Ma T, Pai S B, Zhu Y L, Lin J S, Shanmuganathan K, Du J, Wang C, Kim H, Newton M G, Cheng Y C, Chu C K
Department of Medicinal Chemistry, College of Pharmacy, University of Georgia, Athens 30602, USA.
J Med Chem. 1996 Jul 5;39(14):2835-43. doi: 10.1021/jm960098l.
Since 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU) has been shown to be a potent anti-HBV agent in vitro, it was of interest to study the structure-activity relationships of related nucleosides. Thus, a series of 1-(2-deoxy-2-fluoro-beta-L-arabinofuranosyl)pyrimidine nucleosides have been synthesized and evaluated for antiviral activity against HBV in 2.2.15 cells. For this study, L-ribose was initially used as the starting material. Due to the commercial cost of L-ribose, we have developed an efficient procedure for the preparation of L-ribose derivative 6. Starting from L-xylose, 6 was obtained in an excellent total yield (70%) through the pyridinium dichromate oxidation of the 3-OH group followed by stereoselective reduction with NaBH4. It was further converted to the 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-alpha-L-arabinofuranose (10), which was then condensed with various 5-substituted pyrimidine bases to give the nucleosides. Among the compounds synthesized, the lead compound, L-FMAU (13), exhibited the most potent anti-HBV activity (EC50 0.1 microM). None of the other uracil derivatives showed significant anti-HBV activity up to 10 microM. Among the cytosine analogues, the cytosine (27) and 5-iodocytosine (35) derivatives showed moderately potent anti-HBV activity (EC50 1.4 and 5 microM, respectively). The cytotoxicity of these nucleoside analogues has also been assessed in 2.2.15 cells as well as CEM cells. None of these compounds displayed any toxicity up to 200 microM in 2.2.15 cells. Thus, compound 13 (L-FMAU), 27, and 35 showed a selectivity of over 2000, 140, and 40, respectively.
由于2'-氟-5-甲基-β-L-阿拉伯呋喃糖基尿嘧啶（L-FMAU）在体外已被证明是一种有效的抗乙肝病毒药物，因此研究相关核苷的构效关系很有意义。于是，一系列1-(2-脱氧-2-氟-β-L-阿拉伯呋喃糖基)嘧啶核苷被合成出来，并在2.2.15细胞中评估其对乙肝病毒的抗病毒活性。在本研究中，L-核糖最初被用作起始原料。由于L-核糖的商业成本，我们开发了一种制备L-核糖衍生物6的有效方法。从L-木糖开始，通过用重铬酸吡啶鎓氧化3-OH基团，然后用NaBH4进行立体选择性还原，以优异的总收率（70%）得到6。它进一步转化为1,3,5-三-O-苯甲酰基-2-脱氧-2-氟-α-L-阿拉伯呋喃糖（10），然后与各种5-取代嘧啶碱缩合得到核苷。在合成的化合物中，先导化合物L-FMAU（13）表现出最有效的抗乙肝病毒活性（EC50为0.1微摩尔）。其他尿嘧啶衍生物在高达10微摩尔时均未显示出显著的抗乙肝病毒活性。在胞嘧啶类似物中，胞嘧啶（27）和5-碘胞嘧啶（35）衍生物表现出中等强度的抗乙肝病毒活性（EC50分别为1.4和5微摩尔）。这些核苷类似物的细胞毒性也已在2.2.15细胞以及CEM细胞中进行了评估。在2.2.15细胞中，这些化合物在高达200微摩尔时均未显示出任何毒性。因此，化合物13（L-FMAU）、27和35的选择性分别超过2000、140和40。
