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Vern L Schramm - One of the best experts on this subject based on the ideXlab platform.
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a β fluoroamine inhibitor of Purine Nucleoside phosphorylase
Journal of Medicinal Chemistry, 2008Co-Authors: Jennifer M Mason, Vern L Schramm, Graeme J Gainsford, Andrew S Murkin, Brian W SkeltonAbstract:The potent immucillin Purine Nucleoside phosphorylase (PNP) inhibitors F-DADMe-ImmH [(3S,4S)-3], and [(3R,4R)-3] are synthesized in seven steps. Cycloaddition to a fluoroalkene and an enzymic resolution are the key features of the construction of the fluoropyrrolidines 11, from which the immucillins are assembled by use of a three-component Mannich reaction. Slow-onset binding constants (Ki∗) for [(3S,4S)-3] and [(3R,4R)-3] with human PNP are 0.032 and 1.82 nM, respectively. F-DADMe-ImmH [(3S,4S)-3] exhibits oral availability in mice at doses as low as 0.2 mg/kg.
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synthesis of a transition state analogue inhibitor of Purine Nucleoside phosphorylase via the mannich reaction
Organic Letters, 2003Co-Authors: Gary B Evans, Richard H Furneaux, Peter C Tyler, Vern L SchrammAbstract:The expeditious convergent synthesis of the potent human Purine Nucleoside phosphorylase inhibitor DADMe-Immucillin-G (3) was achieved via the Mannich reaction. The Mannich chemistry of a series of deazaPurines and amine hydrochlorides was also investigated.
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exploring structure activity relationships of transition state analogues of human Purine Nucleoside phosphorylase
Journal of Medicinal Chemistry, 2003Co-Authors: Gary B Evans, Richard H Furneaux, Andrzej Lewandowicz, Vern L Schramm, Peter C TylerAbstract:The aza-C-Nucleosides, Immucillin-H and Immucillin-G, are transition state analogue inhibitors of Purine Nucleoside phosphorylase, a therapeutic target for the control of T-cell proliferation. Immucillin analogues modified at the 2‘-, 3‘-, or 5‘-positions of the azasugar moiety or at the 6-, 7-, or 8-positions of the deazaPurine, as well as methylene-bridged analogues, have been synthesized and tested for their inhibition of human Purine Nucleoside phosphorylase. All analogues were poorer inhibitors, which reflects the superior capture of transition state features in the parent immucillins.
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synthesis of transition state analogue inhibitors for Purine Nucleoside phosphorylase and n riboside hydrolases
Tetrahedron, 2000Co-Authors: Gary B Evans, Richard H Furneaux, Vern L Schramm, Graeme J Gainsford, Peter C TylerAbstract:Abstract Syntheses of the ‘Immucillins’, potent aza-C-Nucleoside inhibitors of Purine Nucleoside phosphorylase are reported as well as those of 5-deoxy-, 5-deoxyfluoro- and 2-deoxy- analogues and others having modified bases.
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one third the sites transition state inhibitors for Purine Nucleoside phosphorylase
Biochemistry, 1998Co-Authors: Robert W Miles, Richard H Furneaux, Peter C Tyler, Carey K Bagdassarian, Vern L SchrammAbstract:Genetic defects in human Purine Nucleoside phosphorylase cause T-cell deficiency as the major phenotype. It has been proposed that efficient inhibitors of the enzyme might intervene in disorders of...
Leila Parvaneh - One of the best experts on this subject based on the ideXlab platform.
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Case report Progressive multifocal leukoencephalopathy in Purine Nucleoside phosphorylase deficiency
2007Co-Authors: Nima Parvaneh, Nima Pouladi, Fatemeh Sayarifar, Mehdi Yeganeh, Mahmoud Reza Ashrafi, Leila ParvanehAbstract:Progressive multifocal leukoencephalopathy is a demyelinating disease caused by JC virus, an opportunistic infection of the central nervous system. Although the majority of cases are infected with the human immunodeficiency virus (HIV), other immunocompromised patients are also at risk. Purine Nucleoside phosphorylase is an enzyme in the Purine salvage pathway that reversibly converts inosine to hypoxanthine and guanosine to guanine. Purine Nucleoside phosphorylase deficiency is a combined immunodeficiency with a profound cellular defect. Neurologic abnormalities are salient features of this syndrome. We describe for the first time a patient with this rare disorder presented with progressive multifocal leukoencephalopathy. 2006 Elsevier B.V. All rights reserved.
