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Glycoside hydrolases have been implicated in a wide range of human conditions including lysosomal storage diseases. Consequently, many researchers have directed their efforts towards identifying new classes of glycoside hydrolase inhibitors, both synthetic and from natural sources. A large percentage of such inhibitors are reversible competitive inhibitors that bind in the active site often due to them possessing structural features, often a protonatable basic nitrogen atom, that mimic the enzymatic transition state. We report that mechanism-based small molecule galacto-like configured cyclohexenyl carbasugars form reversible covalent complexes with both α-galactosidase and β-galactosidase. In addition, we show that the β-galactosidase from Aspergillus oryzae reacts with three different carbasugar inhibitors, with three different second-order rate constants (kinact/Ki), to give the same enzyme–carbasugar covalent intermediate. The surprising observation that the α-galacto-configured inhibitor covalently labels the A. oryzae β-galactosidase highlights the catalytic versatility of glycoside hydrolases. We expect that cyclohexenyl covalent inhibitors will become an important class of compounds in the chemical biologist's tool box. [ABSTRACT FROM AUTHOR]

Cyclophellitol is a potent and selective mechanism‐based retaining β‐glucosidase inhibitor that has served as a versatile starting point for the development of activity‐based glycosidase probes (ABPs). We developed routes of synthesis of eight mono‐ and dideoxycyclophellitols and cyclophellitol aziridines, the latter as ABPs carrying either a biotin or fluorophore linked to the aziridine nitrogen. We reveal the potency of these 24 compounds as inhibitors of the three human retaining β‐glucosidases, GBA1, GBA2 and GBA3. We show that 3,6‐dideoxy‐β‐galacto‐cyclophellitol aziridine selectively captures GBA3 over GBA1 and GBA2 in extracts of cells overexpressing both GBA2 and GBA3. We also identify a probe that selectively labels GBA1 and GBA2 over GBA3 at lower concentrations. In sum, the here‐presented studies reveal new chemistries to prepare chiral, substituted cyclitol epoxides and aziridines, add to the growing suite of cyclophellitols varying in configuration and substitution pattern, and yielded a reagent that may find use to investigate the physiological role and therapeutic relevance of the most elusive of the three retaining β‐glucosidases: GBA3. [ABSTRACT FROM AUTHOR]

Glycoside hydrolases (glycosidases) take part in myriad biological processes and are important therapeutic targets. Competitive and mechanism‐based inhibitors are useful tools to dissect their biological role and comprise a good starting point for drug discovery. The natural product, cyclophellitol, a mechanism‐based, covalent and irreversible retaining β‐glucosidase inhibitor has inspired the design of diverse α‐ and β‐glycosidase inhibitor and activity‐based probe scaffolds. Here, we sought to deepen our understanding of the structural and functional requirements of cyclophellitol‐type compounds for effective human α‐glucosidase inhibition. We synthesized a comprehensive set of α‐configured 1,2‐ and 1,5a‐cyclophellitol analogues bearing a variety of electrophilic traps. The inhibitory potency of these compounds was assessed towards both lysosomal and ER retaining α‐glucosidases. These studies revealed the 1,5a‐cyclophellitols to be the most potent retaining α‐glucosidase inhibitors, with the nature of the electrophile determining inhibitory mode of action (covalent or non‐covalent). DFT calculations support the ability of the 1,5a‐cyclophellitols, but not the 1,2‐congeners, to adopt conformations that mimic either the Michaelis complex or transition state of α‐glucosidases. [ABSTRACT FROM AUTHOR]

Glycoside hydrolases have been implicated in a wide range of human conditions including lysosomal storage diseases. Consequently, many researchers have directed their efforts towards identifying new classes of glycoside hydrolase inhibitors, both synthetic and from natural sources. A large percentage of such inhibitors are reversible competitive inhibitors that bind in the active site often due to them possessing structural features, often a protonatable basic nitrogen atom, that mimic the enzymatic transition state. We report that mechanism-based small molecule galacto-like configured cyclohexenyl carbasugars form reversible covalent complexes with both α-galactosidase and β-galactosidase. In addition, we show that the β-galactosidase from Aspergillus oryzae reacts with three different carbasugar inhibitors, with three different second-order rate constants (kinact/Ki), to give the same enzyme–carbasugar covalent intermediate. The surprising observation that the α-galacto-configured inhibitor covalently labels the A. oryzae β-galactosidase highlights the catalytic versatility of glycoside hydrolases. We expect that cyclohexenyl covalent inhibitors will become an important class of compounds in the chemical biologist’s tool box.

