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

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Synthesis and Evaluation of Asymmetric Acyclic Nucleoside Bisphosphonates as Inhibitors of Plasmodium falciparum and Human Hypoxanthine–Guanine–(Xanthine) Phosphoribosyltransferase
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-08-30 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00926
Petr Špaček ₁ , Dianne T. Keough ₂ , Marina Chavchich ₃ , Martin Dračínský ₁ , Zlatko Janeba ₁ , Lieve Naesens ₄ , Michael D. Edstein ₃ , Luke W. Guddat ₂ , Dana Hocková ₁

Affiliation

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_i 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 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.

中文翻译：

恶性疟原虫和人次黄嘌呤-鸟嘌呤-（黄嘌呤）磷酸核糖基转移酶抑制剂的不对称无环核苷双膦酸酯的合成和评价

无环核苷双膦酸酯（ANbPs）以前已被证明是人次黄嘌呤-鸟嘌呤磷酸核糖基转移酶（HGPRT）和恶性疟原虫（Pf）次黄嘌呤-鸟嘌呤-黄嘌呤磷酸核糖基转移酶（Pf HGXPRT）的良好抑制剂。在该支架的基础上，合成了一系列新的ANbP。这些新的ANbP中的一种，[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HGPRT和Pf HGXPRT的K _i值分别为6和70 nM 。这些低的K _i值是通过在连接N ^9的连接基中插入一个额外的碳原子来实现的鸟嘌呤的一个原子与一个膦酸酯基团相连。该ANbP与人类HGPRT形成复合物的晶体结构已确定为2.0Å分辨率，表明其填充了活性位点的三个关键口袋。这些化合物中最有效的氨基磷酸酯前药在Pf系中的微摩尔浓度范围内IC ₅₀值低，在人A549细胞中的毒性低，表明这些ANbPs是出色的抗疟药领先者。

更新日期：2017-08-30

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