6-Methylpurine derived sugar modified nucleosides: Synthesis and evaluation of their substrate activity with purine nucleoside phosphorylases.
6-Methylpurine derived sugar modified nucleosides: Synthesis and evaluation of their substrate activity with purine nucleoside phosphorylases.
复制标题
6-甲基嘌呤衍生的糖修饰核苷：嘌呤核苷磷酸化酶的合成和底物活性评估。
DOI：
10.1016/j.bioorg.2015.12.006
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发表时间：
2016
影响因子：
5.1
通讯作者：
Secrist3rd,JohnA
中科院分区：
文献类型：
--
作者：
Hassan,AbdallaEA;Abou-Elkhair,RehamAI;Parker,WilliamB;Allan,PaulaW;Secrist3rd,JohnA
6-Methylpurine (MeP) is cytotoxic adenine analog that does not exhibit selectivity when administered systemically, and could be very useful in a gene therapy approach to cancer treatment involvingEscherichia coliPNP. The prototype MeP releasing prodrug, 9-(β-d-ribofuranosyl)-6-methylpurine, MeP-dR has demonstrated good activity against tumors expressingE. coliPNP, but its antitumor activity is limited due to toxicity resulting from the generation of MeP from gut bacteria. Therefore, we have embarked on a medicinal chemistry program to identify non-toxic MeP prodrugs that could be used in conjunction withE. coliPNP. In this work, we report on the synthesis of 9-(6-deoxy-β-d-allofuranosyl)-6-methylpurine (3) and 9-(6-deoxy-5-C-methyl-β-d-ribo-hexofuranosyl)-6-methylpurine (4), and the evaluation of their substrate activity with several phosphorylases. The glycosyl donors; 1,2-di-O-acetyl-3,5-di-O-benzyl-α-d-allofuranose (10) and 1-O-acetyl-3-O-benzyl-2,5-di-O-benzoyl-6-deoxy-5-C-methyl-β-d-ribohexofuran-ose (15) were prepared from 1,2:5,6-di-O-isopropylidine-α-d-glucofuranose in 9 and 11 steps, respectively. Coupling of10and15with silylated 6-methylpurine under Vorbrüggen glycosylation conditions followed conventional deprotection of the hydroxyl groups furnished 5′-C-methylated-6-methylpurine nucleosides3and4, respectively. Unlike 9-(6-deoxy-α-l-talo-furanosyl)-6-methylpurine, which showed good substrate activity withE. coliPNP mutant (M64V), the β-d-allo-furanosyl derivative3and the 5′-di-C-methyl derivative4were poor substrates for all tested glycosidic bond cleavage enzymes.
