About: Acyclic Nucleoside Phosphonates Containing a Second Phosphonate Group Are Potent Inhibitors of 6-Oxopurine Phosphoribosyltransferases and Have Antimalarial Activity

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About: Acyclic Nucleoside Phosphonates Containing a Second Phosphonate Group Are Potent Inhibitors of 6-Oxopurine Phosphoribosyltransferases and Have Antimalarial Activity Goto Sponge NotDistinct Permalink

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Description	Acyclic nucleoside phosphonates (ANPs) that contain a 6-oxopurine base are good inhibitors of the Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) 6-oxopurine phosphoribosyltransferases (PRTs). Chemical modifications based on the crystal structure of 2-(phosphonoethoxy)ethylguanine (PEEG) in complex with human HGPRT have led to the design of new ANPs. These novel compounds contain a second phosphonate group attached to the ANP scaffold. {[(2-[(Guanine-9H-yl)methyl]propane-1,3-diyl)bis(oxy)]bis(methylene)}diphosphonic acid (compound 17) exhibited a K-i value of 30 nM for human HGPRT and 70 nM for Pf HGXPRT. The crystal structure of this compound in complex with human HGPRT shows that it fills or partially fills three critical locations in the active site: the binding sites of the purine base, the 5'-phosphate group, and pyrophosphate. This is the first HG(X)PRT inhibitor that has been able to achieve this result. Prodrugs have been synthesized resulting in IC50 values as low as 3.8 mu M for Pf grown in cell culture, up to 25-fold lower compared to the parent compounds. Acyclic nucleoside phosphonates (ANPs) that contain a 6-oxopurine base are good inhibitors of the Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) 6-oxopurine phosphoribosyltransferases (PRTs). Chemical modifications based on the crystal structure of 2-(phosphonoethoxy)ethylguanine (PEEG) in complex with human HGPRT have led to the design of new ANPs. These novel compounds contain a second phosphonate group attached to the ANP scaffold. {[(2-[(Guanine-9H-yl)methyl]propane-1,3-diyl)bis(oxy)]bis(methylene)}diphosphonic acid (compound 17) exhibited a K-i value of 30 nM for human HGPRT and 70 nM for Pf HGXPRT. The crystal structure of this compound in complex with human HGPRT shows that it fills or partially fills three critical locations in the active site: the binding sites of the purine base, the 5'-phosphate group, and pyrophosphate. This is the first HG(X)PRT inhibitor that has been able to achieve this result. Prodrugs have been synthesized resulting in IC50 values as low as 3.8 mu M for Pf grown in cell culture, up to 25-fold lower compared to the parent compounds. (en)
Title	Acyclic Nucleoside Phosphonates Containing a Second Phosphonate Group Are Potent Inhibitors of 6-Oxopurine Phosphoribosyltransferases and Have Antimalarial Activity Acyclic Nucleoside Phosphonates Containing a Second Phosphonate Group Are Potent Inhibitors of 6-Oxopurine Phosphoribosyltransferases and Have Antimalarial Activity (en)
skos:prefLabel	Acyclic Nucleoside Phosphonates Containing a Second Phosphonate Group Are Potent Inhibitors of 6-Oxopurine Phosphoribosyltransferases and Have Antimalarial Activity Acyclic Nucleoside Phosphonates Containing a Second Phosphonate Group Are Potent Inhibitors of 6-Oxopurine Phosphoribosyltransferases and Have Antimalarial Activity (en)
skos:notation	RIV/61388963:_____/13:00392258!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(GAP207/11/0108)
http://linked.open...iv/cisloPeriodika	6
http://linked.open...vai/riv/dodaniDat	2014
http://linked.open...aciTvurceVysledku	Špaček, Petr Janeba, Zlatko Hocková, Dana Slavětínská, Lenka Tichý, Tomáš
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	59439
http://linked.open...ai/riv/idVysledku	RIV/61388963:_____/13:00392258
http://linked.open...riv/jazykVysledku	eng - angličtina
http://linked.open.../riv/klicovaSlova	enzyme inhibitors; ANPs; malaria; bisphosphonates (en)
http://linked.open.../riv/klicoveSlovo	malaria ANPs enzyme inhibitors bisphosphonates
http://linked.open...odStatuVydavatele	US - Spojené státy americké
http://linked.open...ontrolniKodProRIV	[BA37F03FD863]
http://linked.open...i/riv/nazevZdroje	Journal of Medicinal Chemistry
http://linked.open...in/vavai/riv/obor	CC
http://linked.open...ichTvurcuVysledku	5 (xsd:int)
http://linked.open...cetTvurcuVysledku	13 (xsd:int)
http://linked.open...vavai/riv/projekt	Novel types of acyclic nucleoside phosphonates with potential antimalarial activity:hypoxanthine-guanine-xanthine phosphoribosyltransferase inhibitors
http://linked.open...UplatneniVysledku	2013
http://linked.open...v/svazekPeriodika	56
http://linked.open...iv/tvurceVysledku	Hocková, Dana Janeba, Zlatko Tichý, Tomáš Špaček, Petr Slavětínská, Lenka Guddat, L. W. Keough, D. T. Naesens, L. de Jersey, J. Chavchich, M. Edstein, M. D. Vrbková, S. Wang, T. H.
http://linked.open...ain/vavai/riv/wos	000317032200028
issn	0022-2623
number of pages	14 (xsd:int)
http://bibframe.org/vocab/doi	10.1021/jm301893b

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