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Progressive multifocal leukoencephalopathy in Purine Nucleoside phosphorylase deficiency.
Brain & Development, 2006Co-Authors: Nima Parvaneh, Nima Pouladi, Fatemeh Sayarifar, Mehdi Yeganeh, Mahmoud Reza Ashrafi, Leila ParvanehAbstract:Progressive multifocal leukoencephalopathy is a demyelinating disease caused by JC virus, an opportunistic infection of the central nervous system. Although the majority of cases are infected with the human immunodeficiency virus (HIV), other immunocompromised patients are also at risk. Purine Nucleoside phosphorylase is an enzyme in the Purine salvage pathway that reversibly converts inosine to hypoxanthine and guanosine to guanine. Purine Nucleoside phosphorylase deficiency is a combined immunodeficiency with a profound cellular defect. Neurologic abnormalities are salient features of this syndrome. We describe for the first time a patient with this rare disorder presented with progressive multifocal leukoencephalopathy.
Peter C Tyler - One of the best experts on this subject based on the ideXlab platform.
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inhibition and structure of trichomonas vaginalis Purine Nucleoside phosphorylase with picomolar transition state analogues
Biochemistry, 2007Co-Authors: Agnes Rinaldomatthis, Gary B Evans, Richard H Furneaux, Peter C Tyler, Corin Wing, Mahmoud Ghanem, Hua Deng, Peng Wu, Arti Gupta, Steven C AlmoAbstract:Trichomonas vaginalis is a parasitic protozoan Purine auxotroph possessing a unique Purine salvage pathway consisting of a bacterial type Purine Nucleoside phosphorylase (PNP) and a Purine Nucleoside kinase. Thus, T. vaginalis PNP (TvPNP) functions in the reverse direction relative to the PNPs in other organisms. Immucillin-A (ImmA) and DADMe-Immucillin-A (DADMe-ImmA) are transition state mimics of adenosine with geometric and electrostatic features that resemble early and late transition states of adenosine at the transition state stabilized by TvPNP. ImmA demonstrates slow-onset tight-binding inhibition with TvPNP, to give an equilibrium dissociation constant of 87 pM, an inhibitor release half-time of 17.2 min, and a Km/Kd ratio of 70,100. DADMe-ImmA resembles a late ribooxacarbenium ion transition state for TvPNP to give a dissociation constant of 30 pM, an inhibitor release half-time of 64 min, and a Km/Kd ratio of 203,300. The tight binding of DADMe-ImmA supports a late SN1 transition state. Despite...
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synthesis of a transition state analogue inhibitor of Purine Nucleoside phosphorylase via the mannich reaction
Organic Letters, 2003Co-Authors: Gary B Evans, Richard H Furneaux, Peter C Tyler, Vern L SchrammAbstract:The expeditious convergent synthesis of the potent human Purine Nucleoside phosphorylase inhibitor DADMe-Immucillin-G (3) was achieved via the Mannich reaction. The Mannich chemistry of a series of deazaPurines and amine hydrochlorides was also investigated.
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exploring structure activity relationships of transition state analogues of human Purine Nucleoside phosphorylase
Journal of Medicinal Chemistry, 2003Co-Authors: Gary B Evans, Richard H Furneaux, Andrzej Lewandowicz, Vern L Schramm, Peter C TylerAbstract:The aza-C-Nucleosides, Immucillin-H and Immucillin-G, are transition state analogue inhibitors of Purine Nucleoside phosphorylase, a therapeutic target for the control of T-cell proliferation. Immucillin analogues modified at the 2‘-, 3‘-, or 5‘-positions of the azasugar moiety or at the 6-, 7-, or 8-positions of the deazaPurine, as well as methylene-bridged analogues, have been synthesized and tested for their inhibition of human Purine Nucleoside phosphorylase. All analogues were poorer inhibitors, which reflects the superior capture of transition state features in the parent immucillins.
