The synthesis of two polyhydroxylated
pyrrolidines as 1,4-dideoxy-1,4-imino-
d
-arabinitol (DAB)
analogues bearing a hydrazide moiety is described.
The DAB analogues act as selective and potent inhibitors of α-mannosidase
in the submicromolar concentration ranges (
K
i
values ranging from 0.23 to 1.4 μM).
Natural products are rich sources of interesting scaffolds possessing a plethora of biological activity. With the isolation of the martinella alkaloids in 1995, namely martinelline and martinellic acid, the pyrrolo[3,2-c]quinoline scaffold was discovered. Since then, this scaffold has been found in two additional natural products, viz. incargranine B and seneciobipyrrolidine. These natural products have attracted attention from synthetic chemists both due to the interesting scaffold they contain, but also due to the biological activity they possess. This review highlights the synthetic efforts made for the preparation of these alkaloids and formation of analogues with interesting biological activity.
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.
Minimally protected aminopolyols are novel substrates for the galactose oxidase variant F2. Site-selective oxidation proceeds at the terminal primary alcohol, followed by spontaneous cyclisation to afford stable hemiaminal/hemiacetal anomers of...
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