Synthesis and anti-HIV activities of bis-(cycloSaligenyl) pronucleotides derivatives of 3'-fluoro-3'-deoxythymidine and 3'-azido-3'-deoxythymidine.
Synthesis and anti-HIV activities of bis-(cycloSaligenyl) pronucleotides derivatives of 3'-fluoro-3'-deoxythymidine and 3'-azido-3'-deoxythymidine.
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DOI：
10.1016/j.tetlet.2010.12.038
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发表时间：
2011-02-16
影响因子：
1.8
通讯作者：
Parang K
中科院分区：
文献类型：
--
作者：
Ahmadibeni Y;Tiwari R;Swepson C;Pandhare J;Dash C;Doncel GF;Parang K
由于带负电荷的磷酸基团的存在，抗HIV核苷一磷酸的细胞摄取有限。合成了含有两种抗HIV核苷3‘-氟-3’-脱氧胸苷(Flt)和3‘-叠氮-3’-脱氧胸苷(AZT)的双(环-盐基)衍生物，以增加核苷单磷酸在细胞内的转运。以2，5-二(羟亚甲基)苯-1，4-二醇为单环双齿骨架，分别以bis(hydroxymethylene)cyclohexan-1，4-diene-1，4-diol，和2，5-二羟基对苯二甲酸二乙酯为原料，采用三种不同的合成方法进行合成。在2，6-Lutidine存在下，四醇与二异丙基磷酰胺二氯化物反应，然后与核苷(即Flt和AZT)发生共轭反应，然后氧化得到对称和不对称的双(环盐基)二磷酸三酯产物，AZT-AZT，Flt-Flt和Flt-AZT，总收率63-74%，适度的抗HIV活性(IC50=2.8-69.6微米)。
Anti-HIV nucleoside monophosphates have limited cellular uptake due to the presence of negatively-charged phosphate group. Bis-(cycloSaligenyl) derivatives containing two anti-HIV nucleosides, 3′-fluoro-3′-deoxythymidine (FLT) and 3′-azido-3′-deoxythymidine (AZT) were synthesized to increase intracellular delivery of nucleoside monophosphates. 2,5-Bis(hydroxymethylene)benzene-1,4-diol was selected as a monocyclic bidentate scaffold and synthesized by three different methods from bis(hydroxymethylene)cyclohexan-1,4-diene-1,4-diol, or diethyl 2,5-dihydroxyterephthalate. The reaction of the tetraol with diisopropylphosphoramidous dichloride in the presence of 2,6-lutidine, followed by conjugation reactions with nucleosides (i.e., FLT and AZT) and oxidation afforded symmetrical and unsymmetrical bis-(cycloSaligenyl) diphosphate triester products, AZT–AZT, FLT–FLT, and FLT–AZT conjugates, in 63–74% overall yields and modest anti-HIV activities (IC50 = 2.8–69.6 µM).