Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Bifunctional aryloxyphosphoramidate prodrugs of 2'-C-Me-uridine: synthesis and anti-HCV activity.

ABSTRACT: In an attempt to identify novel nucleoside phosphoramidate analogues for improving the anti-HCV activity of 2'-C-Me-uridine, we have synthesized for the first time a series of l-glutamic acid, l-serine, l-threonine and l-tyrosine containing aryloxyphosphoramidate prodrugs of 2'-C-Me-uridine. Evaluation of their activity against HCV revealed that they displayed very potent anti-HCV activity, with EC50 values that are in the same range as of Sofosbuvir.

SUBMITTER: Maiti M

PROVIDER: S-EPMC5079539 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Bifunctional aryloxyphosphoramidate prodrugs of 2'-C-Me-uridine: synthesis and anti-HCV activity.

Maiti Munmun M Gao Ling-Jie LJ Huang Chunsheng C Ptak Roger G RG Murray Michael G MG De Jonghe Steven S Herdewijn Piet P

Organic & biomolecular chemistry 20160901 37

In an attempt to identify novel nucleoside phosphoramidate analogues for improving the anti-HCV activity of 2'-C-Me-uridine, we have synthesized for the first time a series of l-glutamic acid, l-serine, l-threonine and l-tyrosine containing aryloxyphosphoramidate prodrugs of 2'-C-Me-uridine. Evaluation of their activity against HCV revealed that they displayed very potent anti-HCV activity, with EC<sub>50</sub> values that are in the same range as of Sofosbuvir. ...[more]

PMID: 27714209

Similar Datasets

Synthesis and anti-HCV activity of a series of ?-d-2'-deoxy-2'-dibromo nucleosides and their corresponding phosphoramidate prodrugs.

Project description:Several ?-d-2'-deoxy-2'-substituted nucleoside analogs have displayed potent and selective anti-HCV activities and some of them have reached human clinical trials. In that regard, we report herein the synthesis of a series of 2'-deoxy,2'-dibromo substituted U, C, G and A nucleosides 10a-d and their corresponding phosphoramidate prodrugs 13a-d. The synthesized nucleosides 10a-d and prodrugs 13a-d were evaluated for their inhibitory activity against HCV as well as cellular toxicity. The results showed that the most potent compound was prodrug 13a, which exhibited micromolar inhibitory activity (EC50?=?1.5?±?0.8?µM) with no observed toxicity. In addition, molecular modeling and free energy perturbation calculations for the 5'-triphosphate formed from 13a and related 2'-modified nucleotides are discussed.

| S-EPMC5693771 | biostudies-literature

Phosphotyrosine prodrugs: design, synthesis and anti-STAT3 activity of ISS-610 aryloxy triester phosphoramidate prodrugs.

Project description:Unmasked phohate groups of phosphotyrosine-containing molecules carry two negative charges at physiological pH, which compromise their (passive) cellular uptake. Also, these phosphate groups are often cleaved off by phosphatases. Together, these ultimately limit the pharmacological efficacy of the phosphotyrosine-containing compounds. To address these drawbacks, we herein present the application of the aryloxy triester phosphoramidate prodrug technology, a monophosphate prodrug technology, to the phosphotyrosine-containing compound ISS-610-Met, an analogue of the anticancer STAT3 dimerization inhibitor ISS-610. Our data shows that the generated ISS-610-Met prodrugs exhibited enhanced pharmacological activity and inhibition of STAT3 downstream signaling compared to the parent compound ISS-610-Met and the known STAT3 dimerization inhibitor ISS-610. These encouraging results provide a compelling proof of concept for the potential of the aryloxy triester phosphoramidate prodrug technology in the discovery of novel therapeutics that contain phosphotyrosine and its phospho mimics.

| S-EPMC6390693 | biostudies-literature

Rethinking Remdesivir: Synthesis of Lipid Prodrugs that Substantially Enhance Anti-Coronavirus Activity.

