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

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• 作者：Dianne T. Keough ; Petr 艩pa膷ek ; Dana Hockov谩 ; Tom谩拧 Tich媒 ; Silvie Vrbkov谩 ; Lenka Slav臎t铆nsk谩 ; Zlatko Janeba ; Lieve Naesens ; Michael D. Edstein ; Marina Chavchich ; Tzu-Hsuan Wang ; John de Jersey ; Luke W. Guddat
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 28, 2013
• 年：2013
• 卷：56
• 期：6
• 页码：2513-2526
• 全文大小：521K
• 年卷期：v.56,no.6(March 28, 2013)
• ISSN：1520-4804

文摘

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 <b>17b>) exhibited a Kb>ib> 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鈥?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 ICb>50b> values as low as 3.8 渭M for Pf grown in cell culture, up to 25-fold lower compared to the parent compounds.