Department of Chemistry, The City College and The City University of New York, 160 Convent Avenue, New York, New York 10031, USA.
J Org Chem. 2012 Jul 20;77(14):5870-83. doi: 10.1021/jo300628y. Epub 2012 Jul 3.
O(6)-(Benzotriazol-1H-yl)guanosine and its 2'-deoxy analogue are readily converted to the O(6)-allyl derivatives that upon diazotization with t-BuONO and TMS-N(3) yield the C-2 azido derivatives. We have previously analyzed the solvent-dependent azide·tetrazole equilibrium of C-6 azidopurine nucleosides, and in contrast to these, the O(6)-allyl C-2 azido nucleosides appear to exist predominantly in the azido form, relatively independent of solvent polarity. In the presently described cases, the tetrazole appears to be very minor. Consistent with the presence of the azido functionality, each neat C-2 azide displayed a prominent IR band at 2126-2130 cm(-1). A screen of conditions for the ligation of the azido nucleosides with alkynes showed that CuCl in t-BuOH/H(2)O is optimal, yielding C-2 1,2,3-triazolyl nucleosides in 70-82% yields. Removal of the silyl groups with Et(3)N·3HF followed by deallylation with PhSO(2)Na/Pd(PPh(3))(4) gave the C-2 triazolylinosine nucleosides. In a continued demonstration of the versatility of O(6)-(benzotriazol-1H-yl)purine nucleosides, one C-2 triazolylinosine derivative was converted to two adenosine analogues via these intermediates, under mild conditions. Products were desilylated for biological assays. The two C-2 triazolyl adenosine analogues demonstrated pronounced antiproliferative activity in human ovarian and colorectal carcinoma cell cultures. When evaluated for antiviral activity against a broad spectrum of DNA and RNA viruses, some of the C-2 triazolylinosine derivatives showed modest inhibitory activity against cytomegalovirus.
O(6)-(苯并三唑-1H-基)鸟苷及其 2'-脱氧类似物很容易转化为 O(6)-烯丙基衍生物，这些衍生物经 t-BuONO 和 TMS-N(3)重氮化后生成 C-2 叠氮衍生物。我们之前分析了 C-6 叠氮嘌呤核苷的溶剂依赖性叠氮·四唑平衡，与这些核苷不同，O(6)-烯丙基 C-2 叠氮核苷似乎主要以叠氮形式存在，相对独立于溶剂极性。在目前描述的情况下，四唑似乎很少。与叠氮官能团的存在一致，每个纯 C-2 叠氮都在 2126-2130 cm(-1)处显示出一个显著的红外带。对叠氮核苷与炔烃的连接条件进行筛选后发现，CuCl 在 t-BuOH/H(2)O 中是最佳的，以 70-82%的产率生成 C-2 1,2,3-三唑核苷。用 Et(3)N·3HF 脱除硅烷基后，再用 PhSO(2)Na/Pd(PPh(3))(4)脱烯丙基得到 C-2 三唑基肌苷核苷。在继续展示 O(6)-(苯并三唑-1H-基)嘌呤核苷的多功能性时，通过这些中间体，一种 C-2 三唑基肌苷核苷衍生物在温和条件下转化为两种腺苷类似物。产物经脱硅处理后用于生物测定。两种 C-2 三唑基腺苷类似物在人卵巢和结直肠癌细胞培养物中表现出明显的抗增殖活性。当评估它们对广谱 DNA 和 RNA 病毒的抗病毒活性时，一些 C-2 三唑基肌苷衍生物对巨细胞病毒显示出适度的抑制活性。
