George Fleet

University of Oxford | OX · Department of Chemistry

This study provides the first example of a strategy to design a practical ligand toward lysosomal acid α-glucosidase (GAA) focusing on N-alkyl derivatives of 1,4-dideoxy-1,4-imino-d-arabinitol (DAB). The optimized N-4'-(p-trifluoromethylphenyl)butyl-DAB (5g) showed a Ki value of 0.73 μM, which was 353-fold higher affinity than N-butyl-DAB (3f) with...

d-Aldotetroses are rare sugars are obtained via chemical synthesis in low yield. In this study, we demonstrated that D-aldotetroses could be produced using three isomerases. First, L-erythrulose was epimerized using D-tagatose 3-epimerase from Pseudomonas cichorii ST-24. The specific optical rotation of the reaction solution gradually decreased to...

A series of iso-allo-DNJ and L-isoDALDP derivatives were synthesized from dithioacetal 16 with sequential and highly diastereoselective Ho and Henry reactions, and aziridinium intermediate-mediated ring rearrangement as key steps. Glycosidase inhibition assay found four of them as selective α-glucosidase inhibitors, and the less substituted compoun...

A series of DAB-peptide and DAB-dipeptide derivatives were synthesized from D-tartrate-derived nitrone 18. The DAB peptides 16 are derivatives of trans,trans-3,4-dihydroxy-L-proline. Glycosidase inhibition assay found four of them to be weak and selective bovine liver β-galactosidase inhibitors, and the C-2' methyl substituted compound 23b showed t...

A series of α-1-C-alkyl DAB (1,4-dideoxy-1,4-imino-d-arabinitol) and LAB (1,4-dideoxy-1,4-imino-l-arabinitol) derivatives with aryl substituents have been designed as analogues of broussonetine W (12), and assayed as glycosidase inhibitors. While the inhibition spectrum of α-1-C-alkyl DAB derivative 16 showed a good correlation to that of broussone...

A series of C-6 fluorinated casuarine derivatives have been synthesized via organocatalytic stereoselective α-fluorination of iminosugar-based aldehydes or direct nucleophilic fluorination of polyhydroxylated pyrrolizidines. Glycosidase assays against various glycosidases allowed systematic structure-activity relationship (SAR) study using molecula...

L-ido-Deoxynojirimycin (L-ido-DNJ) itself showed no affinity for human lysosomal acid α-glucosidase (GAA), whereas 5-C-methyl-L-ido-DNJ showed a strong affinity for GAA, comparable to the glucose analog DNJ, with a Ki value of 0.060 μM. This excellent affinity for GAA and enzyme stabilization was observed only when methyl and ethyl groups were intr...

(1) Background. Inflammation is reported to be a key factor in neurodegeneration. The microglia are immune cells present in the central nervous system; their activation results in the release of inflammatory cytokines and is thought to be related to aging and neurodegenerative disorders, such as Alzheimer’s disease. (2) Methods. A mouse BV-2 microg...

C-7-fluorinated derivatives of two important polyhydroxylated pyrrolizidines, casuarine and australine, were synthesized with organocatalytic stereoselective α-fluorination of aldehydes as the key step. The strategy is extensively applicable to some synthetically challenging fluorinated iminosugars and carbohydrates. The docking studies indicated t...

Two series of C-4 alkylated and arylated LAB (1,4-dideoxy-1,4-imino-L-arabinitol) and DAB (1,4-dideoxy-1,4-imino-D-arabinitol) derivatives, synthesized in 6 steps from enantiomeric cyclic nitrones derived from l- and d-tartaric acid, were designed and assayed against various glycosidases. C-4 Branched LAB alkyl and phenyl derivatives 5La-d showed p...

Four diastereomers of the family of casuarines, including casuarine (1), 6-epi-casuarine (2), 7-epi-casuarine (13) and 6,7-diepi-casuarine (14), have been synthesized from D-arabinose-derived cyclic nitrone 7 and nitrone-derived aldehyde 4 by...

