Rega Institute for Medical Research, Medicinal Chemistry, KU Leuven, Herestraat 49-Box 1041, 3000 Leuven, Belgium.
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy.
J Med Chem. 2022 Jul 14;65(13):9396-9417. doi: 10.1021/acs.jmedchem.2c00667. Epub 2022 Jun 27.
Minor structural modifications of acyclic nucleoside phosphonates can dramatically affect their antiviral properties. This work discloses a shift in the selectivity spectrum of 3-hydroxy-2-(phosphonomethoxy)propyl (HPMP) nucleotides from herpesviruses toward hepatitis B virus (HBV) induced by their acyclic chain 2-substitution with a nonpolar group. Two series of racemic (,)-2-methyl-3-hydroxy-2-(phosphonomethoxy)propyl (MHPMP) and (,)-2-ethynyl-3-hydroxy-2-(phosphonomethoxy)propyl (EHPMP) nucleotides were initially synthesized. Among these, guanine-containing derivatives exhibited significant anti-HBV activities in the submicromolar range. Enantioenriched MHPMPG and EHPMPG analogues were subsequently obtained by Sharpless asymmetric epoxidation. The ()-enantiomers possessed an 8- to 26-fold higher potency than the relative ()-forms. A further comparison of the EC values indicated that ()-EHPMPG inhibited HBV replication more effectively than its 2-methyl analogue. A phosphonodiamidate prodrug of ()-EHPMPG was thus prepared and found to exert a remarkably high anti-HBV activity (EC = 9.27 nM) with excellent selectivity (SI > 10,787), proving to be a promising candidate for anti-HBV drug development.
非循环核苷膦酸酯的微小结构修饰可以显著影响它们的抗病毒特性。这项工作揭示了 3-羟基-2-(膦酸甲氧基)丙基（HPMP）核苷酸的选择性谱从疱疹病毒向乙型肝炎病毒（HBV）的转移，这是由它们的非极性基团取代非循环链 2 位引起的。最初合成了两个系列的外消旋（，）-2-甲基-3-羟基-2-（膦酸甲氧基）丙基（MHPMP）和（，）-2-乙炔基-3-羟基-2-（膦酸甲氧基）丙基（EHPMP）核苷酸。在这些核苷酸中，含鸟嘌呤的衍生物在亚微摩尔范围内表现出显著的抗 HBV 活性。随后通过 Sharpless 不对称环氧化获得了对映体富集的 MHPMPG 和 EHPMPG 类似物。（）-对映异构体的效力比相应的（）-形式高 8 到 26 倍。进一步比较 EC 值表明，（）-EHPMPG 比其 2-甲基类似物更有效地抑制 HBV 复制。因此，制备了（）-EHPMPG 的磷酰胺二酯前药，并发现其具有非常高的抗 HBV 活性（EC = 9.27 nM）和优异的选择性（SI > 10,787），证明它是一种很有前途的抗 HBV 药物开发候选物。
