The Experts below are selected from a list of 267 Experts worldwide ranked by ideXlab platform
Jan Balzarini - One of the best experts on this subject based on the ideXlab platform.
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The Pyrimidine Nucleoside phosphorylase of Mycoplasma hyorhinis and how it may affect Nucleoside-based therapy.
Nucleosides nucleotides & nucleic acids, 2014Co-Authors: Johan Vande Voorde, Sandra Liekens, Federico Gago, Jan BalzariniAbstract:Mycoplasmas are opportunistic parasites and some species are suggested to preferentially colonize tumor tissue in cancer patients. We could demonstrate that the annotated thymidine phosphorylase (TP) gene in the genome of Mycoplasma hyorhinis encodes a Pyrimidine Nucleoside phosphorylase (PyNPHyor) that not only efficiently catalyzes thymidine but also uridine phosphorolysis. The kinetic characteristics of PyNPHyor-catalyzed Nucleoside and Nucleoside analogue (NA) phosphorolysis were determined. We demonstrated that the expression of such an enzyme in mycoplasma-infected cell cultures dramatically alters the activity of various anticancer/antiviral NAs such as 5-halogenated Pyrimidine Nucleosides, including 5-trifluorothymidine (TFT). Due to their close association with human cancers, the presence of mycoplasmas may markedly influence the therapeutic efficiency of Nucleoside-based drugs.
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characterization of Pyrimidine Nucleoside phosphorylase of mycoplasma hyorhinis implications for the clinical efficacy of Nucleoside analogues
Biochemical Journal, 2012Co-Authors: Johan Vande Voorde, Sandra Liekens, Federico Gago, Kristof Vrancken, Jan BalzariniAbstract:In the present paper we demonstrate that the cytostatic and antiviral activity of Pyrimidine Nucleoside analogues is markedly decreased by a Mycoplasma hyorhinis infection and show that the phosphorolytic activity of the mycoplasmas is responsible for this. Since mycoplasmas are (i) an important cause of secondary infections in immunocompromised (e.g. HIV infected) patients and (ii) known to preferentially colonize tumour tissue in cancerpatients,catabolicmycoplasmaenzymesmaycompromise efficient chemotherapy of virus infections and cancer. In the genome of M. hyorhinis ,a TP (thymidine phosphorylase) gene has been annotated. This gene was cloned, expressed in Escherichia coli and kinetically characterized. Whereas the mycoplasma TP efficiently catalyses the phosphorolysis of thymidine (Km =473 μM) and deoxyuridine (Km =578 μM), it prefers uridine (Km =92 μM) as a substrate. Our kinetic data and sequence analysis revealed that the annotated M. hyorhinis TP belongs to the NP (Nucleoside phosphorylase)-II class PyNPs (Pyrimidine NPs), and is distinct from the NP-II class TP and NPI class UPs (uridine phosphorylases). M. hyorhinis PyNP also markedly differs from TP and UP in its substrate specificity towards therapeutic Nucleoside analogues and susceptibility to clinically relevant drugs. Several kinetic properties of mycoplasma PyNP were explained by in silico analyses.
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Retained sensitivity to cytotoxic Pyrimidine Nucleoside analogs in thymidine kinase 2 deficient human fibroblasts.
Nucleosides nucleotides & nucleic acids, 2010Co-Authors: Mia Bjerke, Magnus Johansson, Jan Balzarini, Nicola Solaroli, Nicole Lesko, Anna KarlssonAbstract:Thymidine kinase 2 (TK2) is a mitochondrial deoxyriboNucleoside kinase that phosphorylates several Nucleoside analogs used in anti-viral and anti-cancer therapy. A fibroblast cell line with decreased TK2 activity was investigated in order to obtain insights in the effects of TK2 deficiency on nucleotide metabolism. The role of TK2 for the sensitivity against cytotoxic Nucleoside analogs was also investigated. The TK2 deficient cells retained their sensitivity against all Pyrimidine Nucleoside analogs tested. This study suggests that Nucleoside analog phosphorylation mediated by TK2 may be less important, compared to other deoxyriboNucleoside kinases, for the cytotoxic effects of these compounds.
