Robins M J, Wood S G, Dalley N K, Herdewijn P, Balzarini J, De Clercq E
Department of Chemistry, Brigham Young University, Provo, Utah 84602.
J Med Chem. 1989 Aug;32(8):1763-8. doi: 10.1021/jm00128a017.
Trimethylsilyl triflate-catalyzed transfer glycosylation of 2,6-diamino-9-(3-azido-2,3-dideoxy-alpha- and -beta-D-erythro-pentofuranosyl)purines (3 and 4) in low yields. Selective 2'-O-tosylation of 2,6-diamino-9-(beta-D-ribofuranosyl)purine (2,6-diaminopurine riboside, DAPR, 5) followed by our lithium triethylborohydride promoted 1,2-hydride rearrangement gave 2,6-diamino-9-(2-deoxy-beta-D-threo-pentofuranosyl)purine (7). Tritylation of 7 followed by mesylation at O3', deprotection, and displacement of the 3'-mesylate with azide provided a stereodefined synthesis of 2,6-diamino-9-(3-azido-2, 3-dideoxy-beta-D-erythro-pentofuranosyl)purine (AzddDAPR, 4). X-ray crystallographic analysis of 4 showed two orientations of the azido group, but consistent conformational features in the remainder of the molecule. In contrast, two independent conformations have been found for AZT. The azido function confers enhanced lipophilicity, which could be expected to contribute significantly to nonselective transport across membranes. A large difference in the octanol/water partition coefficients of the alpha (3) and beta (4) anomers wes found. The beta anomer (4) exerts potent inhibition of HIV-induced cytopathogenicity in human MT-4 cells (ED50: 0.3 microM). This concentration is an order of magnitude lower than that required for ddDAPR, AzddAdo, and AzddGuo. Potent inhibition of Moloney sarcoma virus induced transformation of murine C3H cells by AzddDAPR (4) was also observed. The alpha anomer (3) had no observed antiviral activity.
三氟甲磺酸三甲基硅酯催化下，2,6 - 二氨基 - 9 -（3 - 叠氮基 - 2,3 - 二脱氧 - α - 和 - β - D - 赤藓糖基）嘌呤（3和4）发生转移糖基化反应，产率较低。对2,6 - 二氨基 - 9 -（β - D - 呋喃核糖基）嘌呤（2,6 - 二氨基嘌呤核糖苷，DAPR，5）进行选择性2'-O - 甲苯磺酰化，随后在三乙基硼氢化锂促进下进行1,2 - 氢迁移重排，得到2,6 - 二氨基 - 9 -（2 - 脱氧 - β - D - 苏型 - 呋喃戊糖基）嘌呤（7）。7经三苯甲基化，然后在O3'位进行甲磺酰化、脱保护，并用叠氮基取代3'-甲磺酸酯，实现了2,6 - 二氨基 - 9 -（3 - 叠氮基 - 2,3 - 二脱氧 - β - D - 赤藓糖基）嘌呤（叠氮双脱氧二氨基嘌呤核糖苷，AzddDAPR，4）的立体定向合成。4的X射线晶体学分析表明叠氮基有两种取向，但分子其余部分具有一致的构象特征。相比之下，发现齐多夫定（AZT）有两种独立的构象。叠氮基功能赋予了增强的亲脂性，这有望对跨膜的非选择性转运有显著贡献。发现α（3）和β（4）异头物的正辛醇/水分配系数有很大差异。β异头物（4）对人MT - 4细胞中HIV诱导的细胞病变具有强效抑制作用（半数有效浓度：0.3 microM）。该浓度比双脱氧二氨基嘌呤核糖苷（ddDAPR）、叠氮双脱氧腺苷（AzddAdo）和叠氮双脱氧鸟苷（AzddGuo）所需浓度低一个数量级。还观察到叠氮双脱氧二氨基嘌呤核糖苷（4）对莫洛尼肉瘤病毒诱导的小鼠C3H细胞转化有强效抑制作用。α异头物（3）未观察到抗病毒活性。
