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

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 Ki values of 6 and 70 nM for human HGPRT and Pf HGXPRT, respectively. These low Ki values were achieved by inserting an extra carbon atom in the linker connecting the N9 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 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.

此前研究表明，无环核苷双膦酸酯（Acyclic nucleoside bisphosphonates, ANbPs）对人次黄嘌呤-鸟嘌呤磷酸核糖转移酶（human hypoxanthine–guanine phosphoribosyltransferase, HGPRT）以及恶性疟原虫（Plasmodium falciparum, Pf）次黄嘌呤-鸟嘌呤-黄嘌呤磷酸核糖转移酶（PfHGXPRT）均具有良好的抑制活性。基于该骨架，本研究合成了一系列新型ANbPs。其中一款化合物[3-(鸟嘌呤-9-基)-2-((2-膦酰乙氧基)甲基)丙氧基]甲基膦酸，对人HGPRT和PfHGXPRT的抑制常数Ki值分别为6 nM和70 nM。该化合物通过在连接鸟嘌呤N9原子与其中一个膦酸酯基团的连接臂中引入额外碳原子，实现了极低的Ki值。该ANbP与人HGPRT复合物的晶体结构经解析，分辨率达2.0 Å，结果显示其可占据活性位点内的三个关键口袋。此类化合物中活性最强的磷酰胺酯前药，在恶性疟原虫株中的半最大抑制浓度IC50处于低微摩尔级别，且对人A549细胞毒性较低，证实这类ANbPs是极具潜力的抗疟疾药物候选先导化合物。