5-C-Alkyl-DNJ and 5-C-alkyl-l-ido-DNJ derivatives have been designed and synthesized efficiently from an l-sorbose-derived cyclic nitrone. The DNJ and l-ido-DNJ derivatives with C-5 alkyl chains ranging from methyl to dodecyl were assayed against various glycosidases to study the effect of chain length on enzyme inhibition. Glycosidase inhibition s...

Pancreatic cancer is one of the most aggressive cancers with a poor prognosis. Previous studies suggested that nutrient-deprived conditions may play a critical role in pancreatic cancer cell survival and resistance to chemotherapy. We describe a novel series of azobenzene derivatives including (E)-1-(4-methyl-3-((2-methyl-5-(naphthalen-1-yl)phenyl)...

Special Issue on Iminosugars

Cucumbers have been anecdotally claimed to have anti-inflammatory activity for a long time, but the active principle was not identified. idoBR1, (2R,3R,4R,5S)-3,4,5-trihydroxypiperidine-2-carboxylic acid, is an iminosugar amino acid isolated from fruits of certain cucumbers, Cucumis sativus (Cucurbitaceae). It has no chromophore and analytically be...

Deoxynojirimycin (DNJ) is the archetypal iminosugar, in which the configuration of the hydroxyl groups in the piperidine ring truly mimic those of d-glucopyranose; DNJ and derivatives have beneficial effects as therapeutic agents, such as anti-diabetic and antiviral agents, and pharmacological chaperones for genetic disorders, because they have bee...

Ten pairs of pyrrolidine analogues of pochonicine and its stereoisomers have been synthesized from four enantiomeric pairs of polyhydroxylated cyclic nitrones. Among the ten N-acetylamino pyrrolidine analogues, only compounds with 2,5-dideoxy-2,5-imino-d-mannitol (DMDP) and pochonicine (1) configurations showed potent inhibition of β-N-acetylhexosa...

Calling for contributions to an Special Issue of the scientific Journal Molecules, entitled "Iminosugars: Beyond Glycosidase Inhibition". Guest editors: Ramon J. Estevez, George W. J. Fleet, Atsushi Kato and Robert Nash

N-Substituted derivatives of DIM (1,4-dideoxy-1,4-imino-D-mannitol), the pyrrolidine core of swainsonine, have been synthesized efficiently and stereoselectively from D-mannose with 2,3:5,6-di-O-isopropylidene DIM (10) as key intermediate. These N-substituted derivatives include N-alkylated, N-alkenylated, N-hydroxyalkylated and N-aralkylated DIMs...

The key step in the syntheses of highly substituted trans-3,4-dihydroxypyrrolidines is introduction of bromide by stereospecific and regiospecific Hanessian-Hullar reactions; benzylidene lactones of l-rhamnonolactone and 6-deoxy-this should be small unnpercase d not l why can I not correct this-gulonolactone allow introduction of N at C2 with inver...

The synthesis of highly functionalized bicyclic and cyclic β-amino acids from β-nitrosugars is reported. Specifically, our strategy for the synthesis of polyhydroxylated cyclopentane β-amino acids via the intramolecular C-alkylation of 6-nitro-2-O-triflates of furanosides has been applied to the preparation of the first two examples of a novel clas...

A practical synthesis of the very rare sugar d-idose and the stable building blocks for d-idose, d-iduronic, and d-idonic acids from ido-heptonic acid requires only isopropylidene protection, Shing silica gel-supported periodate cleavage of the C6-C7 bond of the heptonic acid, and selective reduction of C1 and/or C6. d-Idose is the most unstable of...

Cross-metathesis (CM) and Keck asymmetric allylation, which allows access to defined stereochemistry of a remote side chain hydroxyl group, are the key steps in a versatile synthesis of broussonetine M (3) from the d-arabinose-derived cyclic nitrone 14. By a similar strategy, ent-broussonetine M ( ent -3) and six other stereoisomers have been synth...

DMDP acetic acid [N-carboxymethyl-2,5-dideoxy-2,5-imino-d-mannitol] 5 from Stevia rebaudiana is the first isolated natural amino acid derived from iminosugars bearing an N-alkyl acid side chain; it is clear from GCMS studies that such derivatives with acetic and propionic acids are common in a broad range of plants including mulberry, Baphia, and E...

