Synthesis and evaluation of d-gluco-pyranocyclopropyl amines as potential glucosidase inhibitors (original) (raw)
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—Glycoside trimming enzymes are crucially important in a broad range of metabolic pathways, including glycoprotein and glyco-lipid processing and carbohydrate digestion in the intestinal tract. Amongst the large array of enzymes, glucosidases are postulated to be a powerful therapeutic target since they catalyze the cleavage of glycosidic bonds releasing glucose from the non-reducing end of an oligo-or polysaccharide chain involved in glycoprotein biosynthesis. Glucosidase inhibitors are currently of interest owing to their promising therapeutic potential in the treatment of disorders such as diabetes, human immunodeficiency virus (HIV) infection, metastatic cancer, and lyso-somal storage diseases. Glucosidase inhibitors have also been useful in probing biochemical pathways and understanding structure–activity relationship patterns required for mimicking the enzyme transition state. Amongst the various types of glucosidase inhibitors, disaccharides, iminosugars, carbasugars, thiosugars, and non-sugar derivatives have received great attention. This review is aimed at highlighting the main chemical classes of glucosidase inhibitors, as well as their biological activities toward a-and b-glucosidases, but it is not intended to be an exhaustive review on the subject. Inhibition data on the compounds covered in this review are included in a tabular form as an Appendix, where the type of each glucosidase associated with a specific inhibitor is also given.
and β-Glucosidase inhibitors: chemical structure and biological activity
Tetrahedron, 2006
Glycoside trimming enzymes are crucially important in a broad range of metabolic pathways, including glycoprotein and glycolipid processing and carbohydrate digestion in the intestinal tract. Amongst the large array of enzymes, glucosidases are postulated to be a powerful therapeutic target since they catalyze the cleavage of glycosidic bonds releasing glucose from the non-reducing end of an oligo-or polysaccharide chain involved in glycoprotein biosynthesis. Glucosidase inhibitors are currently of interest owing to their promising therapeutic potential in the treatment of disorders such as diabetes, human immunodeficiency virus (HIV) infection, metastatic cancer, and lysosomal storage diseases. Glucosidase inhibitors have also been useful in probing biochemical pathways and understanding structure-activity relationship patterns required for mimicking the enzyme transition state. Amongst the various types of glucosidase inhibitors, disaccharides, iminosugars, carbasugars, thiosugars, and non-sugar derivatives have received great attention. This review is aimed at highlighting the main chemical classes of glucosidase inhibitors, as well as their biological activities toward aand b-glucosidases, but it is not intended to be an exhaustive review on the subject. Inhibition data on the compounds covered in this review are included in a tabular form as an Appendix, where the type of each glucosidase associated with a specific inhibitor is also given.
α- and β-Glucosidase Inhibitors: Chemical Structure and Biological Activity
ChemInform, 2007
Glycoside trimming enzymes are crucially important in a broad range of metabolic pathways, including glycoprotein and glycolipid processing and carbohydrate digestion in the intestinal tract. Amongst the large array of enzymes, glucosidases are postulated to be a powerful therapeutic target since they catalyze the cleavage of glycosidic bonds releasing glucose from the non-reducing end of an oligo-or polysaccharide chain involved in glycoprotein biosynthesis. Glucosidase inhibitors are currently of interest owing to their promising therapeutic potential in the treatment of disorders such as diabetes, human immunodeficiency virus (HIV) infection, metastatic cancer, and lysosomal storage diseases. Glucosidase inhibitors have also been useful in probing biochemical pathways and understanding structure-activity relationship patterns required for mimicking the enzyme transition state. Amongst the various types of glucosidase inhibitors, disaccharides, iminosugars, carbasugars, thiosugars, and non-sugar derivatives have received great attention. This review is aimed at highlighting the main chemical classes of glucosidase inhibitors, as well as their biological activities toward aand b-glucosidases, but it is not intended to be an exhaustive review on the subject. Inhibition data on the compounds covered in this review are included in a tabular form as an Appendix, where the type of each glucosidase associated with a specific inhibitor is also given.
