Hakimelahi G H, Moosavi-Movahedi A A, Sadeghi M M, Tsay S C, Hwu J R
Organosilicon and Synthesis Laboratory, Institute of Chemistry, Academia Sinica, Nankang, Taipei, Taiwan, Republic of China.
J Med Chem. 1995 Nov 10;38(23):4648-59. doi: 10.1021/jm00023a004.
A new acyclic nucleoside phosphonate (13) containing an adenine moiety was synthesized, which acted as an excellent inhibitor of calf mucosal adenosine deaminase. This inhibitory property allows it to exert great synergistic effect on certain antiviral agents (e.g., ara-A, 37). Phosphonate 13 was not phosphorylated by the bovine brain guanylate kinase nor by 5-phosphoribosyl 1-pyrophosphate synthetase. Syntheses of biologically active nucleotide phosphonate 40 and its phosphonoamidate derivative 42 were accomplished, which showed remarkable activity against herpes viruses and exhibited low host cell toxicity. 3'-Azido-nucleoside phosphonate 20 and 3'-fluoronucleoside phosphonate 32, as well as the corresponding dinucleotide analogs 47 and 48, and their respective phosphonoamidates 53-56 were also synthesized as new compounds, among which phosphonoamidates 53-56 showed potent activity against human immunodeficiency virus. Phosphonoamidates 55 and 56 bearing a methyl D-alaninate moiety exhibited less cellular toxicity than 53 and 54 bearing a methyl L-alaninate moiety. Nucleotide phosphonate 40 as well as dinucleotide phosphonates 47 and 48 were found susceptible to degradation by phosphodiesterases. Their respective phosphonoamidates 42 and 53-56, however, were completely resistant to snake venom and spleen enzymes.
合成了一种含有腺嘌呤部分的新型无环核苷膦酸酯（13），它是小牛黏膜腺苷脱氨酶的优良抑制剂。这种抑制特性使其对某些抗病毒药物（如阿糖腺苷，37）发挥强大的协同作用。膦酸酯13既不能被牛脑鸟苷酸激酶磷酸化，也不能被5-磷酸核糖-1-焦磷酸合成酶磷酸化。完成了具有生物活性的核苷酸膦酸酯40及其膦酰胺衍生物42的合成，它们对疱疹病毒显示出显著活性且宿主细胞毒性较低。还合成了3'-叠氮核苷膦酸酯20和3'-氟核苷膦酸酯32，以及相应的二核苷酸类似物47和48，及其各自的膦酰胺53 - 56作为新化合物，其中膦酰胺53 - 56对人类免疫缺陷病毒显示出强效活性。带有甲基D-丙氨酸酯部分的膦酰胺55和56比带有甲基L-丙氨酸酯部分的膦酰胺53和54表现出更低的细胞毒性。发现核苷酸膦酸酯40以及二核苷酸膦酸酯47和48易被磷酸二酯酶降解。然而，它们各自的膦酰胺42和53 - 56对蛇毒和脾脏酶完全具有抗性。
