ABSTRACT
The synthesis of three libraries (1a-l, 1a'-l' and 2a-l) of dimeric iminosugars through CuAAC reaction between three different alkynyl pyrrolidines and a set of diazides was carried out. The resulting crude dimers were screened in situ against two α-fucosidases (libraries 1a-l and 1a'-l') and one ß-galactosidase (2a-l). This method is pioneer in the search of divalent glycosidase inhibitors. It has allowed the rapid identification of dimer 1i as the best inhibitor of α-fucosidases from bovine kidney (Kiâ¯=â¯0.15â¯nM) and Homo sapiens (Kiâ¯=â¯60â¯nM), and dimer 2e as the best inhibitor of ß-galactosidase from bovine liver (Kiâ¯=â¯5.8⯵M). In order to evaluate a possible divalent effect in the inhibition, the synthesis and biological analysis of the reference monomers were also performed. Divalent effect was only detected in the inhibition of bovine liver ß-galactosidase by dimer 2e.
Subject(s)
Imino Sugars/chemistry , Imino Sugars/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , alpha-L-Fucosidase/antagonists & inhibitors , beta-Galactosidase/antagonists & inhibitors , Animals , Cattle , Click Chemistry , Dimerization , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Structure-Activity Relationship , alpha-L-Fucosidase/metabolism , beta-Galactosidase/metabolismABSTRACT
The preliminary screening of two libraries of epimeric (pyrrolidin-2-yl)triazoles (14a-s and 22a-s), generated via click chemistry, allowed the rapid identification of four α-galactosidase (coffee beans) inhibitors (22b,k,p,r) and two ß-glucosidase (almond) inhibitors (14b,f) in the low µM range. The additional biological analysis of 14b,f towards ß-glucocerebrosidase (human lysosomal ß-glucosidase), as target enzyme for Gaucher disease, showed a good correlation with the inhibition results obtained for the plant (almond) enzyme. Surprisingly, although these compounds showed inhibition towards ß-glucocerebrosidase as acid hydrolase, they did not inhibit bovine liver ß-glucosidase as neutral hydrolase. In contrast to what was observed for ß-glucosidase inhibition, the coffee bean α-galactosidase inhibitors of the epimeric library (22b,k,p,r) only showed weak inhibition towards human lysosomal α-galactosidase.
Subject(s)
Enzyme Inhibitors/pharmacology , Pyrrolidines/pharmacology , Small Molecule Libraries/pharmacology , Triazoles/pharmacology , alpha-Galactosidase/antagonists & inhibitors , beta-Glucosidase/antagonists & inhibitors , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry , alpha-Galactosidase/metabolism , beta-Glucosidase/metabolismABSTRACT
Multi-valent inhibitors offer promise for the enhancement of therapeutic compounds across a range of chemical and biological processes. Here, a significant increase in enzyme-inhibition potencies was observed with a dimeric iminosugar-templated fucosidase inhibitor (IC50 = 0.108 µM) when compared to its monovalent equivalent (IC50 = 2.0 µM). Such a gain in binding is often attributed to a "multivalent effect" rising from alternative recapture of the scaffolded binding epitopes. The use of control molecules such as the meso analogue (IC50 = 0.365 µM) or the enantiomer (IC50 = 569 µM), as well as structural analysis of the fucosidase-inhibitor complex, allowed a detailed analysis of the possible mechanism of action, at the molecular level. Here, the enhanced binding affinity of the dimer over the monomer can be attributed to additional interactions in non-catalytic sites as also revealed in the 3-D structure of a bacterial fucosidase inhibitor complex.
Subject(s)
Dimerization , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , alpha-L-Fucosidase/antagonists & inhibitors , Animals , Cattle , Inhibitory Concentration 50 , Models, Molecular , Protein Conformation , StereoisomerismABSTRACT
A small library of divalent fucosidase inhibitors containing pyrrolidine motifs and separated by polyamino and triazole-benzylated spacers was prepared and evaluated as α-fucosidase inhibitors. Although a weak multivalent effect was observed in polyamino derived dimers, useful structural information can be deduced about the length of the bridge, the number of nitrogen atoms present and the moieties close to the pyrrolidine. Within these investigations one of the best α-fucosidase inhibitors containing a pyrrolidine framework was obtained (18, Ki = 3.7 nM).
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , alpha-L-Fucosidase/antagonists & inhibitors , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Humans , Molecular Conformation , Pyrrolidines/chemical synthesis , Structure-Activity Relationship , alpha-L-Fucosidase/metabolismABSTRACT
Rh(II)-catalyzed oxonium ylide formation-[2,3] sigmatropic rearrangement of α-diazo-ß-ketoesters possessing γ-cyclic unsaturated acetal substitution, followed by acid-catalyzed elimination-lactonization, provides a concise approach to 1,7-dioxaspiro[4.4]non-2-ene-4,6-diones. The process creates adjacent quaternary stereocenters with full control of the relative stereochemistry. An unsymmetrical monomethylated cyclic unsaturated acetal leads to hyperolactone C, where ylide formation-rearrangement proceeds with high selectivity between subtly nonequivalent acetal oxygen atoms.
