1,4-Dideoxy-1,4-imino-d-arabinitol (DAB) Analogues Possessing a Hydrazide Imide Moiety as Potent and Selective α-Mannosidase Inhibitors

Abstract

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).

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

“…Paper / PSP / Special Topic The spectroscopic data were in full accord with the previously reported data. 20 2,3,5-Tri-O-benzyl-D-xylofuranose (D-7) 22 Step 1: To a solution of AcCl (0.29 mL, 4 mmol) in MeOH (40 mL) was added L-xylose (3 g, 20 mmol) at room temp. The reaction was kept stirring at room temp.…”

“…The spectroscopic data were in full accord with the previously reported data for its enantiomer. 20 2,3,5-Tri-O-benzyl-4-(2-tert-butoxycarbonyl)hydrazinyl-4-deoxy-Larabinonitrile (L-9)…”

“…Another interesting finding when comparing D-iminosugars with the corresponding synthetic L-iminosugars is that the mirror compounds can exhibit strong inhibition of different glycosidases. [16][17][18] As part of our ongoing iminosugar program, [19][20][21][22] we recently reported the synthesis and glycosidase inhibitory activity of compounds D-2, D-3, and D-4 (Figure 1). 20 The glycosidase inhibitory tests showed that hydrazide imides D-2 and D-3 were selective inhibitors (low micromolar range) against jack bean αmannosidase, which is a member of the retaining glycoside hydrolase family 38 that hosts α-mannosidases of pharmaceutical relevance.…”

“…[16][17][18] As part of our ongoing iminosugar program, [19][20][21][22] we recently reported the synthesis and glycosidase inhibitory activity of compounds D-2, D-3, and D-4 (Figure 1). 20 The glycosidase inhibitory tests showed that hydrazide imides D-2 and D-3 were selective inhibitors (low micromolar range) against jack bean αmannosidase, which is a member of the retaining glycoside hydrolase family 38 that hosts α-mannosidases of pharmaceutical relevance. 23 Following this line, we herein report: 1) the synthesis of the D-iminosugars D-5 and D-6 from commercially available L-xylose in which the hydrazide imide moiety in D-2 has been replaced by an amidine and amide oxime moiety, respectively; 2) the synthesis of all the enantiomers of D-2-D-6, namely, L-2-L-6 from commercially available D-xylose; and 3) the evaluation of D-5 and D-6 and L-2-L-6 as glycosidase inhibitors.…”

Synthesis of Piperidine Nucleosides as Conformationally Restricted Immucillin Mimics

“…Piperidine iminosugars belonging to the unnatural l -series ( l -iminosugars) also exhibit pharmacological properties, such as in the case of l -DGJ [ 21 ], l -NBDNJ [ 22 ] ( Figure 1 ), and its congeners [ 23 , 24 ]. Similarly, iminosugars with a pyrrolidine skeleton (in both enantiomeric series) have been found to hold excellent glycomimetic properties, as in the case of naturally occurring Radicamine A and B [ 25 ], 2,5-dideoxy-2,5-imino- d -mannitol ( d -DMDP), 1,4-dideoxy-1,4-imino- d -arabinitol ( d -DAB-1) ( Figure 1 ), and their structurally related compounds [ 26 , 27 ]. Polyhydroxylated pyrrolidine scaffolds can also be recognized in the structure of Immucillins, which are chemically stable 9-deazapurine C -nucleoside analogues endowed with a variety of therapeutic applications, ranging from the treatment of cancer and autoimmune disorders to parasitic and viral infections [ 28 ].…”