Synthesis and Evaluation of Asymmetric Acyclic Nucleoside Bisphosphonates as Inhibitors of Plasmodium falciparum and Human Hypoxanthine-Guanine-(Xanthine) Phosphoribosyltransferase

0479744 - ÚOCHB 2018 RIV US eng J - Journal Article
Špaček, Petr - Keough, D. T. - Chavchich, M. - Dračínský, Martin - Janeba, Zlatko - Naesens, L. - Edstein, M. D. - Guddat, L. W. - Hocková, Dana
Synthesis and Evaluation of Asymmetric Acyclic Nucleoside Bisphosphonates as Inhibitors of Plasmodium falciparum and Human Hypoxanthine-Guanine-(Xanthine) Phosphoribosyltransferase.
Journal of Medicinal Chemistry. Roč. 60, č. 17 (2017), s. 7539-7554. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA ČR(CZ) GA16-06049S
Institutional support: RVO:61388963
Keywords : hypoxanthine-guanine phosphoribosyltransferase * 2nd phosphonate group * 6-oxopurine phosphoribosyltransferases
OECD category: Organic chemistry
Impact factor: 6.253, year: 2017

Acyclic nucleoside bisphosphonates (ANbPs) have previously been shown to be good inhibitors of human hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and Plasmodium falciparum (Pf) hypoxanthine-guanine-xanthine phosphoribosyltransferase (PfHGXPRT). On the basis of this scaffold, a new series of ANbPs was synthesized. One of these new ANbPs, [3-(guanine-9-71)-24(2-phosphonoethoxy)methyl)propoxy] methylphosphonic acid, exhibited K-1 values of 6 and 70 nM for human HGPRT and Pf HGXPRT, respectively. These low K-i values were achieved by inserting an extra carbon atom in the linker connecting the N-9 atom of guanine to one of the phosphonate groups. The crystal structure of this ANbP in complex with human HGPRT was determined at 2.0 angstrom resolution and shows that it fills three key pockets in the active site. The most potent phosphoramidate prodrugs of these compounds have IC50 values in the low micromolar range in Pf lines and low toxicity in human A549 cells, demonstrating that these ANbPs are excellent antimalarial drug leads.
Permanent Link: http://hdl.handle.net/11104/0275689