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bicyclic Pyrimidine Nucleoside analogues bcnas as highly selective and potent inhibitors of varicella zoster virus replication
Journal of Antimicrobial Chemotherapy, 2002Co-Authors: Jan Balzarini, Christopher McguiganAbstract:Bicyclic Pyrimidine Nucleoside analogues (BCNAs) represent highly potent and selective inhibitors of varicella-zoster virus (VZV) replication in cell culture. The compounds inhibit a variety of clinical VZV strains, in the higher picomolar range, whilst being non-toxic at micromolar concentrations. The compounds do not inhibit the closely related simian varicella virus or any other viruses, including herpes simplex virus type 1 (HSV-1), HSV-2 and cytomegalovirus. The BCNAs owe at least part of their antiviral selectivity to a specific activation/phosphorylation by the VZV-encoded thymidine kinase (TK) and associated thymidylate kinase (dTMP-K) activity, while being not recognized by the closely related HSV-1-encoded TK/dTMP-K enzyme. In addition, the 5'-monophosphates of BCNAs are neither a substrate nor an inhibitor of the cellular dTMP-K, and are not subject of back-conversion to the corresponding Nucleosides by 5'-deoxynucleotidases. In contrast to the anti-HSV-1/VZV drug (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), the BCNAs are not catabolized by human (erythrocyte) or bacterial (Escherichia coli) thymidine phosphorylase to release the free bicyclic Pyrimidine base. Also, unlike BVU (the free base of BVDU), the BCNA bases do not inhibit dihydroPyrimidine dehydrogenase. Consequently, the catabolism of the anticancer drug 5-fluorouracil (5-FU) is not influenced by the BCNA base in cell-free enzyme assays or in mice that were exposed to combinations of 5-FU with BCNAs or their free base. BCNAs have a good oral bioavailability and, owing to their highly lipophilic nature, are assumed to be able to cross the blood-brain barrier efficiently. Given the above-mentioned favourable properties, BCNAs may represent a promising novel class of highly selective anti-VZV drugs that should be further pursued for clinical application.
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Bystander effect of purine Nucleoside analogues in HSV-1tk suicide gene therapy is superior to that of Pyrimidine Nucleoside analogues
Gene therapy, 1999Co-Authors: Bart Degrève, E. De Clercq, Jan BalzariniAbstract:Bystander effect of purine Nucleoside analogues in HSV-1tk suicide gene therapy is superior to that of Pyrimidine Nucleoside analogues
Vicky M. Avery - One of the best experts on this subject based on the ideXlab platform.
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Investigation of Pyrimidine Nucleoside analogues as chemical probes to assess compound effects on the proliferation of Trypanosoma cruzi intracellular parasites
PLoS neglected tropical diseases, 2020Co-Authors: Melissa Sykes, David H. Hilko, Livia Isabella Kung, Sally-ann Poulsen, Vicky M. AveryAbstract:Trypanosoma cruzi parasites utilise de novo Pyrimidine biosynthesis to produce DNA and survive within mammalian host cells. This pathway can be hijacked to assess the replication of intracellular parasites with the exogenous addition of a DNA specific probe. To identify suitable probe compounds for this application, a collection of Pyrimidine Nucleoside analogues was assessed for incorporation into T. cruzi intracellular amastigote DNA using image-based technology and script-based analysis. Associated mammalian cell toxicity of these compounds was also determined against both the parasite host cells (3T3 cells) and HEK293 cells. Incorporation of 5-ethynyl-2′-deoxyuridine (EdU) into parasite DNA was the most effective of the probes tested, with minimal growth inhibition observed following either two or four hours EdU exposure. EdU was subsequently utilised as a DNA probe, followed by visualisation with click chemistry to a fluorescent azide, to assess the impact of drugs and compounds with previously demonstrated activity against T. cruzi parasites, on parasite replication. The inhibitory profiles of these molecules highlight the benefit of this approach for identifying surviving parasites post-treatment in vitro and classifying compounds as either fast or slow-acting. F-ara-EdU resulted in
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investigation of Pyrimidine Nucleoside analogues as chemical probes to assess compound effects on the proliferation of trypanosoma cruzi intracellular parasites
PLOS Neglected Tropical Diseases, 2020Co-Authors: Melissa Sykes, David H. Hilko, Sally-ann Poulsen, Livia Kung, Vicky M. AveryAbstract:Trypanosoma cruzi parasites utilise de novo Pyrimidine biosynthesis to produce DNA and survive within mammalian host cells. This pathway can be hijacked to assess the replication of intracellular parasites with the exogenous addition of a DNA specific probe. To identify suitable probe compounds for this application, a collection of Pyrimidine Nucleoside analogues was assessed for incorporation into T. cruzi intracellular amastigote DNA using image-based technology and script-based analysis. Associated mammalian cell toxicity of these compounds was also determined against both the parasite host cells (3T3 cells) and HEK293 cells. Incorporation of 5-ethynyl-2′-deoxyuridine (EdU) into parasite DNA was the most effective of the probes tested, with minimal growth inhibition observed following either two or four hours EdU exposure. EdU was subsequently utilised as a DNA probe, followed by visualisation with click chemistry to a fluorescent azide, to assess the impact of drugs and compounds with previously demonstrated activity against T. cruzi parasites, on parasite replication. The inhibitory profiles of these molecules highlight the benefit of this approach for identifying surviving parasites post-treatment in vitro and classifying compounds as either fast or slow-acting. F-ara-EdU resulted in <50% activity observed against T. cruzi amastigotes following 48 hours incubation, at 73 μM. Collectively, this supports the further development of Pyrimidine Nucleosides as chemical probes to investigate replication of the parasite T. cruzi.
