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Purine Synthesis Inhibitor

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1. Maintenance treatment using the purine-synthesis inhibitor mizoribine in a patient with relapsing thrombotic thrombocytopenic purpura Full Text available with Trip Pro

Maintenance treatment using the purine-synthesis inhibitor mizoribine in a patient with relapsing thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening disease. Although plasma exchange (PE) therapy and corticosteroids are standard remission induction and maintenance therapies, some patients are easily refractory and frequently relapse under treatment with this therapy, and require additional treatment. However, there are limited data about (...) additional treatment interventions. We report a case of 56-year-old man who was hospitalized for fever, general fatigue and hemoglobinuria. Owing to the symptoms and the laboratory findings of hemolysis, he was diagnosed with TTP. He was treated with PE therapy and corticosteroids, and the TTP went into remission. However, his TTP relapsed and remission induction was attempted again. As a remission maintenance treatment, we used combination therapy with the purine-synthesis inhibitor mizoribine (MZR

2017 CEN Case Reports

2. Purine Synthesis Inhibitor

Purine Synthesis Inhibitor Purine Synthesis Inhibitor Toggle navigation Brain Head & Neck Chest Endocrine Abdomen Musculoskeletal Skin Infectious Disease Hematology & Oncology Cohorts Diagnostics Emergency Findings Procedures Prevention & Management Pharmacy Resuscitation Trauma Emergency Procedures Ultrasound Cardiovascular Emergencies Lung Emergencies Infectious Disease Pediatrics Neurologic Emergencies Skin Exposure Miscellaneous Abuse Cancer Administration 4 Purine Synthesis Inhibitor (...) Purine Synthesis Inhibitor Aka: Purine Synthesis Inhibitor , Mycophenolate , Cellcept , Mycophenolic acid , MyFortic II. Indications immunosuppression (maintenance prevention of rejection) III. Adverse Effects: Mycophenolate or Mycophenolic acid See ( ) suppression Gastrointestinal adverse effects (e.g. , , , ) IV. Preparations ( ) Mycophenolate (Cellcept) Mycophenolic acid (MyFortic) V. Drug Interactions See Agents that increase Purine Synthesis Inhibitor concentrations Valganciclovir (Valcyte

2018 FP Notebook

3. Study of purinosome assembly in cell-based model systems with de novo purine synthesis and salvage pathway deficiencies. Full Text available with Trip Pro

Study of purinosome assembly in cell-based model systems with de novo purine synthesis and salvage pathway deficiencies. The enzymes involved in de novo purine synthesis (DNPS), one of the basic processes in eukaryotic cells, transiently and reversibly form a dynamic multienzyme complex called the purinosome in the cytoplasm. The purinosome has been observed in a broad spectrum of cells, but some studies claim that it is an artefact of the constructs used for visualization or stress granules (...) medium.In conclusion, both methods are useful for the detection of purinosomes in HeLa cells. Moreover, the cell-based models prepared represent a unique system for the study of purinosome assembly with deficiencies in DNPS or in the salvage pathway as well as for the study of purinosome formation under the action of DNPS inhibitors. This approach is a promising step toward the treatment of purine disorders and can also provide targets for anticancer therapy.

2018 PLoS ONE

4. Synthesis of 2,6-Diamino-Substituted Purine Derivatives and Evaluation of Cell Cycle Arrest in Breast and Colorectal Cancer Cells Full Text available with Trip Pro

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

2018 Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry

5. Design and synthesis of chalcone derivatives as potential non-purine xanthine oxidase inhibitors Full Text available with Trip Pro

Design and synthesis of chalcone derivatives as potential non-purine xanthine oxidase inhibitors Based on some previous research, the chalcone derivatives exhibited potent xanthine oxidase inhibitory activity, e.g. sappanchalcone (7), with IC50 value of 3.9 μM, was isolated from Caesalpinia sappan. Therefore, objectives of this research are design and synthesis of 7 and other chalcone derivatives by Claisen-Schmidt condensation and then evaluate their XO inhibitory activity.Fifteen chalcone (...) sappanchalcone (7) by Claisen-Schmidt condensation. The overall yield of this procedure was 6.6 %, higher than that of reported procedure (4 %). Design, synthesis, and evaluation of chalcone derivatives were carried out. This result suggests that the chalcone derivative can be used as potential non-purine XO inhibitors.Graphical abstractThe chalcone derivatives as potential non-purine xanthine oxidase inhibitors.

