ABSTRACT
Iminosugars are one of the compounds that mimic the structure of monosaccharides. Such sugar mimics have the ability to effectively and specifically inhibit various glycosidases and glycosyltransferases. After studying iminopyranose, miglitol, which has α-glucosidase inhibitory activity, was approved and used in the clinical treatment of diabetes. This study focused on l-iminofuranose derivatives to develop new anti-diabetic drug. As a result, it was found that l-iminofuranose having an alkyl group at C1 position show potent α-glucosidase inhibitory activity. Further structural-activity relationship studies were conducted, and interesting findings were obtained. This paper describes the details of those research developments.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Diabetes Mellitus/drug therapy , Glycoside Hydrolase Inhibitors , Hypoglycemic Agents , Imino Pyranoses/chemical synthesis , Imino Pyranoses/pharmacology , 1-Deoxynojirimycin/chemical synthesis , 1-Deoxynojirimycin/chemistry , 1-Deoxynojirimycin/pharmacology , 1-Deoxynojirimycin/therapeutic use , Animals , Humans , Imino Pyranoses/chemistry , Imino Pyranoses/therapeutic use , Structure-Activity Relationship , alpha-GlucosidasesABSTRACT
We have designed unprecedented cholinesterase inhibitors based on 1-deoxynojirimycin as potential anti-Alzheimer's agents. Compounds are comprised of three key structural motifs: the iminosugar, for interaction with cholinesterase catalytic anionic site (CAS); a hydrocarbon tether with variable lengths, and a fragment derived from 2-phenylethanol for promoting interactions with peripheral anionic site (PAS). Title compounds exhibited good selectivity towards BuChE, strongly depending on the substitution pattern and the length of the tether. The lead compounds were found to be strong mixed inhibitors of BuChE (IC50 = 1.8 and 1.9 µM). The presumptive binding mode of the lead compound was analysed using molecular docking simulations, revealing H-bond interactions with the catalytic subsite (His438) and CAS (Trp82 and Glu197) and van der Waals interactions with PAS (Thr284, Pro285, Asn289). They also lacked significant antiproliferative activity against tumour and non-tumour cells at 100 µM, making them promising new agents for tackling Alzheimer's disease through the cholinergic approach.
Subject(s)
1-Deoxynojirimycin/pharmacology , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , 1-Deoxynojirimycin/chemical synthesis , 1-Deoxynojirimycin/chemistry , Animals , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Horses , Molecular Docking Simulation , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of novel N-alkyl-1-deoxynojirimycin derivatives 25 â¼ 44 were synthesised and evaluated for their in vitro α-glucosidase inhibitory activity to develop α-glucosidase inhibitors with high activity. All twenty compounds exhibited α-glucosidase inhibitory activity with IC50 values ranging from 30.0 ± 0.6 µM to 2000 µM as compared to standard acarbose (IC50 = 822.0 ± 1.5 µM). The most active compound 43 was â¼27-fold more active than acarbose. Kinetic study revealed that compounds 43, 40, and 34 were all competitive inhibitors on α-glucosidase with Ki of 10 µM, 52 µM, and 150 µM, respectively. Molecular docking demonstrated that the high active inhibitors interacted with α-glucosidase by four types of interactions, including hydrogen bonds, π-π stacking interactions, hydrophobic interactions, and electrostatic interaction. Among all the interactions, the π-π stacking interaction and hydrogen bond played a significant role in a various range of activities of the compounds.
