Inhibition of Nonmammalian Glycosidases by Azetidine Iminosugars Derived from Stable 3,5-Di-O-triflates of Pentoses

Abstract

Efficient ring closure of stable crystalline 3,5-di-O-triflates of pentofuranosides with amines to form azetidines allowed preliminary evaluation of four-ring iminosugars as glycosidase inhibitors; significant and specific inhibition of nonmammalian α-glucosidases is shown by L-xylo- and L-arabino-iminosugar azetidines.

3‐Hydroxyazetidine Carboxylic Acids: Non‐Proteinogenic Amino Acids for Medicinal Chemists

“…[40] Azetidine carboxylic acid derivatives with an unprotected hydroxy group at C3, such as the amide 11, are susceptible to retro-aldol reactions under base catalysis; however, the amide 11 is stable indefinitely under neutral or acidic pH. [41] Among recent studies on the bioactivity of iminosugar azetidines, [42] potent inhibition of purine nucleoside phosphorylase [43] and specific inhibition of non-mammalian glycosidases [44,45] have been reported. Inhibition by the azetidines 10 L, 11 L, 10 D, 11 D, and 20 of the following glycosidases were studied (Table 1): [46] Neither of the enantiomeric acids 10 L and 10 D showed any inhibition (IC 50 < 50 % at 1000 mm) of any glycosidases ( Figure 4).…”

“…Iminosugars that are good to potent inhibitors of other a-glucosidases generally show no significant inhibition of the yeast enzyme; DAB 27 (IC 50 0.15 mm) and DMDP 28 (IC 50 0.71 mm) are the only natural iminosugars that are potent inhibitors of yeast a-glucosidase. [48] Early indications [44,45] are that azetidines are selective inhibitors of nonmammalian glycosidases-unlike their pyrrolidine and piperidine counterparts-and may have significance for the development of use of such compounds.…”

First total synthesis of kipukasin A

“…R f 0.30 (CH 2 Cl 2 /CH 3 OH 10:1, v:v); mp 90–91 °C (lit. [38] 87–89 °C); [α] D 25 +62.3 ( c 0.1, CH 3 OH) (lit. [38] [α] D 25 +49 ( c 0.94, CHCl 3 )); 1 H NMR (400 MHz, DMSO- d 6 ) δ 5.65 (d, J = 3.7 Hz, 1H), 4.98 (d, J = 6.7 Hz, 1H), 4.64 (t, J = 5.6 Hz, 1H), 4.43 (t, J = 3.9 Hz, 1H), 3.79–3.56 (m, 3H), 3.41–3.35 (m, 1H), 1.43 (s, 3H), 1.26 (s, 3H); 13 C NMR (101 MHz, DMSO- d 6 ) δ 111.1, 103.3, 80.3, 79.1, 70.5, 60.2, 26.6, 26.4; LRMS (ESI) m/z : 213.3 [M + Na] + , 189.3 [M − H] − ; HRMS (ESI) m/z : [M + Na] + calcd for C 8 H 13 O 5 Na, 213.0733; found, 213.0731.…”

Synthesis of polyhydroxylated azetidine iminosugars and 3-hydroxy-N-methylazetidine-2-carboxylic acid from d-glucose

“…11,12 Removal of hydroxymethyl group as in 4 slightly reduced inhibition of amyloglucosidase (IC 50 432AE5 mM and Ki 56 mM). Compared to other test compounds, 3-hydroxy-N-methylazetidine-2-carboxylic acid 5 exhibited significantly enhanced activity (IC 50 12.32AE0.68 mM and K i 2.68 mM).…”