Borylated 5-Membered Ring Iminosugars: Synthesis and Biological Evaluation for Glycosidase Inhibition and Anticancer Properties for Application in Boron Neutron Capture Therapy (BNCT) - Part 2

Background: The synthesis and biological investigation of pyrrolidine (L-gulo) iminosugars bearing an organic boron pharmacophore in ortho and meta positions of an N-benzyl group is reported. This paper completes the structure–activity relationship data for this novel family of boron-bearing iminosugars. These can establish reversible intramolecular interactions via dative bonding from nucleophilic amino acid side chains to the empty p-orbital of the boron atom. 

Methods: Inhibitory activities against two panels of glycosidases and cancer cell lines were investigated to ascertain structure–activity relationship profiles for these novel iminosugar drug leads. 

Results: These iminosugars display selective, moderate-to-weak inhibitions (IC ₅₀s = 116–617 μM) of β-D-galactosidase (bovine liver), and indications of inhibition of β-D-glucosidases (almond, bovine liver) (IC ₅₀s = 633 and 710 μM) and α-D-glucosidases (rice, yeast, rat intestinal maltase) (IC ₅₀s = 106–784 μM). The boronic acid group emerges as a useful pharmacophore for management of lysosomal storage disorders via the chaperone-mediated therapy approach. The cancer assays revealed that the A2780 ovarian carcinoma cell line is selectively inhibited by all compounds screened and the MIA-Pa-Ca2 pancreatic carcinoma cell line is selectively inhibited by most compounds. Growth inhibition and GI ₅₀ values were most potent for the meta 7 side-product. 

Conclusions: Beyond the cancer cell line inhibition and dose-response capabilities, the real therapeutic potential of these borylated drugs lies in their switch on/switch off activation under boron neutron capture therapy (BNCT) radiotherapeutic conditions, thus providing an important area of application for borylated monosaccharides.