ABSTRACT
The key step in the concise syntheses of calystegine B2 and its C-2 epimer calystegine B3 was the construction of cycloheptanone 8via an intramolecular Nozaki-Hiyama-Kishi (NHK) reaction of 9, an aldehyde containing a Z-vinyl iodide. Vinyl iodide 9 was obtained by the Stork olefination of aldehyde 10, derived from carbohydrate starting materials. Calystegines B2 (3) and B3 (4) were synthesized from d-xylose and l-arabinose derivatives respectively in 11 steps in excellent overall yields (27% and 19%).
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Nortropanes/chemistry , Nortropanes/chemical synthesis , Solanaceous Alkaloids/chemistry , Solanaceous Alkaloids/chemical synthesis , Aldehydes/chemistry , Chemistry Techniques, Synthetic , Cycloheptanes/chemistry , Enzyme Inhibitors/pharmacology , Glycoside Hydrolases/antagonists & inhibitors , Nortropanes/pharmacology , Solanaceous Alkaloids/pharmacology , StereoisomerismABSTRACT
This paper identifies the required configuration and orientation of α-glucosidase inhibitors, miglitol, α-1-C-butyl-DNJ, and α-1-C-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(S)-hydroxy labystegine (6a) 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.
Subject(s)
Drug Design , Enzyme Inhibitors/pharmacology , Imino Sugars/pharmacology , Nortropanes/pharmacology , Sucrase/antagonists & inhibitors , alpha-Glucosidases/metabolism , Arabinose/chemistry , Binding Sites/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Imino Furanoses/chemistry , Imino Sugars/chemical synthesis , Imino Sugars/chemistry , Intestines/enzymology , Molecular Conformation , Molecular Dynamics Simulation , Nortropanes/chemical synthesis , Nortropanes/chemistry , Sucrase/metabolism , Sugar Alcohols/chemistry , Tropanes/chemistryABSTRACT
In the title compound, C(16)H(15)NO(2), the isoindoline ring system is approximately planar (mean deviation = 0.0186â Å) and makes a dihedral angle of 61.91â (4)° with the phenyl ring. In the crystal, mol-ecules form inversion dimers via pairs of O-Hâ¯O hydrogen bonds.