2016 SpringerPlus

6. Synthesis and Evaluation of 2,6-Modified Purine 2′-C-Methyl Ribonucleosides as Inhibitors of HCV Replication Full Text available with Trip Pro

Synthesis and Evaluation of 2,6-Modified Purine 2′-C-Methyl Ribonucleosides as Inhibitors of HCV Replication A variety of 2,6-modified purine 2'-C-methylribonucleosides and their phosphoramidate prodrugs were synthesized and evaluated for inhibition of HCV RNA replication in Huh-7 cells and for cytotoxicity in various cell lines. Cellular pharmacology and HCV polymerase incorporation studies on the most potent and selective compound are reported.

2015 ACS medicinal chemistry letters

7. Synthesis and Biological Evaluation of Novel Hybrid Molecules Containing Purine, Coumarin and Isoxazoline or Isoxazole Moieties Full Text available with Trip Pro

Synthesis and Biological Evaluation of Novel Hybrid Molecules Containing Purine, Coumarin and Isoxazoline or Isoxazole Moieties The 1,3-dipolar cycloaddition reactions of nitrile oxides formed in situ (in the presence of NCS and Et3N) from the oximes of (purin-9-yl)acetaldehyde or (coumarinyloxy)acetaldehyde with allyloxycoumarins or 9-allylpurines, respectively resulted in 3,5-disubstituted isoxazolines. The similar reactions of propargyloxycoumarins or 9-propargylpurines led to 3,5 (...) -disubstituted isoxazoles by treatment with PIDA and catalytic amount of TFA.The new compounds were tested in vitro as antioxidant agents and inhibitors of soybean lipoxygenase LO, AChE and MAO-B.The majority of the compounds showed significant hydroxyl radical scavenging activity. Compounds 4k and 4n presented LO inhibitory activity.Compound 13e presents an antioxidant significant profile combining anti-LO, anti-AChE and anti-MAO-B activities.

2017 The open medicinal chemistry journal

8. Small molecule purine and pseudopurine derivatives: synthesis, cytostatic evaluations and investigation of growth inhibitory effect in non-small cell lung cancer A549 Full Text available with Trip Pro

Small molecule purine and pseudopurine derivatives: synthesis, cytostatic evaluations and investigation of growth inhibitory effect in non-small cell lung cancer A549 Novel halogenated purines and pseudopurines with diverse aryl-substituted 1,2,3-triazoles were prepared. While p-(trifluoromethyl)-substituted 1,2,3-triazole in N-9 alkylated purine and 3-deazapurine was critical for strong albeit unselective activity on pancreatic adenocarcinoma cells CFPAC-1,1-(p-fluorophenyl)-1,2,3-triazole (...) derivative of 7-deazapurine showed selective cytostatic effect on metastatic colon cancer cells SW620. Importantly, 1-(p-chlorophenyl)-1,2,3-triazole-tagged benzimidazole displayed the most pronounced and highly selective inhibitory effect in nM range on non-small cell lung cancer A549. This compound revealed to target molecular processes at the extracellular side and inside the plasma membrane regulated by GPLD1 and growth factor receptors PDGFR and IGF-1R leading to the inhibition of cell proliferation

2017 Journal of enzyme inhibition and medicinal chemistry

9. Purine synthesis promotes maintenance of brain tumor initiating cells in glioma Full Text available with Trip Pro

Purine synthesis promotes maintenance of brain tumor initiating cells in glioma Brain tumor initiating cells (BTICs), also known as cancer stem cells, hijack high-affinity glucose uptake active normally in neurons to maintain energy demands. Here we link metabolic dysregulation in human BTICs to a nexus between MYC and de novo purine synthesis, mediating glucose-sustained anabolic metabolism. Inhibiting purine synthesis abrogated BTIC growth, self-renewal and in vivo tumor formation (...) by depleting intracellular pools of purine nucleotides, supporting purine synthesis as a potential therapeutic point of fragility. In contrast, differentiated glioma cells were unaffected by the targeting of purine biosynthetic enzymes, suggesting selective dependence of BTICs. MYC coordinated the control of purine synthetic enzymes, supporting its role in metabolic reprogramming. Elevated expression of purine synthetic enzymes correlated with poor prognosis in glioblastoma patients. Collectively, our