The red maple and sugar maple (Acer rubrum and A. saccharum, respectively) contain acertannins (ginnalins and maplexins), galloylated derivatives of 1,5-anhydro-D-glucitol (1,5-AG, 1). These compounds have a variety of potential medicinal properties and we have shown that some of them promote the expression of ceramide synthase 3. We now report on...

3,4,5‐Trihydroxypiperidines represent a family of biologically active natural products, found to modulate principally the glycosidase enzymes. This is ascribed to their structural and electronic resemblance to the pyranose monosaccharides, their natural counterparts. Expedient syntheses are crucial to access these valuable high Fsp3 index drug lead...

3,4,5‐Trihydroxypiperidines belong to the family of 1,5‐dideoxy‐1,5‐iminosugar natural products and are structural analogues of pentose monosaccharides in the pyranose form. The biological activities of these apparently structurally simple molecules and their N‐ and O‐alkylated and ‐arylated derivatives are no less remarkable than their C‐6 hydroxy...

Students of single crystal X-ray diffraction are often give advice as to how best to collect their data when attempting absolute configuration determination. These 'rules' often have more grounding in gut-feeling than evidence. Thus, in an effort to provide advice and evidence that today's crystallographers can pass onto to tomorrow's young scienti...

The affinity of a series of iminosugar-based inhibitors exhibiting various ring sizes toward Hex A and their essential interactions with the enzyme active site were investigated. All the Hex A-inhibiting iminosugars tested formed hydrogen bonds with Arg178, Asp322, Tyr421 and Glu462 and had the favorable cation - π interaction with Trp460. Among th...

This paper explores the computer modelling aided design and synthesis of β-N-acetylhexosaminidase inhibitors along with their applicability to human disease treatment through biological evaluation in both an enzymatic and cellular setting. We investigated the importance of individual stereocenters, variations in structure-activity relationships alo...

Derived from the genus maple (Acer), acertannins are a group of gallotannins which have a characteristic 1,5-anhydro-d-glucitol (1,5-AG) occupying the central core position in the tannic acid structure whose hydroxyl groups have one or more galloyl residues. We have synthesized all ten naturally-occurring acertannins and seven new acertannin deriva...

This study shows that the cyclization of L-DMDP thioureas to bicyclic L-DMDP isothioureas improved α-L-rhamnosidase inhibition which was further enhanced by increasing the length of the alkyl chain. The addition of a long alkyl chain, such as decyl or dodecyl, to the nitrogen might lead to the production of highly potent inhibitors of α-L-rhamnosid...

Ease of separation of petrol-soluble acetonides derived from the triacetonide of methyl glucoheptonate allows scalable syntheses of rare sugars containing the l-gluco or d-gulo structural motif with any oxidation level at the C6 or C1 position of the hexose, usually without chromatography: meso-d-glycero-d-guloheptitol available in two steps is an...

In the search for alternative non-metabolizable inducers in the l-rhamnose promoter system, the synthesis of fifteen 6-deoxyhexoses from l-rhamnose demonstrates the value of synergy between biotechnology and chemistry. The readily available 2,3-acetonide of rhamnonolactone allows inversion of configuration at C4 and/or C5 of rhamnose to give 6-deox...

Fluorinated derivatives of radicamine A (Ia-d) and radicamine B (Ie,f) are synthesized from a D-arabinose-derived cyclic nitrone using established methods.

External control of gene expression is crucial in synthetic biology and biotechnology research and applications, and is commonly achieved using inducible promoter systems. The E. coli rhamnose-inducible rhaBAD promoter has properties superior to more commonly-used inducible expression systems, but is marred by transient expression caused by degrada...

The first total synthesis of (+)-broussonetine W (), a naturally-occurring pyrrolidine iminosugar isolated from the traditional Chinese medical plant Broussonetia kazinoki SIEB (Moraceae), has been completed through a concise synthetic route starting from the readily available d-arabinose derived cyclic nitrone in 11 steps and 31% overall yield, wi...