Helvetica Chimica Acta, 2006
The racemic 2-azabicyclo[3.2.2]nonanes 5 and 18 were synthesized and tested as b-glycosidase inhibitors. The intramolecular Diels-Alder reaction of the masked o-benzoquinone generated from 2-(allyloxy)phenol (6) gave the a-keto acetal 7 which was reduced with SmI 2 to the hydroxy ketone 8. Dihydroxylation, isopropylidenation (! 12), and Beckmann rearrangement provided lactam 15. N-Benzylation of this lactam, reduction to the amine 17, and deprotection provided the amino triol 19 which was debenzylated to the secondary amine 5. Both 5 and 19 proved weak inhibitors of snail b-mannosidase (IC 50 > 10 mM), Caldocellum saccharolyticum b-glucosidase (IC 50 > 10 mM), sweet almond b-glucosidase (IC 50 > 10 mM), yeast a-glucosidase (5: IC 50 > 10 mM; 19: IC 50 = 1.2 mM), and Jack bean a-mannosidase (no inhibition detected).
Tetrahedron: Asymmetry, 2009
A series of N-alkyl-and N-arylalkyl-DNJ compounds have been evaluated for their efficacy for inhibition of endoplasmic reticulum resident a-glucosidases in cells. A recently developed free oligosaccharide (FOS) assay allowed the products of glucosidase inhibition to be quantified and compounds compared for relative inhibitory activity. A N-alkyl chain of one to six carbon atoms provided a flexible linker between deoxynojirimycin (DNJ) and a phenyl, cyclohexyl or cyclopentyl group to explore the requirements for glucosidase inhibition. The most effective compounds were those in which the linker contained four to six carbon atoms and a phenyl group. These compounds all significantly inhibited a-glucosidase I at concentrations of 100 lM following addition to cells for 24 h whereas DNJ was without effect. Inhibition of a-glucosidase II was evident by all inhibitors, consistent with a previously identified mechanism of action of imino sugar inhibitors in cells.
Hybrid sugars as glycosidase inhibitors en route to 2-deoxy-2-amino C-glycosyl amino acids
Tetrahedron Letters, 2006
Sugar-azasugar hybrid molecules made up of D D-galactose with nojirimycin-d-lactam and pyrrolidine analogues are synthesized using intramolecular cyclization as a key step from 2-nitro galactal and found to be glycosidase inhibitors. Further, some of the intermediate compounds are converted into 2-deoxy-2-amino C-glycosyl glycines and C-glycosyl alanines.
Bioorganic & Medicinal Chemistry, 2013
The design and synthesis of a small library of pyrrolidine iminocyclitol inhibitors with a structural similarity to 1,4-dideoxy-1,4-imino-D-arabitol (DAB-1) is reported. This library was specifically designed to gain a better insight into the mechanism of inhibition of glycosidases by polyhydroxylated pyrrolidines or iminocyclitols. Pyrrolidine-3,4-diol 15a and pyrrolidine-3,4-diol diacetate 15b had emerged as the most potent a-glucosidase inhibitors in the series. Docking studies performed with an homology model of a-glucosidase disclosed binding poses for compounds 15a, 15b, 16a, and 16a 0 occupying the same region as the NH group of the terminal ring of acarbose and suggest a closer and stronger binding of compound 15a and 15b with the enzyme active site residues. Our studies indicate that 2 or 5-hydroxyl substituents appear to be vital for high inhibitory activity.
Synthesis and evaluation of sulfamide-type indolizidines as glycosidase inhibitors
Bioorganic & Medicinal Chemistry Letters, 2008
A practical synthesis of reducing sulfamide-derived iminosugar glycomimetics related to the indolizidine glycosidase inhibitor family is reported. The polyhydroxylated bicyclic system was built from readily accessible hexofuranose derivatives through a synthetic scheme that involves 5,6-cyclic sulfamides. Further intramolecular nucleophilic addition of the sulfamide nitrogen atom to the masked aldehyde group of the monosaccharide in the open chain form afforded the target sugar mimics. By starting from D D-glucose and D D-mannose precursors, 2-aza-3,3-dioxo-3-thiaindolizidine derivatives with hydroxylation profiles that matched those of (+)-castanospermine and 6-epi-(+)-castanospermine were obtained. In vitro screening against a panel of glycosidases evidenced a high selectivity towards a-mannosidase.
Bioorganic & Medicinal Chemistry Letters, 2004
As potential lead structures for a new class of glycosidase inhibitors the novel O-glycosyl amino acid mimetics 3 0-O-[2,6anhydro-d-glycero-l-gluco-heptitol-1-yl]-l-serine 3 and-l-threonine 4 were synthesized, employing regio-and stereoselective aziridine ring opening methodology. They proved to be stable in the presence of glycosidases and showed competitive inhibition of agalactosidase from Aspergillus niger.