ABSTRACT
Four branched tetra- and pentahydroxylated azepanes have been synthesized from a common azepane precursor through dihydroxylation followed by deoxygenation. They have been assayed as glycosidase inhibitors on a panel of 22 glycosidases and one methylated azepane displayed selective, competitive, and moderate inhibition toward bovine kidney α-L-fucosidase.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Imino Sugars/chemical synthesis , alpha-L-Fucosidase/antagonists & inhibitors , Animals , Cattle , Enzyme Inhibitors/pharmacology , Glycoside Hydrolases/antagonists & inhibitors , Glycoside Hydrolases/metabolism , Imino Sugars/pharmacology , Kidney/enzymology , Magnetic Resonance Spectroscopy , Molecular Structure , Oxygen/chemistry , Plants/enzymology , Stereoisomerism , Yeasts/enzymology , alpha-L-Fucosidase/metabolismABSTRACT
Many natural products of biological interest contain [6,5]- and [6,6]-spiroketal moieties that can adopt various configurations, benefiting or not from anomeric conformation stabilizing effects. The spiroketal fragments are often important for the biological activity of the compounds containing them. Most stable spiroketal stereoisomers, including those benefiting from conformational anomeric effects (gauche conformers can be more stable than anti conformers because of a contra-steric stabilizing effect), are obtained easily under acidic conditions that permit acetal heterolysis (formation of tertiary oxycarbenium ion intermediates). The synthesis of less stable stereoisomers requires stereoselective acetal forming reactions that do not permit their equilibration with their most stable stereoisomers or, in the case of suitably substituted derivatives, concomitant reactions generating tricyclic products that quench the less stable spiroketal conformers. Ingenuous approaches have been recently developed for the synthesis of naturally occurring [6,6]- and [5,6]-nonanomeric spiroketals and analogues. The identification of several parameters that can influence the stereochemical outcome of spirocyclization processes has led to seminal improvements in the selective preparation of the non-anomeric isomers that are discussed herein. This review also gives an up-dated view of conformational anomeric effect which represents a small fraction of the enthalpic anomeric effect that makes gem-dioxy substituted compounds much more stable that their 1,n-dioxy substituted isomers (n > 1). Although models assuming sp3-hybridized oxygen atoms have been very popular (rabbit ears for the two non-bonding electron pairs of oxygen atom), sp2-hybridized oxygen atoms are used to describe the conformational anomeric effect.
Subject(s)
Biological Products/chemistry , Furans/chemical synthesis , Spiro Compounds/chemical synthesis , Drug Stability , Structure-Activity RelationshipABSTRACT
Several members of a new family of seven-membered azasugars, which can be seen as 1-azasugar ring homologues, have been obtained by simple chemical transformations starting from a sugar-derived azidolactol. Unlike their piperidine counterparts, these molecules are chemically stable when they possess a hydroxy group at the pseudo-C-2 position. Biological assays with a range of carbohydrate-processing enzymes have revealed interesting potential for these compounds. A trihydroxymethyl-substituted azepane displayed strong competitive inhibition on almond beta-glucosidase (K(i)=2.5 microM) while a trihydroxylated carboxylic acid derivative proved to be a potent and selective L-fucosidase inhibitor (K(i)=41 nM). N-Butylation of these seven-membered 1-azasugars generated derivatives with some activity towards the Gaucher's disease-related glucosylceramide transferase (IC(50) 75 microM) that did not interact significantly with digestive glucosidases.
Subject(s)
Aza Compounds/chemical synthesis , Azepines/chemical synthesis , Carbohydrates/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Glucosylceramides/antagonists & inhibitors , Glycoside Hydrolases/antagonists & inhibitors , Glycosyltransferases/antagonists & inhibitors , Aza Compounds/pharmacology , Azepines/pharmacology , Biological Assay , Carbohydrates/pharmacology , Crystallography, X-Ray , Enzyme Inhibitors/pharmacology , Gaucher Disease/drug therapy , Gaucher Disease/pathologyABSTRACT
A sequence of highly diastereoselective functionalizations allowed transformation of a meso-methylenebis(cyclohept-3-ene-1,6-diyl diester) into an advanced precursor of the AB spiroketal of spongistatins. This route illustrates the potential of this bis-cycloheptene derivative for the synthesis of a key fragment of complex bioactive natural compounds.
Subject(s)
Macrolides/chemical synthesis , Spiro Compounds/chemistry , Macrolides/chemistry , Molecular Conformation , StereoisomerismABSTRACT
A solid-phase synthesis of new N-substituted valienamines has been developed and new synthesis of (+/-)-conduramine F-1, (-)-conduramine F-1, and (+)-ent-conduramine F-1 is presented, together with the preparation of N-benzylated conduramines F-1. N-Benzylation of both valienamine and (+)-ent-conduramine F-1 improves their inhibitory activity toward alpha-glucosidases significantly. The additional hydroxymethyl group makes valienamine derivatives more active than their (+)-ent-conduramine F-1 analogues.
Subject(s)
Cyclohexanols/pharmacology , Cyclohexylamines/pharmacology , Enzyme Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors , Hexosamines/pharmacology , Cyclohexanols/chemical synthesis , Cyclohexanols/chemistry , Cyclohexenes , Cyclohexylamines/chemical synthesis , Cyclohexylamines/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hexosamines/chemical synthesis , Hexosamines/chemistry , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A range of new tetra- and pentahydroxylated seven-membered iminoalditols has been efficiently synthesized from epoxyazepane precursors via nucleophilic opening with hydride or oxygenated species and subsequent hydrogenolysis. One tetrahydroxylated azepane, a ring homologue of deoxymannojirimycin, displays a selective and fairly good inhibition of alpha-L-fucosidase.
Subject(s)
Azepines/chemistry , Enzyme Inhibitors/chemical synthesis , Epoxy Compounds/chemistry , Glycoside Hydrolases/antagonists & inhibitors , alpha-L-Fucosidase/antagonists & inhibitors , 1-Deoxynojirimycin , Sugar Alcohols/chemical synthesisABSTRACT
New substituted pyrrolidine-3,4-diol derivatives were prepared from d-(-)- and l-(+)-phenyl glycinol. The influence of the configuration and the substitution of the lateral side chain of these derivatives on the inhibition of 25 commercial glycosidases were determined. (2R,3R,4S)-2-({[(1R)-2-Hydroxy-1-phenylethyl]amino}methyl)pyrrolidine-3,4-diol ((+)-7a) was a potent and selective inhibitor of jack bean alpha-mannosidase (K(i) = 135 nM). However, when evaluated on human tumor cells, 7a, and the reference compound swainsonine, did not efficiently inhibit the growth of glioblastoma cells. Further derivatization of the hydroxyl group with lipophilic groups to increase bioavailability improved their growth inhibitory properties for human glioblastoma and melanoma cells. In particular, the 4-bromobenzoyl derivative 26 demonstrated high efficacy for human tumor cells whereas primary human fibroblasts were less sensitive to 26. Therefore, functionalized pyrrolidines have the potential to inhibit the growth of tumor cells and display selectivity for tumor cells when compared to normal cells.