The key step in the concise syntheses of calystegine B2 and its C-2 epimer calystegine B3 was the construction of the cycloheptanone 8 via an intramolecular Nozaki–Hiyama–Kishi (NHK) reaction of 9, an aldehyde containing a Z-vinyl iodide. The vinyl iodide 9 was obtained by the Stork olefination of aldehyde 10, derived from carbohydrate starting mat...

Epimerization of C5 of an N-hydroxypyrrolidine ring by regioselective oxidation to a nitrone followed by diastereoselective reduction provides a new approach to the synthesis of swainsonine and related compounds. The only protection in the synthesis of the potent mannosidase inhibitor DIM (1,4-dideoxy-1,4-imino-d-mannitol) was the acetonation of d-...

Fluorinated derivatives of radicamine A and radicamine B have been synthesized from D-arabinose-derived cyclic nitrone. Structure-activity relationship studies showed that glycosidase inhibition of these fluorinated derivatives was significantly influenced by the position of the fluorine atom. C-7 or C-11 fluorination of the aromatic ring decreased...

Gem-difluoromethylated and trifluoromethylated derivatives of DMDP-related iminosugars have been synthesized from cyclic nitrones 12, 13, 18, ent-18 or 23 and nitrone-derived aldehydes 20 or ent-20. The fluorinated iminosugars were assayed against various glycosidases, and ent-8 showed moderate but selective α-L-rhamnosidase inhibition. Difluoro or...

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...

Fluorinated and conformationally-fixed derivatives of L-homoDMDP, i.e. 2,5-dideoxy-2,5-imino-DL-glycero-L-manno-heptitol, have been synthesized from D-xylose derived cyclic nitrone 10 with oxazolidinones 19, 28 or oxazinanones 22 or 32 as key intermediates. Glycosidase inhibition evaluation showed replacement of the C-6 hydroxyl groups with fluorid...

Reverse aldol opening renders amides of 3-hydroxy azetidine carboxylic acids (3-OH-Aze) unstable above pH 8. Aze, found in sugar beet, is misincorporated for proline in peptides in humans and is associated with multiple sclerosis and teratogenesis. Aze-containing peptides may be oxygenated by prolyl hydroxylases resulting in potential damage of the...

This paper identifies the required configuration and orientation of alpha-glucosidase inhibitors, miglitol, alpha-1-C-butyl-DNJ, and alpha-1-C-butyl-LAB for binding to ntSI (isomaltase). Molecular dynamics (MD) calculations suggested that the flexibility around the keyhole of ntSI is lower than that of ctSI (sucrase). Furthermore, a molecular docki...

A stereoselective synthesis of (3R,4S,5R,7R)-7-(hydroxymethyl)azepane-3,4,5-triol hydrochloride from (−)-shikimic acid is described. The method involves the transformation of (−)-shikimic acid into (4S,5R)-2,2-dimethyl-5-((R)-1′,4′-di(tert-butyldimethylsilyl)oxy-3′-oxobutyl)-1,3-dioxolane-4-carbaldehyde 9b, followed by a double reductive amination...

A compound of Formula I are provided: wherein R is: R1 is a substituted or unsubstituted alkyl group; W1-4 are independently selected from hydrogen, substituted or unsubstituted alkyl groups, substituted or unsubstituted haloalkyl groups, substituted or unsubstituted alkanoyl groups, substituted or unsubstituted aroyl groups, or substituted or un...

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 i...

We report the isolation and structural determination of fourteen iminosugars, containing five pyrrolizidines and five indolizidines, from Castanospermum australe. The structure of a new alkaloid was elucidated by spectroscopic methods as 6,8-diepi-castanospermine (13). Our side-by-side comparison between bicyclic and corresponding monocyclic iminos...

Addition of human milk oligosaccharides (HMO) to baby foods may protect infants from disease. As many simple HMOs are fucosylated this is likely to increase the demand for l-fucose as a synthetic building block. Any chemical synthesis must be cheap to compete with a biotechnological process. Acetonide is the only protecting group we have used in th...