Xuesen Fan - One of the best experts on this subject based on the ideXlab platform.
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ru iii catalyzed oxidative reaction in ionic liquid an efficient and practical route to 2 substituted benzothiazoles and their hybrids with Pyrimidine Nucleoside
Tetrahedron Letters, 2010Co-Authors: Xuesen Fan, Xinying Zhang, Yangyang Wang, Jianji WangAbstract:Abstract An efficient, practical and environmentally benign synthesis of 2-substituted benzothiazoles was developed through RuCl 3 -catalyzed oxidative condensation of 2-aminothiophenol with aldehyde in ionic liquid by using air as the oxidant. With this procedure, a series of 2-substituted benzothiazoles and benzothiazole/Pyrimidine Nucleoside hybrids with antimicrobial activities were efficiently prepared from easily accessible starting materials.
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ionic liquid promoted multi component reaction novel and efficient preparation of pyrazolo 3 4 b pyridinone pyrazolo 3 4 b quinolinone and their hybrids with Pyrimidine Nucleoside
Molecular Diversity, 2010Co-Authors: Xinying Zhang, Xuesen Fan, Xia Wang, Jianji WangAbstract:The utilization of an ionic liquid, [bmim][BF4] as both reaction medium and promoter for a multi-component reaction of aldehyde (1) and 5-amino-3-methyl-1-phenylpyrazole (2) with Meldrum acid (3) or dimedone (5) is studied. From this reaction, pyrazolo[3,4-b]pyridinone (4) and pyrazolo[3,4-b]quinolinone (6) derivatives were prepared in high yields. This novel procedure showed such advantages as environmentally benign nature, enhanced efficiency, simple operation process, and mild reaction conditions. As an application, the procedure was successfully used in the preparation of a set of Pyrimidine Nucleoside–pyrazolo[3,4-b]pyridine and pyrazolo[3,4-b]quinolinone hybrids with potential biological activities.
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Ionic liquid mediated and promoted eco-friendly preparation of thiazolidinone and Pyrimidine Nucleoside-thiazolidinone hybrids and their antiparasitic activities.
Bioorganic & medicinal chemistry letters, 2009Co-Authors: Xinying Zhang, Jianji Wang, Philippe M. Loiseau, Xuesen FanAbstract:Abstract Without any catalyst, 2,3-disubstituted-1,3-thiazolidin-4-one derivatives were synthesized efficiently via the three-component reaction of aldehyde, amine and mercaptoacetic acid in [bmim][PF6]. The whole procedure is simple and straightforward and no aqueous work-up is needed. By employing this protocol, a series of novel Pyrimidine Nucleoside–thiazolidin-4-one hybrids were prepared and their preliminary antiparasitic activities were also studied and reported.
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Ionic liquid promoted preparation of 4H-thiopyran and Pyrimidine Nucleoside-thiopyran hybrids through one-pot multi-component reaction of thioamide
Molecular diversity, 2008Co-Authors: Xinying Zhang, Xuesen Fan, Xia Wang, Jianji WangAbstract:One-pot multi-component reactions of aldehydes, cyanothioacetamide and malononitrile promoted by ionic liquid proved to be an efficient way for the synthesis of thiopyran derivatives. Without any added catalyst, both aromatic and aliphatic aldehydes participated in this reaction smoothly. As an application of this method, a Pyrimidine Nucleoside-thiopyran chimera with potential biological activities was obtained in high yield from 5-formyl-2’-deoxyuridine. In addition, the ionic liquid used can be easily recovered and effectively reused for at least 5 times.
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a Pyrimidine pyrazolone Nucleoside chimera with potent in vitro anti orthopoxvirus activity
Bioorganic & Medicinal Chemistry Letters, 2006Co-Authors: Xuesen Fan, Xinying Zhang, Longhu Zhou, Kathy A Keith, Earl R Kern, Paul F TorrenceAbstract:Synthetic hybridization of two privileged drug scaffolds, pyrazolone on the one hand and Pyrimidine Nucleoside on the other, resulted in the generation of two novel 5-substituted Pyrimidine Nucleosides with potent in vitro antiviral activity against two representative orthopoxviruses, vaccinia virus and cowpox virus.
Erik De Clercq - One of the best experts on this subject based on the ideXlab platform.