Project description:The FDA has granted Remdesivir (RDV, GS-5734) an emergency use authorization on the basis of an acceleration of clinical recovery in hospitalized patients with COVID-19. Unfortunately, the drug must be administered intravenously, restricting its use to those with relatively advanced disease. RDV is also unstable in plasma and has a complex activation pathway which may contribute to its highly variable antiviral efficacy in SARS-CoV-2 infected cells. A potent orally bioavailable antiviral for early treatment of SARS-CoV-2 infection is needed. We focused on making simple orally bioavailable lipid analogs of Remdesivir nucleoside (RVn, GS-441524) that are processed to RVn-monophosphate, the precursor of the active RVn-triphosphate, by a single step intracellular cleavage. In addition to likely improved oral bioavailability and simpler metabolic activation, two of the three new lipid prodrugs of RVn had anti-SARS-CoV-2 activity 9 to 24 times greater than that of RDV in Vero E6 cells.

| S-EPMC7457622 | biostudies-literature

Synthesis and Anti-HCV Activity of 4-Hydroxyamino ?-Pyranone Carboxamide Analogues.

Project description:High genetic variability in hepatitis C virus (HCV), emergence of drug resistant viruses and side effects demand the requirement for development of new scaffolds to show an alternate mechanism. Herein, we report discovery of new scaffold I based on 4-hydroxyamino ?-pyranone carboxamide as promising anti-HCV agents. A comprehensive structure-activity relationship (SAR) was explored with several newly synthesized compounds. In all promising compounds (17-19, 21-22, 24-25, and 49) with EC50 ranging 0.15 to 0.40 ?M, the aryl group at C-6 position of ?-pyranone were unsubstituted. In particular, 25 demonstrated potential anti-HCV activity with EC50 of 0.18 ?M in cell based HCV replicon system with lower cytotoxicity (CC50 > 20 ?M) and provided a new scaffold for anti-HCV drug development. Further investigations, including biochemical characterization, are yet to be performed to elucidate its possible mode of action.

| S-EPMC4027742 | biostudies-literature

Design, Synthesis, and Anti-HBV Activity of New Bis(l-amino acid) Ester Tenofovir Prodrugs.

Project description:A series of bis(l-amino acid) ester prodrugs of tenofovir (TFV) were designed and synthesized as new anti-HBV agents in this work. Four compounds 11, 12a, 12d, and 13b displayed better anti-HBV activity (IC50: 0.71-4.22 ?M) than the parent drug TFV. The most active compound 11 (IC50: 0.71 ?M), a bis(l-valine) ester prodrug of TFV, was found to have obviously greater AUC0-?, C max, and F% than tenofovir disoproxil fumarate (TDF), and potent in vivo efficacy which is not inferior to TDF in a duck HBV (DHBV) model and a HBV DNA hydrodynamic mouse model, and it may serve as a promising lead compound for further anti-HBV drug discovery.

| S-EPMC6580537 | biostudies-literature

Synthesis, evaluation of anti-HIV-1 and anti-HCV activity of novel 2',3'-dideoxy-2',2'-difluoro-4'-azanucleosides.

Project description:A series of 2',3'-dideoxy-2',2'-difluoro-4'-azanucleosides of both pyrimidine and purine nucleobases were synthesized in an efficient manner starting from commercially available L-pyroglutamic acid via glycosylation of difluorinated pyrrolidine derivative 15. Several 4'-azanucleosides were prepared as a separable mixture of ?- and ?-anomers. The 6-chloropurine analogue was obtained as a mixture of N(7) and N(9) regioisomers and their structures were identified based on NOESY and HMBC spectral data. Among the 4'-azanucleosides tested as HIV-1 inhibitors in primary human lymphocytes, four compounds showed modest activity and the 5-fluorouracil analogue (18d) was found to be the most active compound (EC(50)=36.9?M) in this series. None of the compounds synthesized in this study demonstrated anti-HCV activity.

| S-EPMC3489957 | biostudies-literature

Synthesis, nitric oxide release, and anti-leukemic activity of glutathione-activated nitric oxide prodrugs: Structural analogues of PABA/NO, an anti-cancer lead compound.

Project description:Diazeniumdiolate anions and their prodrug forms are reliable sources of nitric oxide (NO) that have generated interest as promising therapeutic agents. A number of structural analogues of O(2)-(2,4-dinitro-5-(4-(N-methylamino)benzoyloxy)phenyl) 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (PABA/NO), an anti-cancer lead compound that is designed to release NO upon activation by glutathione, were prepared. The nitric oxide release patterns of these O(2)-(2,4-dinitrophenyl) diazeniumdiolates in the presence of glutathione were tested and it was found that in the absence of competing pathways, these compounds release nearly quantitative amounts of NO. The ability of PABA/NO and its structural analogues to inhibit human leukemia cell proliferation was determined and it was found that compounds releasing elevated amounts of NO displayed superior cytotoxic effects.

| S-EPMC2631658 | biostudies-literature

Serine peptide phosphoester prodrugs of cyclic cidofovir: synthesis, transport, and antiviral activity.