The glycosidase inhibitory properties of synthetic C-alkyl and N-alkyl six-membered iminosugars have been extensively studied leading to therapeutic candidates. The related seven-membered iminocyclitols have been less examined despite the report of promising structures. Using an in house ring enlargement/C-alkylation as well as cross-metathesis met...

Methyl N-butyl-2,4-dideoxy-2,4-imino-3-O-trifluoromethanesulfonyl-6-O-trityl-β-d-talopyranosideC31H34F3NO6S[α]D20=-27.1 (c 0.41, CH2Cl2)Source of chirality: d-glucoseAbsolute configuration: (2S,3S,4S,5S)

The enantiomers of XYLNAc (2-N-acetylamino-1,2,4-trideoxy-1,4-iminoxylitol) are prepared from the enantiomers of glucuronolactone; the synthesis of the enantiomers of LYXNAc (2-N-acetylamino-1,2,4-trideoxy-1,4-iminolyxitol) from an l-arabinono-δ-lactone and a d-ribono-δ-lactone is reported. A comparison is made of the inhibition of β-N-acetylhexosa...

Iteamine, o-aminobenzyl β-d-glucopyranoside, is the first alkaloid to be isolated from Itea virginica. Itea is the sole plant source of d-psicose, a rare sugar likely to be a major dietary supplement. The structure of iteamine was established by NMR and confirmed by total synthesis. Iteamine and its galacto-analog (which was not found in Itea plant...

Unbranched, and α-and β-methyl-branched, trihydroxypiperidine α-iminonitriles have been obtained in a single step from protected 5-O-tosylate pentoses. This reaction comprises a one-pot tandem Strecker reaction and iminocyclisation. These trihydroxypiperiidne α-iminonitriles are precursors to trihydropipecolic acids. No formation of pyrrolidine pro...

All 16 stereoisomeric N-methyl 5-hydroxymethyl-3,4-dihydroxy proline amides have been synthesised from lactones accessible from the enantiomers of glucuronolactone. Nine stereoisomers - including all eight with a (3R)-hydroxyl configuration - are low- to sub-micromolar inhibitors of beta-N-acetylhexosaminidases. A structural correlation between the...

The scarcity and expense of access to L‐sugars and other rare sugars have prevented the exploitation of their biological potential; for example D‐psicose, only recently available, has been recognized as an important new food. Here we give the definitive and cheap synthesis of 99.4% pure L‐glucose from D‐glucose which requires purification of neithe...

Das seltene Vorkommen und die Kosten der Herstellung von L-Zuckern und anderen seltenen Zuckern haben die volle Ausschöpfung ihres biologischen Potenzials bisher verhindert; zum Beispiel D-Psicose, erst seit kurzem verfügbar, ist schon als wichtiges neues Nahrungsmittel anerkannt. Hier stellen wir die preiswerte Synthese von 99.4 % reiner L-Glucose...

Three pairs of novel 2-aryl-3,4,5-trihydroxypiperidines (6–8 and their enantiomers), the piperidine analogues of the pyrrolidine alkaloids radicamine A and radicamine B, were prepared from six-membered cyclic nitrones through a concise two-step procedure, i.e., Grignard reagent addition and deprotection. These novel polyhydroxylated piperidine imin...

X-ray crystallography firmly established the relative stereochemistry of the title compound, C16H20N2O3. The acetonide ring adopts an envelope conformation with one of the O atoms as the flap and the piperidine ring adopts a slightly twisted boat conformation. The absolute configuration was determined by use of d-ribose as the starting material. Th...

Pochonicine, the first naturally-occurring polyhydroxylated pyrrolizidine containing an acetamidomethyl group isolated from Pochonia suchlasporia var. suchlasporia TAMA 87, together with its enantiomer and their C-1 and/or C-3 epimers, have been synthesized from the sugar-derived cyclic nitrones 9D and 9L, respectively. An in-depth NMR study showed...

Crystal structures were obtained for the two C2 epimeric azido-γ-lactones 2-azido-2-deoxy-3,5:6,7-di-O-isopropylidene-d-glycero-d-ido-heptono-1,4-lactone and 2-azido-2-deoxy-3,5:6,7-di-O-isopropylidene-d-glycero-d-gulo-heptono-1,4-lactone prepared from kinetic and thermodynamic azide displacements of a triflate derived from d-glucoheptonolactone. A...

