 36, which turned out to be the most promising, was further evaluated in the collagen-induced arthritis model. The pharmacokinetic parameters of this compound were also estimated.ResultsAll the tested compounds exhibited significant analgesic and anti-inflammatory activities. Compound 36 was additionally characterized by an antiarthritic effect and showed a favorable pharmacokinetic profile in rats.ConclusionThe compounds evaluated in this study represent a new class of derivatives with analgesic and anti-inflammatory activities that involve TRPA1 antagonism and PDE4/7 inhibition.

| S-EPMC9584878 | biostudies-literature

2,6-Dichloro-7-isopropyl-7H-purine.

Project description:In the title mol-ecule, C(8)H(8)Cl(2)N(4), the essentially planar imidazole and pyrimidine rings [maximum deviations of 0.0030?(15) and 0.0111?(15)?Å, respectively] make a dihedral angle of 1.32?(8)°. In the crystal, the fused-ring systems are stacked approximately parallel to the bc plane, with a centroid-centroid distance between inversion-related pyrimidine rings of 3.5189?(9)?Å.

| S-EPMC3379198 | biostudies-literature

Identification of 1H-purine-2,6-dione derivative as a potential SARS-CoV-2 main protease inhibitor: molecular docking, dynamic simulations, and energy calculations.

Project description:The rapid spread of the coronavirus since its first appearance in 2019 has taken the world by surprise, challenging the global economy, and putting pressure on healthcare systems across the world. The introduction of preventive vaccines only managed to slow the rising death rates worldwide, illuminating the pressing need for developing effective antiviral therapeutics. The traditional route of drug discovery has been known to require years which the world does not currently have. In silico approaches in drug design have shown promising results over the last decade, helping to decrease the required time for drug development. One of the vital non-structural proteins that are essential to viral replication and transcription is the SARS-CoV-2 main protease (Mpro). Herein, using a test set of recently identified COVID-19 inhibitors, a pharmacophore was developed to screen 20 million drug-like compounds obtained from a freely accessible Zinc database. The generated hits were ranked using a structure based virtual screening technique (SBVS), and the top hits were subjected to in-depth molecular docking studies and MM-GBSA calculations over SARS-COV-2 Mpro. Finally, the most promising hit, compound (1), and the potent standard (III) were subjected to 100 ns molecular dynamics (MD) simulations and in silico ADME study. The result of the MD analysis as well as the in silico pharmacokinetic study reveal compound 1 to be a promising SARS-Cov-2 MPro inhibitor suitable for further development.

| S-EPMC9549888 | biostudies-literature

Synthesis of 2,6-Diamino-Substituted Purine Derivatives and Evaluation of Cell Cycle Arrest in Breast and Colorectal Cancer Cells.

Project description:Reversine is a potent antitumor 2,6-diamino-substituted purine acting as an Aurora kinases inhibitor and interfering with cancer cell cycle progression. In this study we describe three reversine-related molecules, designed by docking calculation, that present structural modifications in the diamino units at positions 2 and 6. We investigated the conformations of the most stable prototropic tautomers of one of these molecules, the N6-cyclohexyl-N6-methyl-N2-phenyl-7H-purine-2,6-diamine (3), by Density Functional Theory (DFT) calculation in the gas phase, water and chloroform, the last solvent considered to give insights into the detection of broad signals in NMR analysis. In all cases the HN(9) tautomer resulted more stable than the HN(7) form, but the most stable conformations changed in different solvents. Molecules 1⁻3 were evaluated on MCF-7 breast and HCT116 colorectal cancer cell lines showing that, while being less cytotoxic than reversine, they still caused cell cycle arrest in G2/M phase and polyploidy. Unlike reversine, which produced a pronounced cell cycle arrest in G2/M phase in all the cell lines used, similar concentrations of 1⁻3 were effective only in cells where p53 was deleted or down-regulated. Therefore, our findings support a potential selective role of these structurally simplified, reversine-related molecules in p53-defective cancer cells.

| S-EPMC6222518 | biostudies-literature

Benzene-1,2,4,5-tetra-carb-oxy-lic acid bis-(1,3,7-trimethyl-2,3,6,7-tetra-hydro-1H-purine-2,6-dione).

Project description:The asymmetric unit of the title co-crystal, C10H6O8·2C8H10N4O2, comprises a centrosymmetric benzene-1,2,4,5-tetra-carb-oxy-lic acid (LH4) mol-ecule and a mol-ecule of caffeine in a general position. LH4 is nonplanar, with the dihedral angles between the ring and pendent carb-oxy-lic acid groups being 44.22?(7) and 49.74?(7)°. By contrast, the caffeine mol-ecule is planar (r.m.s. deviation = 0.040?Å). Supra-molecular layers parallel to (-1-10) are sustained by carb-oxy-lic acid O-H?O(carbon-yl) and O-H?N(imidazole) hydrogen bonds, as well as by meth-yl-carbonyl C-H?O inter-actions. These stack via ?-? inter-actions between the benzene and imidazole rings [inter-centroid distance = 3.4503?(10)?Å].

| S-EPMC3884421 | biostudies-other

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data