Subject(s)
Acetals/chemistry , Furans/chemical synthesis , Onium Compounds/chemistry , Rhodium/chemistry , Spiro Compounds/chemistry , Furans/chemistry , Molecular Structure , StereoisomerismABSTRACT
The synthesis of a small library of (pyrrolidin-2-yl)triazoles via copper catalysed cycloaddition of an alkynyl iminocyclopentitol and a set of commercial and synthetic azides has been achieved. The in situ screening for the activity towards α-fucosidase of the resulting triazoles has allowed the identification of one of the most potent and selective pyrrolidine derived inhibitors of this enzyme (Ki = 4 nM).
Subject(s)
Drug Discovery , Drug Evaluation, Preclinical , Enzyme Inhibitors/pharmacology , Small Molecule Libraries/analysis , Small Molecule Libraries/pharmacology , Triazoles/pharmacology , alpha-L-Fucosidase/antagonists & inhibitors , Animals , Cattle , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hydrogen-Ion Concentration , Kidney/enzymology , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Triazoles/chemical synthesis , Triazoles/chemistry , alpha-L-Fucosidase/metabolismABSTRACT
The synthesis of the first multivalent pyrrolizidine iminosugars is reported. The key azido intermediates 4 and 31 were prepared after suitable synthetic elaboration of the cycloadduct obtained from 1,3-dipolar cycloaddition of D-arabinose derived nitrone to dimethylacrylamide. The key step of the strategy was the stereoselective installation of an azido moiety at C-6 of the pyrrolizidine skeleton. The click reaction with different monovalent and dendrimeric alkyne scaffolds allowed the preparation of a library of new mono- and multivalent pyrrolizidine compounds that were preliminarily assayed as glycosidase inhibitors towards a panel of commercially available glycosyl hydrolases.
Subject(s)
Pyrroles/chemistry , Pyrrolizidine Alkaloids/chemistry , Cycloaddition Reaction , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Glycoside Hydrolases/antagonists & inhibitors , Pyrroles/chemical synthesis , Pyrrolizidine Alkaloids/chemical synthesis , Saccharomyces cerevisiae/enzymologyABSTRACT
The fragmentation reaction of differently functionalized [2.2.2]- and [2.2.1]bicyclic systems that leads to substituted five membered heterocycles and five/six membered carbocycles is broadly studied. This reaction is carried out through a retro-Dieckmann-type condensation on strained [2.2.1]bicyclic ß-ketosulfones and their counterparts ß-ketoesters under very mild catalytic acid or basic conditions and short reaction times. The same reaction is also achieved on [2.2.2]bicyclic ß-ketosulfones requiring harsher reaction conditions.
ABSTRACT
A stereocontrolled synthesis of norphenyl hyperolactone C together with its utility as a direct precursor to the anti-HIV agent hyperolactone C and analogues by addition of organolithiums, are described. Preliminary studies to access this key building block in a catalytic enantioselective manner are also reported.
Subject(s)
Anti-HIV Agents/chemical synthesis , Furans/chemical synthesis , Onium Compounds/chemistry , Anti-HIV Agents/chemistry , Catalysis , Furans/chemistry , Lithium/chemistryABSTRACT
An efficient method has been developed for the preparation of yet unknown acyclic mixed anhydrides of carboxylic and sulfinic acids. Sterically hindered 2-methylbut-3-ene-2-sulfinyl carboxylates add primary and secondary amines preferentially onto the carbonyl moieties realizing a new method for the one-pot preparation of carboxamides. It uses 1:1 mixtures of carboxylic acids and amines without a base, requires no excess of reagents, and liberates only volatile coproducts. Protected di- and tripeptides have been prepared in solution without epimerization by application of this method.
Subject(s)
Amides/chemistry , Amides/chemical synthesis , Amines/chemistry , Anhydrides/chemistry , Carboxylic Acids/chemistry , Sulfonium Compounds/chemistry , Molecular StructureABSTRACT
The high strain of bicyclic systems drives retro-condensation reactions on bridgehead substituted bicyclo[2.2.1]hept-2-enes giving rise to orthogonally functionalized cyclopentene, 2,5-dihydrofuran, and 3-pyrroline scaffolds. Retro-Dieckman reactions were easily carried out on 3-tosyl-(7-carba/7-oxa/7-aza)bicyclo[2.2.1]hept-5-en-2-ones. Retro-aldol reactions of N-Boc-3-tosyl-7-azabicyclo[2.2.1]hept-5-en-2-ol and functionalized N-Boc-3-tosyl-7-azabicyclo[2.2.1]heptan-2-ols yield functionalized pyrrolidine scaffolds stereoselectively. The same reaction does not work with corresponding norbornene and 7-oxanorbornene derivatives.
