Functionalized d- and l-Arabino-Pyrrolidines as Potent and Selective Glycosidase Inhibitors

Abstract

The efficient synthesis of enantiomeric pairs of iminosugars including 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) and 1,4-dideoxy-1,4-imino-L-arabinitol (LAB) analogues with an amidine, hydrazide, hydrazide imide, or amide oxime moiety is described. The preparation of DAB and LAB analogues commenced from L-xylose and D-xylose, respectively. Title iminosugars were tested against a panel of glycosidases with therapeutic relevance, revealing an enhanced activity of DAB analogues in comparison with the LAB analogues. In particular, the D-arabino-configured amidine behaved as a potent (sub micromolar range) and selective inhibitor of α-mannosidase.

Exploring Phthalimide as the Acid Component in the Passerini Reaction

“…The subsequent cleavage of the phthalimide facilitated the straightforward synthesis of α-amidine alcohols and α-amide alcohols, compounds typically challenging to access . Noteworthy, α-amidine alcohols are a class of compounds rarely found in organic chemistry, with an interesting hydrogen bonding pharmacophore, and are highly under-represented in medicinal chemistry . Our novel synthetic approach exhibits significant potential for applications in the screening library enrichment.…”

“… 38 Noteworthy, α-amidine alcohols are a class of compounds rarely found in organic chemistry, with an interesting hydrogen bonding pharmacophore, and are highly under-represented in medicinal chemistry. 39 Our novel synthetic approach exhibits significant potential for applications in the screening library enrichment. Ongoing efforts in our laboratory are underway and will be reported in due course.…”