Subject(s)
Glucosamine/analogs & derivatives , Glycoside Hydrolase Inhibitors/chemical synthesis , alpha-Glucosidases/metabolism , 1-Deoxynojirimycin/chemical synthesis , 1-Deoxynojirimycin/pharmacokinetics , Acarbose/pharmacology , Acarbose/standards , Benzylidene Compounds/chemistry , Glucosamine/chemical synthesis , Glucosamine/pharmacokinetics , Glycoside Hydrolase Inhibitors/pharmacokinetics , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Kinetics , Molecular Docking Simulation , Structure-Activity RelationshipABSTRACT
A series of N-alkylated deoxynojirimycin (DNJ) derivatives connected to a terminal tertiary amine at the alkyl chains of various lengths were prepared. These novel synthetic compounds were assessed for preliminary glucosidase inhibition and anticancer activities in vitro. Potent and selective inhibition was observed among them. Compound 7d (IC50 = 0.052 mM) showed improved and selective inhibitory activity against ?-glucosidase compared to DNJ (IC50 = 0.65 mM). In addition, analysis of the kinetics of enzyme inhibition by using Lineweaver-Burk plots indicated that 7d inhibited ?-glu-cosidase in a competitive manner, suggesting that 7d was expected to bind to the active site of ?-glucosidase. Compounds 8b and 8c were found to be moderate and selective inhibitors of ?-glucosidase. Nevertheless, none of compounds inhib-ited the growth of B16F10 melanoma cells.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , 1-Deoxynojirimycin/pharmacology , Amines/pharmacology , Glycoside Hydrolase Inhibitors/pharmacology , 1-Deoxynojirimycin/chemical synthesis , Amines/chemical synthesis , Animals , Cell Line, Tumor , Cellulases/antagonists & inhibitors , Enzyme Assays , Glycoside Hydrolase Inhibitors/chemical synthesis , Kinetics , Mice , alpha-Glucosidases/chemistryABSTRACT
To obtain α-glucosidase inhibitors with high activity, 19 NB-DNJDs (N-benzyl-deoxynojirimycin derivatives) were designed and synthesized. The results indicated that the 19 NB-DNJDs displayed different inhibitory activities towards α-glucosidase in vitro. Compound 18a (1-(4-hydroxy-3-methoxybenzyl)-2-(hydroxymethyl) piperidine-3,4,5-triol) showed the highest activity, with an IC50 value of 0.207 ± 0.11 mM, followed by 18b (1-(3-bromo-4-hydroxy-5-methoxybenzyl)-2-(hydroxymethyl) piperidine-3,4,5-triol, IC50: 0.276 ± 0.13 mM). Both IC50 values of 18a and 18b were significantly lower than that of acarbose (IC50: 0.353 ± 0.09 mM). According to the structure-activity analysis, substitution of the benzyl and bromine groups on the benzene ring decreased the inhibition activity, while methoxy and hydroxyl group substitution increased the activity, especially with the hydroxyl group substitution. Molecular docking results showed that three hydrogen bonds were formed between compound 18a and amino acids in the active site of α-glucosidase. Additionally, an areneâarene interaction was also modelled between the phenyl ring of compound 18a and Arg 315. The three hydrogen bonds and the areneâarene interaction resulted in a low binding energy (-5.8 kcal/mol) and gave 18a a higher inhibition activity. Consequently, compound 18a is a promising candidate as a new α-glucosidase inhibitor for the treatment of type â ¡ diabetes.
Subject(s)
1-Deoxynojirimycin/chemical synthesis , 1-Deoxynojirimycin/pharmacology , Drug Design , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/pharmacology , 1-Deoxynojirimycin/chemistry , Acarbose/pharmacology , Benzaldehydes/chemical synthesis , Benzaldehydes/chemistry , Catalytic Domain , Glycoside Hydrolase Inhibitors/chemistry , Hydrogen Bonding , Kinetics , Molecular Conformation , Molecular Docking Simulation , alpha-Glucosidases/metabolismABSTRACT
A series of analogs of the iminosugars 1-deoxynojirimycin (DNJ) and 1-deoxymannojirimycin (DMJ), in which an extra five or six-membered ring has been fused to the C1-C2 bond have been prepared. The synthetic strategy exploits a key 2-keto-C-allyl iminosugar, easily accessible from gluconolactam, which upon Grignard addition and RCM furnishes a bicyclic scaffold that can be further hydroxylated at the C[double bond, length as m-dash]C bond. This strategy furnished DNJ mimics with the piperidine ring locked in a 1C4 conformation with all substituents in axial orientation when fused to a six-membered ring. Addition of an extra ring to DNJ and DMJ motif proved to strongly modify the glycosidase inhibition profile of the parent iminosugars leading to modest inhibitors. The 2-keto-C-allyl iminosugar scaffold was further used to access N-acetylglycosamine analogs via oxime formation.
