N-Phosphonocarbonylpyrrolidine Derivatives of Guanine: A New Class of Bi-Substrate Inhibitors of Human Purine Nucleoside Phosphorylase.
Summary of "N-Phosphonocarbonylpyrrolidine Derivatives of Guanine: A New Class of Bi-Substrate Inhibitors of Human Purine Nucleoside Phosphorylase."
A complete series of pyrrolidine nucleotides, (3R)- and (3S)-3-(guanin-9-yl)pyrrolidin-1-N-ylcarbonylphosphonic acids and (3S,4R)-, (3R,4S)-, (3S,4S)-, and (3R,4R)-4-(guanin-9-yl)-3-hydroxypyrrolidin-1-N-ylcarbonylphosphonic acids, were synthesized and evaluated as potential inhibitors of purine nucleoside phosphorylase (PNP) isolated from peripheral blood mononuclear cells (PBMCs) and cell lines of myeloid and lymphoid origin. Two compounds, (S)-3-(guanin-9-yl)pyrrolidin-1-N-ylcarbonylphosphonic acid (2a) and (3S,4R)-4-(guanin-9-yl)-3-hydroxypyrrolidin-1-N-ylcarbonylphosphonic acid (6a), were recognized as nanomolar competitive inhibitors of PNP isolated from cell lines with K(i) values within the ranges of 16-100 and 10-24 nM, respectively. The low (MESG)K(i) and (Pi)K(i) values of both compounds for PNP isolated from PBMCs suggest that these compounds could be bisubstrate inhibitors that occupy both the phosphate and nucleoside binding sites of the enzyme.
Affiliation
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic , v.v.i. Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
Journal Details
This article was published in the following journal.
Name: Journal of medicinal chemistry
ISSN: 1520-4804
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22264015
- DOI: http://dx.doi.org/10.1021/jm201409u
Medical and Biotech [MESH] Definitions
Purines
A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include ADENINE and GUANINE, constituents of nucleic acids, as well as many alkaloids such as CAFFEINE and THEOPHYLLINE. Uric acid is the metabolic end product of purine metabolism.
Monomeric Gtp-binding Proteins
A class of monomeric, low molecular weight (20-25 kDa) GTP-binding proteins that regulate a variety of intracellular processes. The GTP bound form of the protein is active and limited by its inherent GTPase activity, which is controlled by an array of GTPase activators, GDP dissociation inhibitors, and guanine nucleotide exchange factors. This enzyme was formerly listed as EC 3.6.1.47
Gtp-binding Protein Regulators
Proteins that regulate the signaling activity of GTP-BINDING PROTEINS. They are divided into three categories depending upon whether they stimulate GTPase activity (GTPASE-ACTIVATING PROTEINS), inhibit release of GDP; (GUANINE NUCLEOTIDE DISSOCIATION INHIBITORS); or exchange GTP for GDP; (GUANINE NUCLEOTIDE EXCHANGE FACTORS).
Guanosine
A purine nucleoside that has guanine linked by its N9 nitrogen to the C1 carbon of ribose. It is a component of ribonucleic acid and its nucleotides play important roles in metabolism. (From Dorland, 28th ed)
Purine-nucleoside Phosphorylase
An enzyme that catalyzes the reaction between a purine nucleoside and orthophosphate to form a free purine plus ribose-5-phosphate. EC 2.4.2.1.
PubMed Articles
Design, synthesis and antiviral evaluation of purine-beta-lactam and purine-aminopropanol hybrids.
Purine-beta-lactam chimera were prepared as a novel class of hybrid systems through N-alkylation of 6-benzylamino- or 6-benzyloxypurine with (omega-haloalkyl)-beta-lactams, followed by reductive ring...
DNA and RNA undergo photodegradation in UVC (200-290nm) due to direct absorption by the purine and pyrimidine bases. Limited effects are observed under UVB (290-320nm) or UVA (320-400nm). We have obse...
We have simulated ionization of purine nucleic acid components in the gas phase and in a water environment. The vertical and adiabatic ionization processes were calculated at the PMP2/aug-cc-pVDZ leve...
This paper describes the fabrication of graphene on glassy carbon electrode (GCE) by electrochemical reduction of graphene oxide (GO) attached through 1,6-hexadiamine on GCE and the simultaneous deter...
We compared the influence of different adenine and guanine nucleotides on the free fatty acid-induced uncoupling protein (UCP) activity in non-phosphorylating A. castellanii mitochondria when the memb...
Clinical Trials
Substrate Utilization and Hormonal Status in Women
Women sexual hormones (i.e. estrogen) are involved in the regulation of substrate utilization and storage. Being under oral contraception (OC) may conduct to metabolic and hormonal modific...
Does the consumption of various combinations of mono and disaccharides (lactose, sucrose and fructose) and protein isolates (whey or soy) result in altered substrate absorption, substrate...
Changes in Knee Articular Cartilage Volume in Women on Aromatase Inhibitors
Many women with breast cancer are treated with a class of drugs called aromatase inhibitors (mainly letrozole or anastrozole), which lowers the amount of estrogen being produced in the bod...
The work of Nau et. al (Nau KL, Bromberg MB, Forshew DA, Katcha Vl. Individuals with amyotrophic lateral sclerosis are in caloric balance despite losses in mass. J Neurol Sci 1995;129 :47-...
Insulin Resistance and Substrate Metabolism After Acute Erythropoietin (EPO) Administration
Recently EPO receptors have been found in human muscle tissue, but what is still not known is the physiological role of these receptors. In this study the researchers want to investigate i...
