Balzarini J, Holy A, Jindrich J, Dvorakova H, Hao Z, Snoeck R, Herdewijn P, Johns D G, De Clercq E
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4961-5. doi: 10.1073/pnas.88.11.4961.
A new class of compounds, 9-[(2RS)-3-fluoro-2-phosphonylmethoxypropyl] [(RS)-FPMP] derivatives of purines, is described that has selective activity against a broad spectrum of retroviruses [including human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2)] but not other RNA or DNA viruses. This activity spectrum is completely different from that of the parental compounds, 9-[(2S)-3-hydroxy-2-phosphonylmethoxypropyl] [(S)-HPMP] derivatives of purines, which are active against a broad range of DNA viruses. The racemic (RS)-FPMP derivatives of adenine and 2,6-diaminopurine, termed (RS)-FPMPA and (RS)-FPMPDAP, respectively, are markedly more selective as in vitro antiretroviral agents than their 9-(2-phosphonylmethoxyethyl) (PME) counterparts, PMEA and PMEDAP. Also, (RS)-FPMPA and (RS)-FPMPDAP have a substantially higher therapeutic index in mice in inhibiting Moloney murine sarcoma virus-induced tumor formation and associated death and are markedly less inhibitory to human bone marrow cells than PMEA and PMEDAP. The diphosphate derivative of (RS)-FPMPA [(RS)-FPMPApp] is a potent and selective inhibitor of HIV-1 reverse transcriptase but not of HSV-1 DNA polymerase or DNA polymerase alpha. (RS)-FPMPApp, akin to PMEA diphosphate (PMEApp), acts as a DNA chain terminator. The DNA chain-terminating properties of PMEApp and (RS)-FPMPApp seem to be a prerequisite for acyclic nucleoside phosphonates to exhibit antiretrovirus (i.e., anti-HIV) activity.
描述了一类新的化合物，即嘌呤的9-[(2RS)-3-氟-2-膦酰甲氧基丙基][(RS)-FPMP]衍生物，其对多种逆转录病毒[包括1型人类免疫缺陷病毒(HIV-1)和2型人类免疫缺陷病毒(HIV-2)]具有选择性活性，但对其他RNA或DNA病毒无活性。该活性谱与母体化合物嘌呤的9-[(2S)-3-羟基-2-膦酰甲氧基丙基][(S)-HPMP]衍生物完全不同，后者对多种DNA病毒具有活性。腺嘌呤和2,6-二氨基嘌呤的外消旋(RS)-FPMP衍生物，分别称为(RS)-FPMPA和(RS)-FPMPDAP，作为体外抗逆转录病毒药物，比其9-(2-膦酰甲氧基乙基)(PME)对应物PMEA和PMEDAP具有明显更高的选择性。此外，(RS)-FPMPA和(RS)-FPMPDAP在抑制莫洛尼氏鼠肉瘤病毒诱导的肿瘤形成及相关死亡方面，在小鼠中的治疗指数显著更高，并且对人骨髓细胞的抑制作用明显小于PMEA和PMEDAP。(RS)-FPMPA的二磷酸衍生物[(RS)-FPMPApp]是HIV-1逆转录酶的强效选择性抑制剂，但不是单纯疱疹病毒1型DNA聚合酶或DNA聚合酶α的抑制剂。(RS)-FPMPApp与PMEA二磷酸(PMEApp)类似，可作为DNA链终止剂。PMEApp和(RS)-FPMPApp的DNA链终止特性似乎是无环核苷膦酸盐表现出抗逆转录病毒(即抗HIV)活性的先决条件。
