About: 9-Norbornyl-6-chloropurine Is a Novel Antileukemic Compound Interacting with Cellular GSH

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rdf:type	skos:Concept http://linked.opendata.cz/ontology/domain/vavai/Vysledek
Description	Aim: 6-Chloropurines substituted at position 9 with bicyclic skeletons represent promising chemotherapeutic agents. We explored the metabolism and membrane transport of 9-norbornyl-6-chloropurine (NCP) aiming to understand its mechanism of action. Materials and Methods: The metabolism of NCP was studied in vitro in whole cells (CCRF-CEM), cellular extracts, subcellular fractions and purified enzymes. Transport experiments were conducted in Caco-2 cell monolayers. Results: Three metabolites were identified, a glutathione conjugate (NCP-GS), NCP-cysteinylglycine and NCP-cysteine. Both glutathione-S-transferase inhibition and glutathione (GSH) depletion prevented metabolite formation and increased the cytotoxicity of NCP. Transepithelial transport (Caco-2) indicated good permeability, with P-app (12.6+/-0.3) x10(-5) cm/s. Importantly, the drug induced glutathione depletion in treated cells and affected the activity of several GSH-dependent enzymes. Conclusion: The novel nucleoside analog NCP represents a promising orally available antileukemic agent, acting through lowering of GSH levels in tumor cells. Aim: 6-Chloropurines substituted at position 9 with bicyclic skeletons represent promising chemotherapeutic agents. We explored the metabolism and membrane transport of 9-norbornyl-6-chloropurine (NCP) aiming to understand its mechanism of action. Materials and Methods: The metabolism of NCP was studied in vitro in whole cells (CCRF-CEM), cellular extracts, subcellular fractions and purified enzymes. Transport experiments were conducted in Caco-2 cell monolayers. Results: Three metabolites were identified, a glutathione conjugate (NCP-GS), NCP-cysteinylglycine and NCP-cysteine. Both glutathione-S-transferase inhibition and glutathione (GSH) depletion prevented metabolite formation and increased the cytotoxicity of NCP. Transepithelial transport (Caco-2) indicated good permeability, with P-app (12.6+/-0.3) x10(-5) cm/s. Importantly, the drug induced glutathione depletion in treated cells and affected the activity of several GSH-dependent enzymes. Conclusion: The novel nucleoside analog NCP represents a promising orally available antileukemic agent, acting through lowering of GSH levels in tumor cells. (en)
Title	9-Norbornyl-6-chloropurine Is a Novel Antileukemic Compound Interacting with Cellular GSH 9-Norbornyl-6-chloropurine Is a Novel Antileukemic Compound Interacting with Cellular GSH (en)
skos:prefLabel	9-Norbornyl-6-chloropurine Is a Novel Antileukemic Compound Interacting with Cellular GSH 9-Norbornyl-6-chloropurine Is a Novel Antileukemic Compound Interacting with Cellular GSH (en)
skos:notation	RIV/61388963:_____/13:00396057!RIV14-GA0-61388963
http://linked.open...avai/predkladatel	Ústav organické chemie a biochemie AV ČR, v. v. i.
http://linked.open...avai/riv/aktivita	I P
http://linked.open...avai/riv/aktivity	I, P(GAP303/11/1297)
http://linked.open...iv/cisloPeriodika	8
http://linked.open...vai/riv/dodaniDat	2014
http://linked.open...aciTvurceVysledku	Plačková, Pavla Votruba, Ivan Kostinová, Alexandra Hřebabecký, Hubert Nencka, Radim Mertlíková-Kaiserová, Helena Elbert, Tomáš Šála, Michal
http://linked.open.../riv/druhVysledku	J - Článek v odborném periodiku
http://linked.open...iv/duvernostUdaju	S - Úplné a pravdivé údaje nepodléhající ochraně podle zvláštních právních předpisů
http://linked.open...titaPredkladatele	Ústav organické chemie a biochemie AV ČR, v. v. i.
http://linked.open...dnocenehoVysledku	120012
http://linked.open...ai/riv/idVysledku	RIV/61388963:_____/13:00396057
http://linked.open...riv/jazykVysledku	eng - angličtina
http://linked.open.../riv/klicovaSlova	Substituted 6-chloropurines; carbocyclic nucleoside analogs; glutathione-S-transferase; glutathione depletion (en)
http://linked.open.../riv/klicoveSlovo	Substituted 6-chloropurines carbocyclic nucleoside analogs glutathione depletion glutathione-S-transferase
http://linked.open...odStatuVydavatele	GR - Řecká republika
http://linked.open...ontrolniKodProRIV	[BB457E96308E]
http://linked.open...i/riv/nazevZdroje	Anticancer Research
http://linked.open...in/vavai/riv/obor	FD
http://linked.open...ichTvurcuVysledku	8 (xsd:int)
http://linked.open...cetTvurcuVysledku	9 (xsd:int)
http://linked.open...vavai/riv/projekt	Mechanisms of antiviral and cytostatic effects of novel carbocyclic nucleoside analogs
http://linked.open...UplatneniVysledku	2013
http://linked.open...v/svazekPeriodika	33
http://linked.open...iv/tvurceVysledku	Elbert, Tomáš Hřebabecký, Hubert Mertlíková-Kaiserová, Helena Nencka, Radim Votruba, Ivan Šála, Michal Dvořáková, Alexandra Plačková, Pavla Rozumová, N.
http://linked.open...ain/vavai/riv/wos	000322559300025
issn	0250-7005
number of pages	6 (xsd:int)

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