In this article, an efficient and practical stereoselective synthesis of 5a-carba-α-L-mannopyranose from naturally abundant (−)-shikimic acid is discussed. 5a-Carba-α-L-mannopyranose was synthesized via 11 steps in 43% overall yield starting from (−)-shikimic acid. The overall yield of the total synthesis is high, the reaction conditions for all steps are mild, the operation procedures of all steps are simple, and the reagents used in all steps are cheap and readily available. [ABSTRACT FROM AUTHOR]

There is a vast genomic resource for enzymes active on carbohydrates. Lagging far behind, however, are functional chemical tools for the rapid characterization of carbohydrate‐active enzymes. Activity‐based probes (ABPs) offer one chemical solution to these issues with ABPs based upon cyclophellitol epoxide and aziridine covalent and irreversible inhibitors representing a potent and widespread approach. Such inhibitors for enzymes active on polysaccharides are potentially limited by the requirement for several glycosidic bonds, themselves substrates for the enzyme targets. Here, it is shown that non‐hydrolysable trisaccharide can be synthesized and applied even to enzymes with challenging subsite requirements. It was found that incorporation of carbasugar moieties, which was accomplished by cuprate‐assisted regioselective trans‐diaxial epoxide opening of carba‐mannal synthesised for this purpose, yields inactivators that act as powerful activity‐based inhibitors for α‐1,6 endo‐mannanases. 3‐D structures at 1.35–1.47 Å resolutions confirm the design rationale and binding to the enzymatic nucleophile. Carbasugar oligosaccharide cyclophellitols offer a powerful new approach for the design of robust endoglycosidase inhibitors, while the synthesis procedures presented here should allow adaptation towards activity‐based endoglycosidase probes as well as configurational isosteres targeting other endoglycosidase families. [ABSTRACT FROM AUTHOR]

Two unnatural regioisomeric glycosylated Gilvocarcin analogues were proposed as model compounds to study the origin behind the biosynthetic development of the Gilvocarcins, a class of bioactive C‐aryl glycoside natural products. More specifically, the origins behind the proposed O‐ to C‐glycoside migration in the evolution of the biosynthesis for these classes of Angucycline antibiotic natural products. For stability reasons a 5a‐carbasugar motif was used to mimic the sugar portion of the molecule and of synthetic ease the proposed abiotic rearrangement move the sugar analogue along with its O‐glycoside linkage. The two proposed regioisomeric analogues were synthesized by a regio‐divergent synthetic pathway and featured a Mitsunobu‐like invertive cyclictolization reaction to install the carbasugar motif. The two regioisomeric Gilvocarcin analogues were evaluated as antibiotic with Gilvocarcin M as a control. Only one of the two isomers showing weak antibiotic activity as compared to Gilvocarcin M. [ABSTRACT FROM AUTHOR]

A number of bicyclic imino- and carba-sugars (examples are presented in the Scheme) can be obtained from simple monosaccharides (hexoses or pentoses) by various methods. [ABSTRACT FROM AUTHOR]

Novel carbohydrate mimics were designed which contain two 5a-carba- d -glucose residues, one each at reducing and nonreducing end, and thus these mimics are 5a,5a′-dicarba- d -glucobioses. Dicarbadisaccharides have attractive features such as stability against endogenous degradative enzymes and being resistant to glycation reactions such as the Maillard reaction. For the synthesis of dicarba-β- d -isomaltose derivatives, the carbaglucosyl triflate locked in 4 C 1 conformation was synthesized by protecting with butane-2,3-diacetal group or benzylidene group. Then, 5a,5a′-dicarba-β- d -maltose and 5a,5a′-dicarba-α,β- d -trehalose were synthesized by the S N 2-type inversion reaction using 4,6- O -benzylidene carbaglucosyl triflate with 4-OH and 1-OH carba-β- d -glucose derivatives, respectively, and similarly 5a,5a′-dicarba-α- d -isomaltose with 6-OH carba-α- d -glucose derivative. [ABSTRACT FROM AUTHOR]

Glycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series of new cyclopentanoid β-galactosidase inhibitors were prepared and their inhibitory and pharmacological chaperoning activities determined and compared with those of lipophilic analogs of the potent β-d-galactosidase inhibitor 4-epi-isofagomine. Structure-activity relationships were investigated by X-ray crystallography as well as by alterations in the cyclopentane moiety such as deoxygenation and replacement by fluorine of a “strategic” hydroxyl group. New compounds have revealed highly promising activities with a range of β-galactosidase-compromised human cell lines and may serve as leads towards new pharmacological chaperones for GM1-gangliosidosis and Morquio B disease.

Abstract Sialic acid ( N -acetylneuraminic acid) is a carbohydrate that possess a nine carbon backbone, and it is often found at the termini of glycoconjugates in biological systems. Because of this prominence many syntheses have reported routes to sialic acid and many of its derivatives. Most of these compounds retain the endocyclic oxygen atom that becomes part of the ketal glycosidic linkage that joins sialic acid to the penultimate residue in the glycoconjugate. With respect to carba-sialic acid (replacement of the ring oxygen atom with a methylene group) a single synthesis has been reported (Ogawa et al. ( Carbohydr. Res. , 1995 , 269 , 53–78) in 30 steps and 0.5% yield. The current report details a robust synthesis of 6a-carba-α- d -sialic acid that involves 18 steps and give a 5% yield using d -quinic acid as the starting material. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

Abstract By adaptation of a literature method developed in the glucose series and standard protecting group manipulations a 2-deoxy- d -glucose derivative is converted to a series of 1 R ,2 R ,5 R -3-hydroxymethyl-cyclohexen-1,2,5-triol derivatives whose reduction to the corresponding diastereomeric d -gluco and l -ido-2-deoxy carbasugars is studied. When the hydroxymethyl group is tied up in a cyclic isopropylidene acetal with the adjacent 6-hydroxy group the cis -fused products with the ido-configuration are formed preferentially whereas protection of the hydroxymethyl group as a methoxymethyl ether results in the formation of the d -gluco isomer on hydrogenation over Raney nickel. This result is rationalized in terms of the minimization of allylic strain in the course of the reduction, enables the preparation of the carbasugar pseudo-2-deoxy-α- d -glucopyranose, and suggests that the conformation of the side chain is an important control element in the chemistry of the pseudosugars as it is in the sugars themselves. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

In the present study, (3a R ,7a S )-1,3,3a,4,7,7a-hexahydroisobenzofuran was submitted to photooxygenation and two isomeric hydroperoxides were successfully obtained. Without any further purification, reduction of the hydroperoxides with titanium tetraisopropoxide catalyzed by dimethyl sulfide gave two alcohol isomers in high yields. After acetylation of alcohol with Ac 2 O in pyridine, epoxidation reaction of formed monoacetates with m -CPBA, then chromatographed and followed by hydrolysis of the acetate groups with NH 3 in CH 3 OH resulted in the formation of epoxy alcohol isomers respectively. These epoxy alcohol isomers were subjected to trans -dihydroxylation reaction with acid (H 2 SO 4 ) in the presence of water to afford triols. Acetylation of the free hydroxyl groups produced benzofuran triacetates in high yields. Ring-opening reaction of furan triacetates with sulfamic acid catalyzed in the presence of acetic acid/acetic anhydrate and subsequently hydrolysis of the acetate groups with ammonia gave the targeted cyclohexane carbasugar-based pentols. All products were separated and purified by chromatographic and crystallographic methods. Structural analyses of all compounds were conducted by spectral techniques including NMR and X-ray analyses. The biological inhibition activity of the target compounds was tested against glycosidase enzymes, α - and β -glucosidase. [ABSTRACT FROM AUTHOR]

