Fluorinated and Conformationally Fixed Derivatives of l‑HomoDMDP: Synthesis and Glycosidase Inhibition

Fluorinated and conformationally fixed derivatives of l-homoDMDP, i.e., 2,5-dideoxy-2,5-imino-dl-<i>glycero</i>-l-<i>manno</i>-heptitol, have been synthesized from d-xylose-derived cyclic nitrone <b>10</b> with oxazolidinone <b>19</b> or <b>28</b> and oxazinanone <b>22</b> or <b>32</b> as key intermediates. An evaluation of glycosidase inhibition showed replacement of the C-6 hydroxyl groups with fluoride in l-homoDMDP and its C-6 epimer did not have a significant influence on α-glucosidase inhibition by these iminosugars, while replacement of an amino group with a cyclic carbamate group in most conformationally fixed derivatives led to a sharp decrease in the level of glycosidase inhibition, revealing the importance of the free amino group in interaction of enzymes with these molecules

Glycosidase Inhibition by All 10 Stereoisomeric 2,5-Dideoxy-2,5-iminohexitols Prepared from the Enantiomers of Glucuronolactone

The enantiomers of glucuronolactone are excellent chirons for the synthesis of the 10 stereoisomeric 2,5-dideoxy-2,5-iminohexitols by formation of the pyrrolidine ring by nitrogen substitution at C2 and C5, with either retention or inversion of configuration; the stereochemistry at C3 may be adjusted during the synthesis to give seven stereoisomers from each enantiomer. A definitive side-by-side comparison of the glycosidase inhibition of a panel of 13 glycosidases showed that 8 of the 10 stereoisomers showed significant inhibition of at least one glycosidase

3‑Fluoroazetidinecarboxylic Acids and <i>trans,trans-</i>3,4-Difluoroproline as Peptide Scaffolds: Inhibition of Pancreatic Cancer Cell Growth by a Fluoroazetidine Iminosugar

Reverse aldol opening renders amides of 3-hydroxyazetidinecarboxylic acids (3-OH-Aze) unstable above pH 8. Aze, found in sugar beet, is mis-incorporated for proline in peptides in humans and is associated with multiple sclerosis and teratogenesis. Aze-containing peptides may be oxygenated by prolyl hydroxylases resulting in potential damage of the protein by a reverse aldol of the hydroxyazetidine; this, rather than changes in conformation, may account for the deleterious effects of Aze. This paper describes the synthesis of 3-fluoro-Aze amino acids as hydroxy-Aze analogues which are not susceptible to aldol cleavage. 4-(Azidomethyl)-3-fluoro-Aze and 3,4-difluoroproline are new peptide building blocks. <i>trans,trans</i>-2,4-Dihydroxy-3-fluoroazetidine, an iminosugar, inhibits the growth of pancreatic cancer cells to a similar degree as gemcitabine

General Synthesis of Sugar-Derived Azepane Nitrones: Precursors of Azepane Iminosugars

A general and efficient method has been developed for the synthesis of sugar-derived azepane nitrones starting from aldohexoses, with an intramolecular condensation of aldehyde and hydroxylamine as the key step. Through this strategy, each aldohexose produced a pair of azepane nitrones, which are precursors of various azepane iminosugars

α‑1‑<i>C</i>‑Butyl-1,4-dideoxy-1,4-imino‑l‑arabinitol as a Second-Generation Iminosugar-Based Oral α‑Glucosidase Inhibitor for Improving Postprandial Hyperglycemia

We report on the synthesis and the biological evaluation of a series of α-1-<i>C</i>-alkylated 1,4-dideoxy-1,4-imino-l-arabinitol (LAB) derivatives. The asymmetric synthesis of the derivatives was achieved by asymmetric allylic alkylation, ring-closing metathesis, and Negishi cross-coupling as key reactions. α-1-<i>C</i>-Butyl-LAB is a potent inhibitor of intestinal maltase, isomaltase, and sucrase, with IC₅₀ values of 0.13, 4.7, and 0.032 μM, respectively. Matrix-assisted laser desorption ionization time-of-flight mass spectrometric analysis revealed that this compound differs from miglitol in that it does not influence oligosaccharide processing and the maturation of glycoproteins. A molecular docking study of maltase-glucoamylase suggested that the interaction modes and the orientations of α-1-<i>C</i>-butyl-LAB and miglitol are clearly different. Furthermore, α-1-<i>C</i>-butyl-LAB strongly suppressed postprandial hyperglycemia at an early phase, similar to miglitol in vivo. It is noteworthy that the effective dose was about 10-fold lower than that for miglitol. α-1-<i>C</i>-Butyl-LAB therefore represents a new class of promising compounds that can improve postprandial hyperglycemia

Eight Stereoisomers of Homonojirimycin from d-Mannose

Although there are 32 6-azidoheptitols, there are only 16 homonojirimycin (HNJ) stereoisomers. Two epimeric azidoalditols derived from d-mannose allow the synthesis in water of eight stereoisomers of HNJ

Legislative History: An Act to Amend the Charter of the Winterport Water District (HP1719)(LD 2207)

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Synthesis from d‑Altrose of (5<i>R</i>,6<i>R</i>,7<i>R</i>,8<i>S</i>)‑5,7-Dihydroxy-8-hydroxymethylconidine and 2,4-Dideoxy-2,4-imino‑d‑glucitol, Azetidine Analogues of Swainsonine and 1,4-Dideoxy-1,4-imino‑d‑mannitol

Ring closure of a 3,5-di-<i>O</i>-triflate derived from d-altrose with benzylamine allowed the formation of both monocyclic and bicyclic azetidine analogues of swainsonine

Design and Synthesis of Labystegines, Hybrid Iminosugars from LAB and Calystegine, as Inhibitors of Intestinal α‑Glucosidases: Binding Conformation and Interaction for ntSI

This paper identifies the required configuration and orientation of α-glucosidase inhibitors, miglitol, α-1-<i>C</i>-butyl-DNJ, and α-1-<i>C</i>-butyl-LAB for binding to ntSI (isomaltase). Molecular dynamics (MD) calculations suggested that the flexibility around the keyhole of ntSI is lower than that of ctSI (sucrase). Furthermore, a molecular-docking study revealed that a specific binding orientation with a CH−π interaction (Trp370 and Phe648) is a requirement for achieving a strong affinity with ntSI. On the basis of these results, a new class of nortropane-type iminosugars, labystegines, hybrid iminosugars of LAB and calystegine, have been designed and synthesized efficiently from sugar-derived cyclic nitrones with intramolecular 1,3-dipolar cycloaddition or samarium iodide catalyzed reductive coupling reaction as the key step. Biological evaluation showed that our newly designed 3­(<i>S</i>)-hydroxy labystegine (<b>6a</b>) inherited the selectivity against intestinal α-glucosidases from LAB, and its inhibition potency was 10 times better than that of miglitol. Labystegine, therefore, represents a promising new class of nortropane-type iminosugar for improving postprandial hyperglycemia