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highly potent and selective inhibition of varicella zoster virus replication by bicyclic furo 2 3 d Pyrimidine Nucleoside analogues
Medicinal Research Reviews, 2003Co-Authors: Erik De ClercqAbstract:The bicyclic furo[2,3-d]Pyrimidine Nucleoside analogues represent an entirely new class of fused furoPyrimidine derivatives with unprecedented selectivity for varicella-zoster virus (VZV). From extensive structure-activity relationship (SAR) studies, the 6-(p-alkylphenyl)substituted furoPyrimidine derivatives Cf 1742 and Cf 1743 emerged as the most potent inhibitors of VZV replication: they were found to inhibit both laboratory VZV strains and clinical VZV isolates at subnanomolar concentrations, while not being toxic to the host cells at 100,000-fold higher concentrations. Although the precise mechanism of action of these compounds remains to be elucidated, it is clear that for their antiviral activity they depend on phosphorylation by the VZV-encoded thymidine kinase. The furo[2,3-d]Pyrimidine Nucleoside analogues are not susceptible to degradation by human or bacterial thymidine phosphorylase, which may otherwise release the free aglycone. Also, the latter is not inhibitory to dihydroPyrimidine dehydrogenase, an enzyme involved in the degradation of thymine, uracil, and the anticancer agent 5-fluorouracil. Further development of the furo[2,3-d]Pyrimidine Nucleoside analogues as new therapeutic modalities for the treatment of VZV infections (i.e., varicella and herpes zoster) seems highly justified.
Melissa Sykes - One of the best experts on this subject based on the ideXlab platform.
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Investigation of Pyrimidine Nucleoside analogues as chemical probes to assess compound effects on the proliferation of Trypanosoma cruzi intracellular parasites
PLoS neglected tropical diseases, 2020Co-Authors: Melissa Sykes, David H. Hilko, Livia Isabella Kung, Sally-ann Poulsen, Vicky M. AveryAbstract:Trypanosoma cruzi parasites utilise de novo Pyrimidine biosynthesis to produce DNA and survive within mammalian host cells. This pathway can be hijacked to assess the replication of intracellular parasites with the exogenous addition of a DNA specific probe. To identify suitable probe compounds for this application, a collection of Pyrimidine Nucleoside analogues was assessed for incorporation into T. cruzi intracellular amastigote DNA using image-based technology and script-based analysis. Associated mammalian cell toxicity of these compounds was also determined against both the parasite host cells (3T3 cells) and HEK293 cells. Incorporation of 5-ethynyl-2′-deoxyuridine (EdU) into parasite DNA was the most effective of the probes tested, with minimal growth inhibition observed following either two or four hours EdU exposure. EdU was subsequently utilised as a DNA probe, followed by visualisation with click chemistry to a fluorescent azide, to assess the impact of drugs and compounds with previously demonstrated activity against T. cruzi parasites, on parasite replication. The inhibitory profiles of these molecules highlight the benefit of this approach for identifying surviving parasites post-treatment in vitro and classifying compounds as either fast or slow-acting. F-ara-EdU resulted in
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investigation of Pyrimidine Nucleoside analogues as chemical probes to assess compound effects on the proliferation of trypanosoma cruzi intracellular parasites
PLOS Neglected Tropical Diseases, 2020Co-Authors: Melissa Sykes, David H. Hilko, Sally-ann Poulsen, Livia Kung, Vicky M. AveryAbstract:Trypanosoma cruzi parasites utilise de novo Pyrimidine biosynthesis to produce DNA and survive within mammalian host cells. This pathway can be hijacked to assess the replication of intracellular parasites with the exogenous addition of a DNA specific probe. To identify suitable probe compounds for this application, a collection of Pyrimidine Nucleoside analogues was assessed for incorporation into T. cruzi intracellular amastigote DNA using image-based technology and script-based analysis. Associated mammalian cell toxicity of these compounds was also determined against both the parasite host cells (3T3 cells) and HEK293 cells. Incorporation of 5-ethynyl-2′-deoxyuridine (EdU) into parasite DNA was the most effective of the probes tested, with minimal growth inhibition observed following either two or four hours EdU exposure. EdU was subsequently utilised as a DNA probe, followed by visualisation with click chemistry to a fluorescent azide, to assess the impact of drugs and compounds with previously demonstrated activity against T. cruzi parasites, on parasite replication. The inhibitory profiles of these molecules highlight the benefit of this approach for identifying surviving parasites post-treatment in vitro and classifying compounds as either fast or slow-acting. F-ara-EdU resulted in <50% activity observed against T. cruzi amastigotes following 48 hours incubation, at 73 μM. Collectively, this supports the further development of Pyrimidine Nucleosides as chemical probes to investigate replication of the parasite T. cruzi.