This compendium focuses on functionalised sugar amino acids (SAAs) and their 3- to 6-membered nitrogen heterocyclic and carbocyclic analogues. The main benefit of using SAAs and their related nitrogen and carbon congeners in the production of peptidomimetics and glycomimetics is that their properties can be readily altered via modification of their...

The Ho crossed aldol condensation provides access to a series of carbon branched iminosugars as exemplified by the synthesis of enantiomeric pairs of isoDMDP, isoDGDP and isoDAB, allowing comparison of their biological activities with three linear isomeric natural products DMDP, DGDP and DAB and their enantiomers. L-isoDMDP [(2S,3S,4R)-2,4-bis(hydr...

The formation from D-glucose of both enantiomers of 2,4-dideoxy-2,4-iminoribonic acid is the first chemical synthesis of unprotected 3-hydroxyazetidine carboxylic acids. The long-term stability of 3-hydroxyazetidine amides is established at acidic and neutral pH and implies their value as non-proteinogenic amino acid components of peptides, providi...

The synthesis from l-arabinose of an azetidine analogue of 6,7-diepicastanospermine and its glycosidase inhibition profile are described.

Providing 1- or 6-deoxy products corresponding to all of aldohexoses, ketohexoses and sugar alcohols, as based on Deoxy-Izumoring, as well as a method for systematically producing those products. A method for producing deoxyketohexose and a derivative thereof using a deoxyketohexose isomerase derived from Pseudomonas cichorii ST-24 (FERM BP-2736),...

A general and efficient method has been developed for the synthesis of sugar-derived azepane nitrones starting from aldohexoses, with an intramolecular condensation of aldehyde and hydroxylamine as the key step. Through this strategy, each aldohexose produced a pair of azepane nitrones which are precursors of various azepane iminosugars.

Schindler/Kanzaki disease is an inherited metabolic disease with no current treatment options. This neurologic disease results from a defect in the lysosomal α-N-acetylgalactosaminidase (α-NAGAL) enzyme. In this report, we show evidence that the iminosugar DGJNAc can inhibit, stabilize, and chaperone human α-NAGAL both in vitro and in vivo. We demo...

The absolute stereochemistry of the title compound, C(9)H(15)NO(7), was determined from the use of d-glucuronolactone as the starting material. The compound crystallizes as the zwitterion. The five-membered ring adopts an envelope conformation with the -CH(2)OH-substituted C atom forming the flap. An intramolecular N-H⋯O hydrogen-bond occurs. In th...

A series of heterogeneous oligomers based on the sugar ε-amino acid 6-amino-6-deoxygalactonic acid and D-or L-phenylalanine have been synthesised and cyclised. The re-sulting cyclic heterogeneous oligomers have been analysed

The enantiomers of glucuronolactone are excellent chirons for the synthesis of the 10 stereoisomeric 2,5-dideoxy-2,5-iminohexitols by formation of the pyrrolidine ring by nitrogen substitution at C2 and C5, with either retention or inversion of configuration; the stereochemistry at C3 may be adjusted during the synthesis to give seven stereoisomers...

X-ray crystallography confirmed the formation, structure and relative stereochemistry of the title compound, C(15)H(19)NO(3), which contains a sterically congested four-membered azetidine ring system. The absolute configuration was determined by the use of l-arabinose as the starting material.

Ring closure of a 3,5-di-O-triflate derived from D-altrose with benzylamine allowed the formation of both monocyclic and bicyclic azetidine analogues of swainsonine.

The efficient scalable syntheses of 2-acetamido-1,2-dideoxy-D-galacto-nojirimycin (DGJNAc) and 2-acetamido-1,2-dideoxy-D-gluco-nojirimycin (DNJNAc) from D-glucuronolactone, as well as of their enantiomers from L-glucuronolactone, are reported. The evaluation of both enantiomers of DNJNAc and DGJNAc, along with their N-alkyl derivatives, as glycosid...