Subject(s)
1-Deoxynojirimycin/pharmacology , Glycoside Hydrolase Inhibitors/pharmacology , alpha-Glucosidases/metabolism , beta-Glucosidase/antagonists & inhibitors , 1-Deoxynojirimycin/chemical synthesis , 1-Deoxynojirimycin/chemistry , Animals , Cattle , Coffee/enzymology , Dose-Response Relationship, Drug , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/chemistry , Liver/enzymology , Molecular Conformation , Oryza/enzymology , Structure-Activity Relationship , beta-Glucosidase/metabolismABSTRACT
A simple synthesis, which utilizes a thin film microfluidic reactor for a problematic step, of a potent inhibitor of α-N-acetylhexosaminidases, DGJNAc, has been developed.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Chemistry Techniques, Synthetic/instrumentation , Enzyme Inhibitors/chemical synthesis , Hexosaminidases/antagonists & inhibitors , Lab-On-A-Chip Devices , 1-Deoxynojirimycin/chemical synthesis , Chemistry Techniques, Synthetic/economics , Enzyme Inhibitors/chemistry , Humans , Lab-On-A-Chip Devices/economicsABSTRACT
The highly stereocontrolled de novo synthesis of l-NBDNJ (the unnatural enantiomer of the iminosugar drug Miglustat) and a preliminary evaluation of its chaperoning potential are herein reported. l-NBDNJ is able to enhance lysosomal α-glucosidase levels in Pompe disease fibroblasts, either when administered singularly or when coincubated with the recombinant human α-glucosidase. In addition, differently from its d-enantiomer, l-NBDNJ does not act as a glycosidase inhibitor.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Enzyme Activation/drug effects , Fibroblasts/drug effects , Glycogen Storage Disease Type II/drug therapy , alpha-Glucosidases/metabolism , 1-Deoxynojirimycin/chemical synthesis , 1-Deoxynojirimycin/chemistry , 1-Deoxynojirimycin/pharmacology , Allosteric Regulation/drug effects , Cell Line , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Fibroblasts/enzymology , Fibroblasts/metabolism , Glycogen Storage Disease Type II/enzymology , Glycogen Storage Disease Type II/metabolism , Humans , Lysosomes/drug effects , Lysosomes/enzymology , Lysosomes/metabolism , Models, Molecular , StereoisomerismABSTRACT
A series of novel quinazoline-1-deoxynojirimycin hybrids were designed, synthesized and evaluated for their inhibitory activities against two drug target enzymes, epidermal growth factor receptor (EGFR) tyrosine kinase and α-glucosidase. Some synthesized compounds exhibited significantly inhibitory activities against the tested enzymes. Comparing with reference compounds gefitinib and lapatinib, compounds 7d, 8d, 9b and 9d showed higher inhibitory activities against EGFR (IC50: 1.79-10.71nM). Meanwhile the inhibitory activities of 7d, 8d and 9c against α-glucosidase (IC50=0.14, 0.09 and 0.25µM, respectively) were obvious higher than that of miglitol (IC50=2.43µM), a clinical using α-glucosidase inhibitor. Interestingly, compound 9d as a dual inhibitor showed high inhibitory activity to EGFRwt tyrosine kinase (IC50=1.79nM), also to α-glucosidase (IC50=0.39µM). The work could be very useful starting point for developing a new series of enzyme inhibitors targeting EGFR and/or α-glucosidase.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , ErbB Receptors/antagonists & inhibitors , Glycoside Hydrolase Inhibitors/pharmacology , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , alpha-Glucosidases/metabolism , 1-Deoxynojirimycin/chemical synthesis , 1-Deoxynojirimycin/chemistry , 1-Deoxynojirimycin/pharmacology , Dose-Response Relationship, Drug , ErbB Receptors/metabolism , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/chemistry , Humans , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Quinazolines/chemical synthesis , Quinazolines/chemistry , Structure-Activity RelationshipABSTRACT
A series of five new fluorescent deoxynojirimycin (DNJ) conjugates were synthesized and evaluated for their inhibitory effect (IC50) on several α- and ß-glucosidases. Three of the conjugates showed enhanced activity. The two synthetic conjugates, DNJ-CF31 and DNJ-Me 2, exhibited improved α-glucosidase inhibitory effects compared to DNJ and miglitol. Interestingly, conjugates 1 and 2 showed strong inhibition of almond-derived ß-glucosidase, in contrast to the inhibition tendencies of other inhibitors. Conjugate 5 strongly inhibited rat intestinal maltase, even at 0.10µM. A docking study indicated that all five conjugates bind to the active site of α-glucosidase (PDB: 3L4V, derived from Homo sapiens). The DNJ portion of the conjugate fits into the cavity of the enzyme, and the fluorescent part locates randomly on the outside surface. Thus, it is likely that these conjugates can specifically recognize intestinal cells, specifically the α-glucosidase on cell membranes.