2017 Nature neuroscience

10. Synthesis and evaluation of analogs of 5'-(((Z)-4-amino-2-butenyl)methylamino)-5'-deoxyadenosine (MDL 73811, or AbeAdo) – an inhibitor of S-adenosylmethionine decarboxylase with antitrypanosomal activity Full Text available with Trip Pro

Synthesis and evaluation of analogs of 5'-(((Z)-4-amino-2-butenyl)methylamino)-5'-deoxyadenosine (MDL 73811, or AbeAdo) – an inhibitor of S-adenosylmethionine decarboxylase with antitrypanosomal activity We describe our efforts to improve the pharmacokinetic properties of a mechanism-based suicide inhibitor of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (AdoMetDC), essential for the survival of the eukaryotic parasite Trypanosoma brucei responsible for Human African (...) Trypanosomiasis (HAT). The lead compound, 5'-(((Z)-4-amino-2-butenyl)methylamino)-5'-deoxyadenosine (1, also known as MDL 73811, or AbeAdo), has curative efficacy at a low dosage in a hemolymphatic model of HAT but displayed no demonstrable effect in a mouse model of the CNS stage of HAT due to poor blood-brain barrier permeation. Therefore, we prepared and evaluated an extensive set of analogs with modifications in the aminobutenyl side chain, the 5'-amine, the ribose, and the purine fragments. Although we

2017 Bioorganic & medicinal chemistry

11. Mass spectrometric analysis of purine de novo biosynthesis intermediates. Full Text available with Trip Pro

Mass spectrometric analysis of purine de novo biosynthesis intermediates. Purines are essential molecules for all forms of life. In addition to constituting a backbone of DNA and RNA, purines play roles in many metabolic pathways, such as energy utilization, regulation of enzyme activity, and cell signaling. The supply of purines is provided by two pathways: the salvage pathway and de novo synthesis. Although purine de novo synthesis (PDNS) activity varies during the cell cycle, this pathway (...) represents an important source of purines, especially for rapidly dividing cells. A method for the detailed study of PDNS is lacking for analytical reasons (sensitivity) and because of the commercial unavailability of the compounds. The aim was to fully describe the mass spectrometric fragmentation behavior of newly synthesized PDNS-related metabolites and develop an analytical method. Except for four initial ribotide PDNS intermediates that preferentially lost water or phosphate or cleaved the forming

2018 PLoS ONE

12. Purine Synthesis Inhibitor

Purine Synthesis Inhibitor Purine Synthesis Inhibitor Toggle navigation Brain Head & Neck Chest Endocrine Abdomen Musculoskeletal Skin Infectious Disease Hematology & Oncology Cohorts Diagnostics Emergency Findings Procedures Prevention & Management Pharmacy Resuscitation Trauma Emergency Procedures Ultrasound Cardiovascular Emergencies Lung Emergencies Infectious Disease Pediatrics Neurologic Emergencies Skin Exposure Miscellaneous Abuse Cancer Administration 4 Purine Synthesis Inhibitor (...) Purine Synthesis Inhibitor Aka: Purine Synthesis Inhibitor , Mycophenolate , Cellcept , Mycophenolic acid , MyFortic II. Indications immunosuppression (maintenance prevention of rejection) III. Adverse Effects: Mycophenolate or Mycophenolic acid See ( ) suppression Gastrointestinal adverse effects (e.g. , , , ) IV. Preparations ( ) Mycophenolate (Cellcept) Mycophenolic acid (MyFortic) V. Drug Interactions See Agents that increase Purine Synthesis Inhibitor concentrations Valganciclovir (Valcyte