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synthesis of transition state analogue inhibitors for Purine Nucleoside phosphorylase and n riboside hydrolases
Tetrahedron, 2000Co-Authors: Gary B Evans, Richard H Furneaux, Vern L Schramm, Graeme J Gainsford, Peter C TylerAbstract:Abstract Syntheses of the ‘Immucillins’, potent aza-C-Nucleoside inhibitors of Purine Nucleoside phosphorylase are reported as well as those of 5-deoxy-, 5-deoxyfluoro- and 2-deoxy- analogues and others having modified bases.
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one third the sites transition state inhibitors for Purine Nucleoside phosphorylase
Biochemistry, 1998Co-Authors: Robert W Miles, Richard H Furneaux, Peter C Tyler, Carey K Bagdassarian, Vern L SchrammAbstract:Genetic defects in human Purine Nucleoside phosphorylase cause T-cell deficiency as the major phenotype. It has been proposed that efficient inhibitors of the enzyme might intervene in disorders of...
Richard H Furneaux - One of the best experts on this subject based on the ideXlab platform.
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inhibition and structure of trichomonas vaginalis Purine Nucleoside phosphorylase with picomolar transition state analogues
Biochemistry, 2007Co-Authors: Agnes Rinaldomatthis, Gary B Evans, Richard H Furneaux, Peter C Tyler, Corin Wing, Mahmoud Ghanem, Hua Deng, Peng Wu, Arti Gupta, Steven C AlmoAbstract:Trichomonas vaginalis is a parasitic protozoan Purine auxotroph possessing a unique Purine salvage pathway consisting of a bacterial type Purine Nucleoside phosphorylase (PNP) and a Purine Nucleoside kinase. Thus, T. vaginalis PNP (TvPNP) functions in the reverse direction relative to the PNPs in other organisms. Immucillin-A (ImmA) and DADMe-Immucillin-A (DADMe-ImmA) are transition state mimics of adenosine with geometric and electrostatic features that resemble early and late transition states of adenosine at the transition state stabilized by TvPNP. ImmA demonstrates slow-onset tight-binding inhibition with TvPNP, to give an equilibrium dissociation constant of 87 pM, an inhibitor release half-time of 17.2 min, and a Km/Kd ratio of 70,100. DADMe-ImmA resembles a late ribooxacarbenium ion transition state for TvPNP to give a dissociation constant of 30 pM, an inhibitor release half-time of 64 min, and a Km/Kd ratio of 203,300. The tight binding of DADMe-ImmA supports a late SN1 transition state. Despite...
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synthesis of a transition state analogue inhibitor of Purine Nucleoside phosphorylase via the mannich reaction
Organic Letters, 2003Co-Authors: Gary B Evans, Richard H Furneaux, Peter C Tyler, Vern L SchrammAbstract:The expeditious convergent synthesis of the potent human Purine Nucleoside phosphorylase inhibitor DADMe-Immucillin-G (3) was achieved via the Mannich reaction. The Mannich chemistry of a series of deazaPurines and amine hydrochlorides was also investigated.
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exploring structure activity relationships of transition state analogues of human Purine Nucleoside phosphorylase
Journal of Medicinal Chemistry, 2003Co-Authors: Gary B Evans, Richard H Furneaux, Andrzej Lewandowicz, Vern L Schramm, Peter C TylerAbstract:The aza-C-Nucleosides, Immucillin-H and Immucillin-G, are transition state analogue inhibitors of Purine Nucleoside phosphorylase, a therapeutic target for the control of T-cell proliferation. Immucillin analogues modified at the 2‘-, 3‘-, or 5‘-positions of the azasugar moiety or at the 6-, 7-, or 8-positions of the deazaPurine, as well as methylene-bridged analogues, have been synthesized and tested for their inhibition of human Purine Nucleoside phosphorylase. All analogues were poorer inhibitors, which reflects the superior capture of transition state features in the parent immucillins.
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synthesis of transition state analogue inhibitors for Purine Nucleoside phosphorylase and n riboside hydrolases
Tetrahedron, 2000Co-Authors: Gary B Evans, Richard H Furneaux, Vern L Schramm, Graeme J Gainsford, Peter C TylerAbstract:Abstract Syntheses of the ‘Immucillins’, potent aza-C-Nucleoside inhibitors of Purine Nucleoside phosphorylase are reported as well as those of 5-deoxy-, 5-deoxyfluoro- and 2-deoxy- analogues and others having modified bases.
