Wang Ruo-Wen, Qiu Xiao-Long, Bols Mikael, Ortega-Caballero Fernando, Qing Feng-Ling
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China.
J Med Chem. 2006 May 18;49(10):2989-97. doi: 10.1021/jm060066q.
In our ongoing program aimed at the design, synthesis, and biological evaluation of novel gem-difluoromethylenated glycosidase inhibitors, gem-4,4-difluoromethylenated iminosugars (5-9) were synthesized. The biological evaluation of these synthetic iminosugars showed that the gem-difluoromethylenyl group generally reduced the inhibition of glycosidases. However, this was not the case at pH 5.0, where the gem-difluoromethylenated iminosugar 6 was a stronger inhibitor than comparable iminosugars 1 and 36, suggesting that the influence of this group is mainly through its effect on the amine. It is proposed that the unprotonated iminosugar is the species preferably bound by beta-glucosidase, due to the lower pK(a) value of iminosugar 6 than of 1 or 36, leaving iminosugars 1 and 36 mostly protonated at pH 5.0, while iminosugar 6 is not. Iminosugar 6 also displayed good and selective inhibition of beta-glucosidase at pH 6.8.
在我们正在进行的旨在设计、合成和生物学评价新型偕二氟亚甲基化糖苷酶抑制剂的项目中，合成了偕-4,4-二氟亚甲基化亚氨基糖（5-9）。对这些合成亚氨基糖的生物学评价表明，偕二氟亚甲基基团通常会降低对糖苷酶的抑制作用。然而，在pH 5.0时情况并非如此，此时偕二氟亚甲基化亚氨基糖6比类似的亚氨基糖1和36是更强的抑制剂，这表明该基团的影响主要是通过其对胺的作用。有人提出，未质子化的亚氨基糖是更易与β-葡萄糖苷酶结合的物种，因为亚氨基糖6的pK(a)值低于1或36，使得亚氨基糖1和36在pH 5.0时大多处于质子化状态，而亚氨基糖6则不是。亚氨基糖6在pH 6.8时也对β-葡萄糖苷酶表现出良好的选择性抑制作用。
