Špaček Petr, Keough Dianne T, Chavchich Marina, Dračínský Martin, Janeba Zlatko, Naesens Lieve, Edstein Michael D, Guddat Luke W, Hocková Dana
The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences , Flemingovo nám. 2, CZ-16610 Prague 6, Czech Republic.
School of Chemistry and Molecular Biosciences, The University of Queensland , Brisbane, Queensland 4068, Australia.
J Med Chem. 2017 Sep 14;60(17):7539-7554. doi: 10.1021/acs.jmedchem.7b00926. Epub 2017 Aug 30.
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-yl)-2-((2-phosphonoethoxy)methyl)propoxy]methylphosphonic acid, exhibited K values of 6 and 70 nM for human HGPRT and Pf HGXPRT, respectively. These low K values were achieved by inserting an extra carbon atom in the linker connecting the N 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 Å resolution and shows that it fills three key pockets in the active site. The most potent phosphoramidate prodrugs of these compounds have IC 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.
无环核苷双膦酸盐（ANbPs）此前已被证明是人类次黄嘌呤 - 鸟嘌呤磷酸核糖转移酶（HGPRT）和恶性疟原虫（Pf）次黄嘌呤 - 鸟嘌呤 - 黄嘌呤磷酸核糖转移酶（PfHGXPRT）的良好抑制剂。基于此骨架，合成了一系列新的ANbPs。其中一种新的ANbP，即[3 - （鸟嘌呤 - 9 - 基） - 2 - （（2 - 膦酰基乙氧基）甲基）丙氧基]甲基膦酸，对人类HGPRT和Pf HGXPRT的K值分别为6 nM和70 nM。这些低K值是通过在连接鸟嘌呤N原子与其中一个膦酸酯基团的连接子中插入一个额外的碳原子实现的。该ANbP与人类HGPRT复合物的晶体结构在2.0 Å分辨率下测定，结果表明它填充了活性位点中的三个关键口袋。这些化合物中最有效的磷酰胺酯前药在Pf株系中的IC值处于低微摩尔范围，在人类A549细胞中的毒性较低，这表明这些ANbPs是优秀的抗疟药物先导物。
