Synthesis and biological evaluation of glycosidase inhibitors: gem-difluoromethylenated nojirimycin analogues.
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.
Wang
Ruo-Wen
RW
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China.
Qiu
Xiao-Long
XL
Bols
Mikael
M
Ortega-Caballero
Fernando
F
Qing
Feng-Ling
FL