ABSTRACT
Diglycose derivatives, consisting of two monosaccharides linked at non-anomeric positions by a bridging nitrogen atom, have been synthesised. Conversion of one of the precursor monosaccharide coupling components into an unsaturated derivative enhances its electrophilicity at the allylic position, facilitating coupling reactions. Mitsunobu coupling between nosylamides and 2,3-unsaturated-4-alcohols gave the 4-amino-pseudodisaccharides with inversion of configuration as single regio- and diastereoisomers. A palladium-catalysed coupling between an amine and a 2,3-unsaturated 4-trichloroacetimidate gave a 2-amino-pseudodisaccharide as the major product, along with other minor products. Derivatisation of the C=C double bond in pseudodisaccharides allowed the formation of Man(N4-6)Glc and Man(N4-6)Man diglycosides. The amine-linked diglycosides were found to show weak glycosidase inhibitory activity.
ABSTRACT
A review dealing with 1,4-iminoalditol (hydroxylated pyrrolidine) derivatives as inhibitors of alpha-L-fucosidases including the different synthetic approaches for their preparation as well as their inhibitory properties is presented.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Imino Furanoses/chemical synthesis , Imino Furanoses/pharmacology , alpha-L-Fucosidase/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Imino Furanoses/chemistry , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Since the discovery of the 'formose reaction' by Butlerow, total synthesis of carbohydrates has undergone rapid development. The most important methods for the asymmetric synthesis of monosaccharides and analogues of biological importance are presented. Nowadays any natural and non-natural monosaccharide can be prepared pure in both enantiomeric forms starting from inexpensive starting materials. Metal-based asymmetric catalysis and organocatalysis have been successfully applied, alone or in combination with chemoenzymatic methods. Alternative methods rely upon substrate- or reagent-controlled diastereo- and enantioselective reactions. Suitably protected carbohydrates have been prepared by total synthesis, thus allowing their direct use in the preparation of oligosaccharides and analogues.
Subject(s)
Monosaccharides/chemical synthesis , Molecular Structure , Monosaccharides/chemistry , StereoisomerismABSTRACT
We present herein a selection of ingenious methods that have been developed to convert inexpensive furan, pyrrole and unsaturated hydrocarbons into enantiomerically enriched monosaccharides and analogues of biological interest.
Subject(s)
Hydrocarbons/chemistry , Monosaccharides/chemical synthesis , Furans/chemistry , Molecular Structure , Monosaccharides/chemistry , Pyrroles/chemistry , StereoisomerismABSTRACT
The synthesis of a novel aminomethyl C-3 substituted L-fuco-azafagomine and of its C-6 epimer from D-lyxose is reported. The key step of the synthesis is the introduction of the biimino (-NH-NH-) moiety by reductive hydrazination of a 1-deoxy-ketohexose with tert-butyl carbazate. The 3-aminomethyl-azafagomine derivatives were used as lead compounds in the generation of libraries of novel types of derivatives by attaching different hydrophobic groups on the aminomethyl substituent through amide linkages. These polyhydroxylated hexahydropyridazines can be viewed as a new type of diaza-C-glycoside analogues having a biimino (-NH-NH-) moiety. The conformational analysis and the glycosidase inhibitory properties of all the new C-3 substituted azafagomines synthesized are also reported. Those having L-fuco configuration have shown a selective inhibition of α-L-fucosidases.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Imino Pyranoses/chemistry , alpha-L-Fucosidase/antagonists & inhibitors , Aza Compounds/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Hydrazines/chemistry , Imino Pyranoses/chemical synthesis , Imino Pyranoses/pharmacology , Molecular Conformation , alpha-L-Fucosidase/metabolismABSTRACT
Efficient methodologies for the synthesis of regioisomeric 3-pyrrolines by reaction of electron-deficient imines and sulfur-containing allenyl derivatives are presented. Lithiated thioallenes give 2-aryl-3-phenylsulfonyl-3-pyrrolines, whereas allenyl sulfones furnish the isomeric 2-aryl-4-phenylsulfonyl-3-pyrrolines through migration of the sulfonyl group that catalyzes the nucleophilic [3 + 2] cycloaddition.
Subject(s)
Imines/chemistry , Pheromones/chemistry , Pyrroles/chemical synthesis , Sulfides/chemistry , Sulfones/chemistry , Catalysis , Cyclization , Molecular Structure , Pyrroles/chemistry , StereoisomerismABSTRACT
The stereoselective synthesis of new 3,4-dihydroxypyrrolidine derivatives starting from D-mannose, D-ribose and L-fucose is presented. Two synthetic strategies employing organometallic addition to hemiacetalic sugars followed by selective nucleophilic displacement or conjugate addition of ammonia to conjugate aldonic esters as key steps, are used. The new compounds were assayed for their inhibitory activity towards 13 commercially available glycosidases. Compounds that share the absolute configuration at C(2,3,4,5) of L-fucopyranosides and incorporate aromatic moieties are potent and selective inhibitors of alpha-L-fucosidases in the nM range.