Yokomatsu T, Hayakawa Y, Kihara T, Koyanagi S, Soeda S, Shimeno H, Shibuya S
School of Pharmacy, Tokyo University of Pharmacy & Life Science, Hachioji, Japan.
Bioorg Med Chem. 2000 Nov;8(11):2571-9. doi: 10.1016/s0968-0896(00)00192-9.
1,1-Difluoro-2-(tetrahydro-3-furanyl)ethylphosphonic acids (+/-)-cis-4a and (+/-)-trans-4a possessing a (purine-9-yl)methyl functionality at the ring as well as their homologues (+/-)-cis-4b and (+/-)-trans-4b were synthesized and tested as 'multi-substrate analogue' inhibitors for purine nucleoside phosphorylases. Radical cyclization of allylic alpha,alpha-difluorophosphonates 8a,b was applied to construct the alpha,alpha-difluorophosphonate-functionalized oxacycles 9a,b. The IC50 values of the nucleotide analogues (+/-)-cis-4a and (+/-)-cis-4b were 88 and 38 nM, respectively, for human erythrocyte PNP-catalyzed phosphorylation of inosine in the presence of 100mM orthophosphate. The stereochemistry of the inhibitors was found to affect significantly the inhibitory potency. The transisomers (+/-)-trans-4a and (+/-)-trans-4b were ca. 4-fold less potent than the corresponding cis-isomers. At an intracellular concentration of orthophosphate (1 mM), (+/-)-cis-4b, the most potent compound of this series, was shown to have IC50 and Ki values of 8.7 and 3.5 nM, respectively.
在环上具有（嘌呤 - 9 - 基）甲基官能团的1,1 - 二氟 - 2 - （四氢 - 3 - 呋喃基）乙基膦酸（±） - 顺式 - 4a和（±） - 反式 - 4a以及它们的同系物（±） - 顺式 - 4b和（±） - 反式 - 4b被合成出来，并作为嘌呤核苷磷酸化酶的“多底物类似物”抑制剂进行了测试。应用烯丙基α,α - 二氟膦酸酯8a,b的自由基环化反应来构建α,α - 二氟膦酸酯官能化的氧杂环9a,b。在100mM正磷酸盐存在下，对于人红细胞PNP催化的肌苷磷酸化反应，核苷酸类似物（±） - 顺式 - 4a和（±） - 顺式 - 4b的IC50值分别为88和38 nM。发现抑制剂的立体化学对抑制效力有显著影响。反式异构体（±） - 反式 - 4a和（±） - 反式 - 4b的效力比相应的顺式异构体低约4倍。在细胞内正磷酸盐浓度为1 mM时，该系列中最有效的化合物（±） - 顺式 - 4b的IC50和Ki值分别为8.7和3.5 nM。
