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

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