Subject(s)
Fluorescent Dyes/chemistry , Glucosamine/analogs & derivatives , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/pharmacology , alpha-Glucosidases/metabolism , 1-Deoxynojirimycin/chemical synthesis , 1-Deoxynojirimycin/chemistry , 1-Deoxynojirimycin/pharmacology , Cell Membrane/drug effects , Cell Membrane/metabolism , Dose-Response Relationship, Drug , Fluorescent Dyes/chemical synthesis , Glucosamine/chemical synthesis , Glucosamine/chemistry , Glucosamine/pharmacology , Glycoside Hydrolase Inhibitors/chemistry , Humans , Molecular Docking Simulation , Molecular Structure , Structure-Activity RelationshipABSTRACT
In this communication, we describe a three-step synthesis of l-ido-1-deoxynojirimycin derivatives starting from readily available 2,3,4,6-tetra-O-benzyl-d-glucopyranose via Ir-catalyzed reductive amination in water, "borrowing hydrogen" under neat conditions, and Pd-catalyzed debenzylation.
Subject(s)
Glucosamine/analogs & derivatives , Hydrogen/chemistry , Water/chemistry , 1-Deoxynojirimycin/chemical synthesis , 1-Deoxynojirimycin/chemistry , Amination , Catalysis , Chemistry Techniques, Synthetic , Glucosamine/chemical synthesis , Glucosamine/chemistry , Iridium/chemistry , Oxidation-ReductionABSTRACT
ß-1,2-Linked oligomannosides substitute the cell wall of numerous yeast species. Several of those including Candida albicans may cause severe infections associated with high rates of morbidity and mortality, especially in immunocompromised patients. ß-1,2-Mannosides are known to be involved in the pathogenic process and to elicit an immune response from the host. In C. albicans, the synthesis of ß-mannosides is under the control of a family of nine genes coding for putative ß-mannosyltransferases. Two of them, CaBmt1 and CaBmt3, have been shown to initiate and prime the elongation of the ß-mannosides on the cell-wall mannan core. In the present study, we have assessed the modulating activities of monovalent and multivalent iminosugar analogs on these enzymes in order to control the enzymatic bio-synthesis of ß-mannosides. We have identified a monovalent deoxynojirimycin (DNJ) derivative that inhibits the CaBmt1-catalyzed initiating activity, and mono-, tetra- and polyvalent deoxymannojirimycin (DMJ) that modulate the CaBmt1 activity toward the formation of a single major product. Analysis of the aggregating properties of the multivalent iminosugars showed their ability to elicit clusterization of both CaBmt1 and CaBmt3, without affecting their activity. These results suggest promising roles for multivalent iminosugars as controlling agents for the biosynthesis of ß-1,2 mannosides and for monovalent DNJ derivative as a first target for the design of future ß-mannosyltransferase inhibitors.
