Docking study and biological evaluation of pyrrolidine-based iminosugars as pharmacological chaperones for Gaucher disease.

We report on the synthesis and biological evaluation of a series of α-1-C-alkylated 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) derivatives as pharmacological chaperones for Gaucher disease. The parent compound, DAB, did not show inhibition of human β-glucocerebrosidase but showed moderate intestinal α-glucosidase inhibition; in contrast, extension of α-1-C-alkyl chain length gave a series of highly potent and selective inhibitors of the β-glucocerebrosidase. Our design of α-1-C-tridecyl-DAB (5j) produced a potent inhibitor of the β-glucocerebrosidase, with IC50 value of 0.

Synthesis and glycosidase inhibition of australine and its fluorinated derivatives.

Australine (1), 7-epi-australine (2), and their C-7-fluorinated derivatives 4 and 5 have been synthesized efficiently from D-arabinose-derived cyclic nitrone 11. Fluorination at the C-7 position enhanced the inhibition against A. niger α-glucosidase, and this constitutes the first example of fluorination substitution for a hydroxyl increasing the inhibition of any glycosidases.

Synthesis and biological evaluation of α-1-C-4'-arylbutyl-L-arabinoiminofuranoses, a new class of α-glucosidase inhibitors.

A series of α-1-C-4'-arylbutyl-L-arabinoiminofuranoses 3 with functional groups attached to the phenyl ring, which are potential α-glycosidase inhibitors, was designed and synthesized by using a Negishi cross-coupling reaction as the key reaction. Arylbutyl derivatives 3a-e showed potent inhibitory activities against intestinal maltase. Among them, difluorophenylbutyl derivative 3e showed good inhibition activities against intestinal isomaltase and sucrase as compared to those of 1 and commercial drugs.

Synthesis and biological evaluation of N-(2-fluorophenyl)-2β-deoxyfuconojirimycin acetamide as a potent inhibitor for α-l-fucosidases.

In this study we revealed that the addition of an N-phenylacetamide substituent to the C-1 position of 1-deoxyfuconojirimycin (DFJ) can lead to highly potent inhibitors of α-l-fucosidases. A structure-activity relationship study showed that a fluoro group on the phenyl ring greatly increased its potency and selectivity. In contrast the addition of two or three fluoro groups decreased their inhibition potency.

Total synthesis and glycosidase inhibition of broussonetine I and J(2).

The first total synthesis of both broussonetine I and J2 together with their enantiomers have been accomplished via the same synthetic route through 18 and 16 steps in excellent overall yields (18% and 19%, respectively), starting from R-glyceraldehyde. Broussonetine I was found to be a potent inhibitor of β-glucosidase (IC50 = 2.9 μM), while ent-broussonetine I and ent-broussonetine J2 were found to be potent inhibitors of α-glucosidase (IC50 = 0.

Synthesis of fully substituted polyhydroxylated pyrrolizidines via Cope-House cyclization.

Total synthesis of the proposed structure of (-)-hyacinthacine C(5) and its epimers at C6 and C7 is described. A key step of the synthesis was the construction of the bicyclic pyrrolizidine system by means of a nucleophilic addition of a dithiane to a cyclic nitrone followed by a Cope-House cyclization.

Microscopic polyangiitis after silicone breast implantation.

We describe the case of a patient who developed microscopic polyangiitis (MPA) after silicone breast implantation. A 60-year-old woman who had undergone silicone breast implantation was admitted to our hospital with complaints of general malaise and hematoproteinuria. She was diagnosed as having MPA with evidence of acute progressive renal failure, pulmonary hemorrhage, and positivity for myeloperoxidase-antineutrophil cytoplasmic antibody (ANCA).

Immunohistochemical evaluation of tissue-specific proteolytic enzymes in adenomas containing foci of early carcinoma: correlations with cathepsin D expression and other malignant features.

Background: Cathepsin D (CD) is an aspartyl lysosomal protease, and the prognostic value of CD expression has been studied in a variety of tumors, however, its role in early adenocarcinomas remains unclear.

Aim Of The Study: We evaluated the expression of CD in a series of colorectal adenomas with severe dysplasia containing foci of early carcinoma and compared the results to several histopathological and immunohistochemical features.

Methods: Adenomas were obtained by endoscopic polypectomy from 33 patients.