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one third the sites transition state inhibitors for Purine Nucleoside phosphorylase
Biochemistry, 1998Co-Authors: Robert W Miles, Richard H Furneaux, Peter C Tyler, Carey K Bagdassarian, Vern L SchrammAbstract:Genetic defects in human Purine Nucleoside phosphorylase cause T-cell deficiency as the major phenotype. It has been proposed that efficient inhibitors of the enzyme might intervene in disorders of...
Gary B Evans - One of the best experts on this subject based on the ideXlab platform.
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inhibition and structure of trichomonas vaginalis Purine Nucleoside phosphorylase with picomolar transition state analogues
Biochemistry, 2007Co-Authors: Agnes Rinaldomatthis, Gary B Evans, Richard H Furneaux, Peter C Tyler, Corin Wing, Mahmoud Ghanem, Hua Deng, Peng Wu, Arti Gupta, Steven C AlmoAbstract:Trichomonas vaginalis is a parasitic protozoan Purine auxotroph possessing a unique Purine salvage pathway consisting of a bacterial type Purine Nucleoside phosphorylase (PNP) and a Purine Nucleoside kinase. Thus, T. vaginalis PNP (TvPNP) functions in the reverse direction relative to the PNPs in other organisms. Immucillin-A (ImmA) and DADMe-Immucillin-A (DADMe-ImmA) are transition state mimics of adenosine with geometric and electrostatic features that resemble early and late transition states of adenosine at the transition state stabilized by TvPNP. ImmA demonstrates slow-onset tight-binding inhibition with TvPNP, to give an equilibrium dissociation constant of 87 pM, an inhibitor release half-time of 17.2 min, and a Km/Kd ratio of 70,100. DADMe-ImmA resembles a late ribooxacarbenium ion transition state for TvPNP to give a dissociation constant of 30 pM, an inhibitor release half-time of 64 min, and a Km/Kd ratio of 203,300. The tight binding of DADMe-ImmA supports a late SN1 transition state. Despite...
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synthesis of a transition state analogue inhibitor of Purine Nucleoside phosphorylase via the mannich reaction
Organic Letters, 2003Co-Authors: Gary B Evans, Richard H Furneaux, Peter C Tyler, Vern L SchrammAbstract:The expeditious convergent synthesis of the potent human Purine Nucleoside phosphorylase inhibitor DADMe-Immucillin-G (3) was achieved via the Mannich reaction. The Mannich chemistry of a series of deazaPurines and amine hydrochlorides was also investigated.
-
exploring structure activity relationships of transition state analogues of human Purine Nucleoside phosphorylase
Journal of Medicinal Chemistry, 2003Co-Authors: Gary B Evans, Richard H Furneaux, Andrzej Lewandowicz, Vern L Schramm, Peter C TylerAbstract:The aza-C-Nucleosides, Immucillin-H and Immucillin-G, are transition state analogue inhibitors of Purine Nucleoside phosphorylase, a therapeutic target for the control of T-cell proliferation. Immucillin analogues modified at the 2‘-, 3‘-, or 5‘-positions of the azasugar moiety or at the 6-, 7-, or 8-positions of the deazaPurine, as well as methylene-bridged analogues, have been synthesized and tested for their inhibition of human Purine Nucleoside phosphorylase. All analogues were poorer inhibitors, which reflects the superior capture of transition state features in the parent immucillins.
-
synthesis of transition state analogue inhibitors for Purine Nucleoside phosphorylase and n riboside hydrolases
Tetrahedron, 2000Co-Authors: Gary B Evans, Richard H Furneaux, Vern L Schramm, Graeme J Gainsford, Peter C TylerAbstract:Abstract Syntheses of the ‘Immucillins’, potent aza-C-Nucleoside inhibitors of Purine Nucleoside phosphorylase are reported as well as those of 5-deoxy-, 5-deoxyfluoro- and 2-deoxy- analogues and others having modified bases.