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Acyclic Nucleoside Phosphonates Containing a Second Phosphonate Group Are Potent Inhibitors of 6-Oxopurine Phosphoribosyltransferases and Have Antimalarial Activity
- 1.0392258 - ÚOCHB 2014 RIV US eng J - Článek v odborném periodiku
Keough, D. T. - Špaček, Petr - Hocková, Dana - Tichý, Tomáš - Vrbková, S. - Slavětínská, Lenka - Janeba, Zlatko - Naesens, L. - Edstein, M. D. - Chavchich, M. - Wang, T. H. - de Jersey, J. - Guddat, L. W.
Acyclic Nucleoside Phosphonates Containing a Second Phosphonate Group Are Potent Inhibitors of 6-Oxopurine Phosphoribosyltransferases and Have Antimalarial Activity.
Journal of Medicinal Chemistry. Roč. 56, č. 6 (2013), s. 2513-2526. ISSN 0022-2623. E-ISSN 1520-4804
Grant CEP: GA ČR GAP207/11/0108
Institucionální podpora: RVO:61388963
Klíčová slova: enzyme inhibitors * ANPs * malaria * bisphosphonates
Kód oboru RIV: CC - Organická chemie
Impakt faktor: 5.480, rok: 2013
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.
Trvalý link: http://hdl.handle.net/11104/0221165
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