About: Conformationally constrained nucleoside phosphonic acids - potent inhibitors of human mitochondrial and cytosolic 5'(3')-nucleotidases

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rdf:type	skos:Concept http://linked.opendata.cz/ontology/domain/vavai/Vysledek
Description	This work describes novel in vitro inhibitors of human mitochondrial (mdN) and cytosolic (cdN) 5'(3')-deoxynucleotidases. We designed a series of derivatives of the lead compound (S)-1-[2-deoxy-3,5-O-(phosphonobenzylidene)-beta-D-threo-pentofuranosyl] thymine bearing various substituents in the para position of the benzylidene moiety. Detailed kinetic study revealed that certain para substituents increase the inhibitory potency (iodo derivative; K-i(mdN) = 2.71 mu M) and some induce a shift in selectivity toward cdN (carboxy derivative, K-i(cdN) = 11.60 mu M; iodoxy derivative, K-i(cdN) = 6.60 mu M). Crystal structures of mdN in complex with three of these compounds revealed that various para substituents lead to two alternative inhibitor binding modes within the enzyme active site. Two binding modes were also identified for cdN complexes by heteronuclear NMR spectroscopy. This work describes novel in vitro inhibitors of human mitochondrial (mdN) and cytosolic (cdN) 5'(3')-deoxynucleotidases. We designed a series of derivatives of the lead compound (S)-1-[2-deoxy-3,5-O-(phosphonobenzylidene)-beta-D-threo-pentofuranosyl] thymine bearing various substituents in the para position of the benzylidene moiety. Detailed kinetic study revealed that certain para substituents increase the inhibitory potency (iodo derivative; K-i(mdN) = 2.71 mu M) and some induce a shift in selectivity toward cdN (carboxy derivative, K-i(cdN) = 11.60 mu M; iodoxy derivative, K-i(cdN) = 6.60 mu M). Crystal structures of mdN in complex with three of these compounds revealed that various para substituents lead to two alternative inhibitor binding modes within the enzyme active site. Two binding modes were also identified for cdN complexes by heteronuclear NMR spectroscopy. (en)
Title	Conformationally constrained nucleoside phosphonic acids - potent inhibitors of human mitochondrial and cytosolic 5'(3')-nucleotidases Conformationally constrained nucleoside phosphonic acids - potent inhibitors of human mitochondrial and cytosolic 5'(3')-nucleotidases (en)
skos:prefLabel	Conformationally constrained nucleoside phosphonic acids - potent inhibitors of human mitochondrial and cytosolic 5'(3')-nucleotidases Conformationally constrained nucleoside phosphonic acids - potent inhibitors of human mitochondrial and cytosolic 5'(3')-nucleotidases (en)
skos:notation	RIV/68378050:_____/14:00435239!RIV15-GA0-68378050
http://linked.open...avai/riv/aktivita	I P S
http://linked.open...avai/riv/aktivity	I, P(GA13-24880S), P(GA13-26526S), P(GA203/09/0820), P(KAN200520801), P(LK11205), S
http://linked.open...iv/cisloPeriodika	40
http://linked.open...vai/riv/dodaniDat	2015
http://linked.open...aciTvurceVysledku	Brynda, Jiří Fábry, Milan
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 molekulární genetiky AV ČR, v. v. i.
http://linked.open...dnocenehoVysledku	8614
http://linked.open...ai/riv/idVysledku	RIV/68378050:_____/14:00435239
http://linked.open...riv/jazykVysledku	eng - angličtina
http://linked.open.../riv/klicovaSlova	5'(3')-nucleotidase; structure; inhibition; cdN; mdN; nucleoside; SAR; phosphonic acid (en)
http://linked.open.../riv/klicoveSlovo	nucleoside inhibition structure SAR phosphonic acid 5'(3')-nucleotidase cdN mdN
http://linked.open...odStatuVydavatele	GB - Spojené království Velké Británie a Severního Irska
http://linked.open...ontrolniKodProRIV	[5B8385277323]
http://linked.open...i/riv/nazevZdroje	Organic & Biomolecular Chemistry
http://linked.open...in/vavai/riv/obor	CC
http://linked.open...ichTvurcuVysledku	2 (xsd:int)
http://linked.open...cetTvurcuVysledku	12 (xsd:int)
http://linked.open...vavai/riv/projekt	Nové DNA a RNA oligonukleotidy s fosfonothioátovými a fosfonoamidátovými internukleotidovými vazbami Struktura a vlastnosti modifikovaných složek nukleových kyselin Biomolecular NMR spectroscopy for rational drug design Structure based drug design of specific nucleotidases inhibitors, potentially pharmacologically important compounds. Targeted expression and transport of bioactive molecules
http://linked.open...UplatneniVysledku	2014
http://linked.open...v/svazekPeriodika	12
http://linked.open...iv/tvurceVysledku	Brynda, Jiří Buděšínský, Miloš Fábry, Milan Pachl, Petr Petrová, Magdalena Rosenberg, Ivan Řezáčová, Pavlína Šimák, Ondřej Hnízda, Aleš Veverka, Václav Jandušík, T. Skleničková, Radka
http://linked.open...ain/vavai/riv/wos	000342992400014
issn	1477-0520
number of pages	12 (xsd:int)
http://bibframe.org/vocab/doi	10.1039/c4ob01332h

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