Subject(s)
Candida albicans/enzymology , Enzyme Inhibitors/pharmacology , Fungal Proteins/antagonists & inhibitors , Glucosamine/analogs & derivatives , Imino Sugars/pharmacology , Mannosyltransferases/antagonists & inhibitors , 1-Deoxynojirimycin/chemical synthesis , 1-Deoxynojirimycin/pharmacology , Candida albicans/drug effects , Candida albicans/genetics , Cell Wall/drug effects , Cell Wall/enzymology , Cloning, Molecular , Enzyme Assays , Enzyme Inhibitors/chemical synthesis , Fungal Proteins/genetics , Fungal Proteins/metabolism , Gene Expression , Glucosamine/chemical synthesis , Glucosamine/pharmacology , Imino Sugars/chemical synthesis , Kinetics , Mannosides/metabolism , Mannosyltransferases/genetics , Mannosyltransferases/metabolism , Pichia/genetics , Pichia/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Substrate SpecificityABSTRACT
A stereocontrolled, facile and high-yield approach for producing (+)-altroDNJ, has been developed starting from the inexpensive commercial cis 2-butene-1,4-diol. Sharpless epoxidation and a subsequent dihydroxylation were used for the introduction of all stereocentres; finally, the ring closure under basic conditions afforded the piperidine heterocycle.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , 1-Deoxynojirimycin/chemical synthesis , 1-Deoxynojirimycin/chemistry , Epoxy Compounds/chemical synthesis , Heterocyclic Compounds , Hydroxylation , Indicators and Reagents , Molecular Conformation , StereoisomerismABSTRACT
Due to their capacity to inhibit hexosaminidases, 2-acetamido-1,2-dideoxy-iminosugars have been widely studied as potential therapeutic agents for various diseases. An efficient stereoselective synthesis of 2-acetamido-1,2-dideoxyallonojirimycin (DAJNAc), the most potent inhibitor of human placenta ß-N-acetylglucosaminidase (ß-hexosaminidase) among the epimeric series, is here described. This novel procedure can be easily scaled up, providing enough material for structural modifications and further biological tests. Thus, two series of sp(2)-iminosugar conjugates derived from DAJNAc have been prepared, namely monocyclic DAJNAc-thioureas and bicyclic 2-iminothiazolidines, and their glycosidase inhibitory activity evaluated. The data evidence the utmost importance of developing diversity-oriented synthetic strategies allowing optimization of electrostatic and hydrophobic interactions to achieve high inhibitory potencies and selectivities among isoenzymes. Notably, strong differences in the inhibition potency of the compounds towards ß-hexosaminidase from human placenta (mature) or cultured fibroblasts (precursor form) were encountered. The ensemble of data suggests that the ratio between them, and not the inhibition potency towards the placenta enzyme, is a good indication of the chaperoning potential of TaySachs disease-associated mutant hexosaminidase.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Hexosaminidases/antagonists & inhibitors , Imino Sugars/chemistry , 1-Deoxynojirimycin/chemical synthesis , 1-Deoxynojirimycin/chemistry , 1-Deoxynojirimycin/pharmacology , Chemistry Techniques, Synthetic , Enzyme Inhibitors/chemical synthesis , Humans , Kinetics , Models, Molecular , Molecular Conformation , StereoisomerismABSTRACT
Glucosylceramide metabolism and the enzymes involved have attracted significant interest in medicinal chemistry, because aberrations in the levels of glycolipids that are derived from glucosylceramide are causative in a range of human diseases including lysosomal storage disorders, typeâ 2 diabetes, and neurodegenerative diseases. Selective modulation of one of the glycoprocessing enzymes involved in glucosylceramide metabolism-glucosylceramide synthase (GCS), acid glucosylceramidase (GBA1), or neutral glucosylceramidase (GBA2)-is therefore an attractive research objective. In this study we took two established GCS inhibitors, one based on deoxynojirimycin and the other a ceramide analogue, and merged characteristic features to obtain hybrid compounds. The resulting 39-compound library does not contain new GCS inhibitors; however, a potent (200â nm) GBA1 inhibitor was identified that has little activity toward GBA2 and might therefore serve as a lead for further biomedical development as a selective GBA1 modulator.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Glucosyltransferases/antagonists & inhibitors , 1-Deoxynojirimycin/chemical synthesis , 1-Deoxynojirimycin/chemistry , 1-Deoxynojirimycin/metabolism , Ceramides/chemical synthesis , Ceramides/chemistry , Ceramides/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Glucosamine/analogs & derivatives , Glucosamine/chemical synthesis , Glucosamine/chemistry , Glucosamine/metabolism , Glucosyltransferases/metabolism , Humans , Inhibitory Concentration 50 , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Protein Binding , Structure-Activity RelationshipABSTRACT
