期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 56, 期 6, 页码 2513-2526出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm301893b
关键词
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资金
- subvention for development of research organization (Institute of Organic Chemistry and Biochemistry) [RVO 61388963]
- Grant Agency of the Czech Republic [P207/11/0108]
- National Health and Medical Research Council, Australia [569703, 1030353]
- Gilead Sciences (Foster City, CA)
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.
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