Kim C U, Luh B Y, Misco P F, Bronson J J, Hitchcock M J, Ghazzouli I, Martin J C
Bristol-Myers Squibb Company, Pharmaceutical Research and Development Division, Wallingford, Connecticut 06492.
J Med Chem. 1990 Apr;33(4):1207-13. doi: 10.1021/jm00166a019.
A series of 9-(phosphonoalkyl)purines, which are analogues of 9-[2-(phosphonomethoxy)ethyl]purines (guanine, PMEG, 1; adenine, PMEA, 2), were synthesized. The analogues were tested for activity against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), human cytomegalovirus (HCMV), Rauscher murine leukemia virus (R-MuLV), and human immunodeficiency virus type 1 (HIV-1). With variations in the length of the alkyl chain, the optimal activity was achieved with two carbons between the purine base and the phosphonomethoxy functionality. Despite the structural similarity and the close pKa2 value of 8 to that of PMEG, no phosphorylation of 8 was observed by the bovine brain guanylate kinase. Since all isosteric analogues of PMEG (7-9) were not inhibitory against HSV-1 and HSV-2, the presence of the 3'-oxygen atom in the PME purines proved critical for anti-HSV activity. Introduction of the 1'-methyl group on the PMEG side chain significantly reduced its anti-HSV activity. Analogue 11, which is a mimic of the phosphate by incorporation of the alpha,alpha-difluoro carbon, was ineffective against HSV-1 and HSV-2. These results suggest that the structural requirements of PME purines for anti-HSV activity appear to be very strict.
合成了一系列9-(膦酰基烷基)嘌呤，它们是9-[2-(膦酰基甲氧基)乙基]嘌呤（鸟嘌呤，PMEG，1；腺嘌呤，PMEA，2）的类似物。对这些类似物进行了抗1型和2型单纯疱疹病毒（HSV-1和HSV-2）、人巨细胞病毒（HCMV）、劳氏鼠白血病病毒（R-MuLV）和1型人类免疫缺陷病毒（HIV-1）活性的测试。随着烷基链长度的变化，在嘌呤碱基和膦酰基甲氧基官能团之间有两个碳原子时可达到最佳活性。尽管8与PMEG结构相似且pKa2值相近，但牛脑鸟苷酸激酶未观察到8的磷酸化。由于PMEG的所有等排类似物（7-9）对HSV-1和HSV-2均无抑制作用，因此PME嘌呤中3'-氧原子的存在被证明对抗HSV活性至关重要。在PMEG侧链上引入1'-甲基显著降低了其抗HSV活性。通过引入α,α-二氟碳模拟磷酸的类似物11对HSV-1和HSV-2无效。这些结果表明，PME嘌呤抗HSV活性的结构要求似乎非常严格。