2016 FP Notebook

13. Dyrk3 loss activates the purine metabolism and promotes hepatocellular carcinoma progression. (Abstract)

) -phosphorylation-regulated kinase 3 (Dyrk3) in HCC metabolism. Dyrk3 was significantly downregulated in HCC compared with normal controls. Its introduction in HCC cells markedly suppressed tumor growth and metastasis in xenograft tumor models. Mass spectrometry analysis of metabolites suggests that the effect of Dyrk3 on HCC occurred at least partially through downregulating purine metabolism, as evidenced by the fact that inhibiting purine synthesis reverted the HCC progression mediated by the loss of Dyrk3 (...) . We further provide evidence that this action of Dyrk3 knockdown requires nuclear receptor coactivator 3 (NCOA3), which previously has been shown as a coactivator of activating transcription factor 4 (ATF4) to target purine pathway genes for transcriptional activation. Mechanistically, Dyrk3 directly phosphorylated NCOA3 at Ser-1330, disrupting its binding to ATF4 and thereby causing the inhibition of ATF4 transcription activity. However, phosphorylation-resistant NCOA3-S1330A mutant has

2019 Hepatology

14. Versatile synthesis and biological evaluation of novel 3’-fluorinated purine nucleosides Full Text available with Trip Pro

Versatile synthesis and biological evaluation of novel 3’-fluorinated purine nucleosides A unified synthetic strategy accessing novel 3'-fluorinated purine nucleoside derivatives and their biological evaluation were achieved. Novel 3'-fluorinated analogues were constructed from a common 3'-deoxy-3'-fluororibofuranose intermediate. Employing Suzuki and Stille cross-coupling reactions, fifteen 3'-fluororibose purine nucleosides 1-15 and eight 3'-fluororibose 2-chloro/2-aminopurine nucleosides (...) 16-23 with various substituents at position 6 of the purine ring were efficiently synthesized. Furthermore, 3'-fluorine analogs of natural products nebularine and 6-methylpurine riboside were constructed via our convergent synthetic strategy. Synthesized nucleosides were tested against HT116 (colon cancer) and 143B (osteosarcoma cancer) tumor cell lines. We have demonstrated 3'-fluorine purine nucleoside analogues display potent tumor cell growth inhibition activity at sub- or low micromolar

2015 Beilstein journal of organic chemistry

15. The mTORC1 signaling network senses changes in cellular purine nucleotide levels Full Text available with Trip Pro

The mTORC1 signaling network senses changes in cellular purine nucleotide levels Mechanistic (or mammalian) target of rapamycin complex 1 (mTORC1) integrates signals from growth factors and nutrients to control biosynthetic processes, including protein, lipid, and nucleic acid synthesis. We find that the mTORC1 pathway is responsive to changes in purine nucleotides in a manner analogous to its sensing of amino acids. Depletion of cellular purines, but not pyrimidines, inhibits mTORC1 (...) , and restoration of intracellular adenine nucleotides via addition of exogenous purine nucleobases or nucleosides acutely reactivates mTORC1. Adenylate sensing by mTORC1 is dependent on the tuberous sclerosis complex (TSC) protein complex and its regulation of Rheb upstream of mTORC1, but independent of energy stress and AMP-activated protein kinase (AMPK). Even though mTORC1 signaling is not acutely sensitive to changes in intracellular guanylates, long-term depletion of guanylates decreases Rheb protein

2017 Cell reports

16. A PHGDH inhibitor reveals coordination of serine synthesis and 1-carbon unit fate Full Text available with Trip Pro

A PHGDH inhibitor reveals coordination of serine synthesis and 1-carbon unit fate Serine is both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical pathway of glucose-derived serine synthesis, Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, rate-limiting step. Genetic loss of PHGDH is toxic toward PHGDH-overexpressing breast cancer cell lines even in the presence of exogenous serine (...) . Here, we used a quantitative high-throughput screen to identify small-molecule PHGDH inhibitors. These compounds reduce the production of glucose-derived serine in cells and suppress the growth of PHGDH-dependent cancer cells in culture and in orthotopic xenograft tumors. Surprisingly, PHGDH inhibition reduced the incorporation into nucleotides of one-carbon units from glucose-derived and exogenous serine. We conclude that glycolytic serine synthesis coordinates the use of one-carbon units from

2016 Nature chemical biology

17. Synthesis of a Norcantharidin-tethered Guanosine: Protein Phosphatase-1 Inhibitors That Change Alternative Splicing Full Text available with Trip Pro