Two novel iminosugars called nojiristegines, being structural hybrids between nor-tropane alkaloid calystegine and nojirimycins, have been synthesised and found to be stable molecules despite the presence of a hemiaminal functionality. The synthesised iminosugars were evaluated against a panel of glycosidases and the best inhibition (IC50), found against α-glucosidases, was in the micromolar region. The compounds were also evaluated as potential antibiotics but no useful level of activity was observed.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/pharmacology , Mannose/chemistry , 1-Deoxynojirimycin/chemical synthesis , 1-Deoxynojirimycin/chemistry , 1-Deoxynojirimycin/pharmacology , Anti-Bacterial Agents/chemical synthesis , Bacteria/drug effects , Chemistry Techniques, Synthetic , Drug Stability , Glycoside Hydrolase Inhibitors/chemical synthesis , Humans , Inhibitory Concentration 50 , alpha-Glucosidases/metabolismABSTRACT
2-Acetamido-1,2-dideoxyiminosugars are selective and potent inhibitors of hexosaminidases and therefore show high therapeutic potential for the treatment of various diseases, including several lysosomal storage disorders. A stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc), the iminosugar analog of N-acetylglucosamine, with a high overall yield is here described. This novel procedure further allowed accessing ureido-DNJNAc conjugates through derivatization of the endocyclic amine on a key pivotal intermediate. Remarkably, some of the ureido-DNJNAc representatives behaved as potent and selective inhibitors of ß-hexosaminidases, including the human enzyme, being the first examples of neutral sp(2)-iminosugar-type inhibitors reported for these enzymes. Moreover, the amphiphilic character of the new ureido-DNJNAc is expected to confer better drug-like properties.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , beta-N-Acetylhexosaminidases/antagonists & inhibitors , 1-Deoxynojirimycin/chemical synthesis , 1-Deoxynojirimycin/chemistry , 1-Deoxynojirimycin/pharmacology , Acetamides/chemical synthesis , Acetamides/chemistry , Animals , Cattle , Chemistry Techniques, Synthetic , Drug Evaluation, Preclinical/methods , Enzyme Inhibitors/chemical synthesis , Humans , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , beta-N-Acetylhexosaminidases/isolation & purificationABSTRACT
An efficient synthesis of deoxygalactonojirimycin and deoxyaltronojirimycin through the use of proline catalyzed asymmetric α-aminoxylation of a higher homologue of Garner's aldehyde, derived from l-aspartic acid, is reported. The method is also used for a highly diastereoselective synthesis of the N-Boc derivative of (2S,3S)-3-hydroxypipecolic acid. The configuration of the proline catalyst used for the asymmetric aminoxylation step ultimately controls the absolute configuration of three adjacent stereogenic centers in the final products.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Aldehydes/chemistry , Pipecolic Acids/chemical synthesis , Proline/chemistry , 1-Deoxynojirimycin/chemical synthesis , 1-Deoxynojirimycin/chemistry , Catalysis , Molecular Conformation , Pipecolic Acids/chemistry , StereoisomerismABSTRACT
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. Consequently, N-(2-fluorophenyl)-2ß-DFJ acetamide (18j) was found to display very potent and selective inhibition of bovine kidney, rat epididymis, and human lysosome α-l-fucosidases, with IC50 value of 0.012, 0.044, and 0.0079µM respectively. It is noteworthy that our designed N-phenyl-2ß-DFJ acetamide derivative exhibited about 18-fold stronger effects on human lysosomal α-l-fucosidase than original DFJ and it occupied the active-site of this enzyme. We therefore expect that this compound may find applications in new therapeutic trials against genetic deficiency disorders.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Acetamides/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Sugar Alcohols/chemistry , alpha-L-Fucosidase/antagonists & inhibitors , 1-Deoxynojirimycin/chemical synthesis , 1-Deoxynojirimycin/chemistry , 1-Deoxynojirimycin/metabolism , Acetamides/chemistry , Acetamides/metabolism , Animals , Catalytic Domain , Cattle , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Epididymis/enzymology , Humans , Kidney/enzymology , Lysosomes/enzymology , Male , Protein Binding , Rats , Structure-Activity Relationship , alpha-L-Fucosidase/metabolismABSTRACT
A practical synthesis of the previously unreported N-acetyl-D-allosamine glycomimetic DAJNAc is described. The reaction sequence involves Pd-catalyzed allylic substitution by phthalimide in an azaheterobicyclic scaffold as the key step. The new iminosugar resulted in being a stronger ß-N-acetylglucosaminidase (human placenta) competitive inhibitor than the D-gluco (DNJNAc) and D-galacto (DGJNAc) stereoisomers.