Project description:Cidofovir (HPMPC, 1), a broad-spectrum antiviral agent, is currently used to treat AIDS-related human cytomegalovirus (HCMV) retinitis and has recognized therapeutic potential for orthopox virus infections, but is limited by its low oral bioavailability. Cyclic cidofovir (2) displays decreased nephrotoxicity compared to 1, while also exhibiting potent antiviral activity. Here we describe in detail the synthesis and evaluation as prodrugs of four cHPMPC dipeptide conjugates in which the free POH of 2 is esterified by the Ser side chain alcohol group of an X-L-Ser(OMe) dipeptide: 3 (X=L-Ala), 4 (X=L-Val), 5 (X=L-Leu), and 6 (X=L-Phe). Perfusion studies in the rat establish that the mesenteric permeability to 4 is more than 20-fold greater than to 1, and the bioavailability of 4 is increased 6-fold relative to 1 in an in vivo murine model. In gastrointestinal and liver homogenates, the cHPMPC prodrugs are rapidly hydrolyzed to 2. Prodrugs 3, 4, and 5 are nontoxic at 100 microM in HFF and KB cells and in cell-based plaque reduction assays had IC 50 values of 0.1-0.5 microM for HCMV and 10 microM for two orthopox viruses (vaccinia and cowpox). The enhanced transport properties of 3-6, conferred by incorporation of a biologically benign dipeptide moiety, and the facile cleavage of the Ser-O-P linkage suggest that these prodrugs represent a promising new approach to enhancing the bioavailability of 2.

| S-EPMC2629803 | biostudies-literature

Chemoenzymatic syntheses and anti-HIV-1 activity of glucose-nucleoside conjugates as prodrugs.

Project description:Phosphodiester linked conjugates of various nucleosides such as d4U, d4T, IdUrd, ddI, ddA, virazole, ara-A, and ara-C containing a glucosyl moiety have been described. These compounds were designed to act as prodrugs, where the corresponding 5'-monophosphates may be generated intracellularly. The synthesis of the glycoconjugates was achieved in good yields by condensation of a glucosyl phosphoramidite 7 with nucleosides in the presence of an activating agent. It was demonstrated that the glucose conjugates improve the water solubility of the nucleoside analogues, for example, up to 31-fold for the ara-A conjugate compared to that of ara-A alone. The new conjugates were tested for their anti-HIV-1 activity in human lymphocytes. These derivatives offer a convenient design for potential prodrug candidates with the possibility of improving the physicochemical properties and therapeutic activity of nucleoside analogues.

| S-EPMC3070195 | biostudies-literature

Integrase Inhibitor Prodrugs: Approaches to Enhancing the Anti-HIV Activity of ?-Diketo Acids.

Project description:HIV integrase, encoded at the 3'-end of the HIV pol gene, is essential for HIV replication. This enzyme catalyzes the incorporation of HIV DNA into human DNA, which represents the point of "no-return" in HIV infection. Integrase is a significant target in anti-HIV drug discovery. This review article focuses largely on the design of integrase inhibitors that are ?-diketo acids constructed on pyridinone scaffolds. Methodologies for synthesis of these compounds are discussed. Integrase inhibition data for the strand transfer (ST) step are compared with in vitro anti-HIV data. The review also examines the issue of the lack of correlation between the ST enzymology data and anti-HIV assay results. Because this disconnect appeared to be a problem associated with permeability, prodrugs of these inhibitors were designed and synthesized. Prodrugs dramatically improved the anti-HIV activity data. For example, for compound, 96, the anti-HIV activity (EC50) improved from 500 nM for this diketo acid to 9 nM for its prodrug 116. In addition, there was excellent correlation between the IC50 and IC90 ST enzymology data for 96 (6 nM and 97 nM, respectively) and the EC50 and EC90 anti-HIV data for its prodrug 116 (9 nM and 94 nM, respectively). Finally, it was confirmed that the prodrug 116 was rapidly hydrolyzed in cells to the active compound 96.

| S-EPMC6332332 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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