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

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 com...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2013-03, Vol.56 (6), p.2513-2526
Main Authors: Keough, Dianne T, Špaček, Petr, Hocková, Dana, Tichý, Tomáš, Vrbková, Silvie, Slavětínská, Lenka, Janeba, Zlatko, Naesens, Lieve, Edstein, Michael D, Chavchich, Marina, Wang, Tzu-Hsuan, de Jersey, John, Guddat, Luke W
Format: Article
Language:English
Subjects:
Antimalarials - chemistry
Antimalarials - pharmacology
Antimalarials - toxicity
Catalytic Domain
Cell Line, Tumor
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Enzyme Inhibitors - toxicity
Humans
Hypoxanthine Phosphoribosyltransferase - antagonists & inhibitors
Hypoxanthine Phosphoribosyltransferase - chemistry
Models, Molecular
Organophosphonates - chemistry
Organophosphonates - pharmacology
Organophosphonates - toxicity
Plasmodium falciparum - drug effects
Plasmodium falciparum - enzymology
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Summary: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 μM for Pf grown in cell culture, up to 25-fold lower compared to the parent compounds.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm301893b