Synthesis of a Norcantharidin-tethered Guanosine: Protein Phosphatase-1 Inhibitors That Change Alternative Splicing Phosphorylation and dephosphorylation of splicing factors play a key role in pre-mRNA splicing events, and cantharidin and norcantharidin analogs inhibit protein phosphatase-1 (PP1) and change alternative pre-mRNA splicing. Targeted inhibitors capable of selectively inhibiting PP-1 could promote exon 7 inclusion in the survival-of-motorneuron-2 gene (SMN2) and shift the proportion (...) of SMN2 protein from a dysfunctional to a functional form. As a prelude to the development of norcantharidin-tethered oligonucleotide inhibitors, the synthesis a norcantharidin-tethered guanosine was developed in which a suitable tether prevented the undesired cyclization of norcantharidin monoamides to imides and possessed a secondary amine terminus suited to the synthesis of oligonucleotides analogs. Application of this methodology led to the synthesis of a diastereomeric mixture of norcantharidin

2015 Bioorganic & medicinal chemistry letters

18. The Effects of Azathioprine (Imuran) on Purine Synthesis in Clinical Disorders of Purine Metabolism Full Text available with Trip Pro

The Effects of Azathioprine (Imuran) on Purine Synthesis in Clinical Disorders of Purine Metabolism Azathioprine, a purine analogue, significantly suppressed the purine synthesis de novo of two gouty patients manifesting overproduction of uric acid, as well as three of four gouty patients who showed normal uric acid production. This suppression is taken as evidence that phosphoribosyl-pyrophosphate amidotransferase, the rate-controlling step in purine synthesis de novo, has a normal sensitivity (...) to feedback inhibitors in the patients who responded to the drug.Two children afflicted with the familial disorder of hyperuricemia, choreo-athetosis, and self-mutilation described by Lesch and Nyhan showed no reduction in the activity of the biosynthetic pathway in response to azathioprine. This inability to respond to azathioprine can be directly related to the absence in these patients of the enzyme hypoxanthine-guanine phosphoribosyltransferase which is required for conversion of the drug or its

1967 Journal of Clinical Investigation

19. A systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors alone or in combination with alpha-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia

not state how many reviewers assessed study quality. Data extraction Primary outcome data were extracted to calculate mean differences between treatment and comparison groups. Numbers (%) of adverse events related to phosphodiesterase type 5 inhibitors were extracted. Two reviewers independently extracted data. Disagreements were referred to a third reviewer. Methods of synthesis A random-effects model was used to calculate standardised mean differences (SMD) and 95% confidence intervals for the primary (...) therapy; Male; Phosphodiesterase 5 Inhibitors /therapeutic use; Piperazines /therapeutic use; Prostatic Hyperplasia /drug therapy; Purines /therapeutic use; Pyrimidines /therapeutic use; Sildenafil Citrate; Sulfonamides /therapeutic use; Sulfones /therapeutic use; Tadalafil; Treatment Outcome; Triazines /therapeutic use; Vardenafil Dihydrochloride AccessionNumber 12012019962 Date bibliographic record published 30/06/2012 Date abstract record published 11/02/2014 Record Status This is a critical

2012 DARE.

20. Inhibition of De Novo Purine Biosynthesis and Interconversion by 6-Methylpurine in Escherichia coli Full Text available with Trip Pro

Inhibition of De Novo Purine Biosynthesis and Interconversion by 6-Methylpurine in Escherichia coli The inhibition of Escherichia coli strain B and strain W-11 by 6-methylpurine depended on the formation of 6-methylpurine ribonucleotide by the action of adenine phosphoribosyltransferase (AMP: pyrophosphate phosphoribosyltransferase, EC 2.4.2.7). 6-Methylpurine ribonucleotide inhibited the de novo synthesis of purines, presumably via pseudofeedback inhibition of phosphoribosylpyrophosphate (...) amidotransferase (EC 2.4.2.14). The same mechanism accounted for its inhibition of adenylosuccinate synthetase [IMP: l-aspartate ligase (GDP), EC 6.3.4.4]. Adenine and 6-methylaminopurine prevented inhibition by competing for the action of adenine phosphoribosyltransferase. In addition, adenine reversed this inhibition by replenishing the AMP to bypass both sites of inhibition. Nonproliferating suspensions of strain B-94, which lacked adenylosuccinate lyase (EC 4.3.2.2), converted exogenous hypoxanthine

1970 Journal of bacteriology

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