Stereoselective and efficient synthesis of hydroxymethyl-substituted rac -quercitols ( 13 – 15 ) was achieved, starting from cis -furan (Kobayashi, 2008) with photooxygenation reaction, which is readily available by the reduction of cis -phtalic anhydride. α- and β -Glucosidase enzyme activity of the target molecules was evaluated and good inhibitor activity was seen. One- and two-dimensional NMR spectroscopy, IR spectroscopy and X-ray crystallography were utilized in the structure characterization of products. [ABSTRACT FROM AUTHOR]

An efficient synthesis of new six-membered carbasugars in both L-form and D-form starting from N –acetylglucosamine is described. The key synthetic steps involved regioselective protection and deprotection, Ferrier carbocyclization, Peterson olefination, hydroboration and stereoselective epoxidation followed by regioselective epoxide ring opening reactions. These six-membered carbasugars showed moderate glycosidase inhibitory activity and one of the compounds was found selective towards β-galactosidase inhibitory activity. [ABSTRACT FROM AUTHOR]

Valienone is a significant natural carbasugar member of the C7-cyclitol family as a valuable precursor for glycosidase inhibitor drugs. It is an intermediate of validamycin A biosynthesis pathway and exhibits minimal accumulation in the fermentation broth of the natural Streptomyces producer. A quantitative analytical method is crucial for the development of a breakthrough microbial process overcoming the consumption of the natural metabolic flux. The present study was designed to develop a pre-column derivatization high-performance liquid chromatography method for quantification of valienone and to help establish a straightforward fermentation process for valienone production by metabolically engineered Streptomyces hygroscopicus 5008. Valienone was derivatized by 2, 4-dinitrophenylhydrazine (DNPH) in 10 mmol·L −1 H 3 PO 4 at 37 °C for 45 min and the derivatives were separated on Eclipse XDB-C 18 (5 μm, 4.6 mm × 150 mm) column at 30 °C eluted with 50% acetonitrile for 18 min. The derivatives were detected by diode array detector at 380 nm and the configurations of the derivatives were determined by computational studies. The method was shown to be effective, sensitive, and reliable. Good linearity was found in the range of 5–2 000 μg·mL −1 . The intra- and inter-day precisions were 1.1%–2.7% and 1.7%–2.2%, respectively. The absolute recovery of the spiked samples was 97.2%–102.6%. To date, this is the first reversed-phase high-performance liquid chromatography detection method for valienone in microbial culture medium. This method successfully helped evaluate the valienone production capability of the engineered Streptomyces hygroscopicus 5008 and could be promising for C7-cyclitol profiling of different engineered mutants combined with the metabonomics methods. [ABSTRACT FROM AUTHOR]

A novel synthesis of N-substituted 4-amino-6-methyl resorcinols from polysubstituted cyclohexanone was developed. The reaction was performed in an easy 'one-pot', tandem manner with well-tolerated substituent on the nitrogen to give the desired compound in good to excellent yield. This highly efficient method will find broad application in the synthesis of some natural products and bioactive interesting compounds. [ABSTRACT FROM AUTHOR]

A series of N -alkyl derivatives of the D-galactosidase inhibitor 1,4-di- epi -validamine featuring lipophilic substituents at position C-5a was prepared and screened for their glycosidase inhibitory properties. Products turned out selective for β-galactosidases as well as β-glucosidases. [ABSTRACT FROM AUTHOR]

Pericosines are unique C7 cyclohexenoid metabolites of Periconia byssoides OUPS-N133 fungus that was originally isolated from the sea hare, Aplysia kurodai. Pericosines show significant in vitro cytotoxicity against P388 lymphocytic leukemia cells. Pericosine A, in particular, shows the most potent activity and significant in vivo antitumor activity against P388 cells. Thus, pericosines are promising candidates for seed compounds of anticancer drugs. However, before the total syntheses of pericosines were accomplished, their stereo structures could not be determined by spectral analyses because they have multifunctionalized cyclohexenoid structures with torsional strain. In this review, synthetic efforts for pericosines in this decade are surveyed.

A sequence of vinylalumination of α-substituted aldehydes, ring-closing metathesis (RCM), and palladium-catalyzed allylic substitution was utilized to prepare the biologically active natural products, pericosines, from d-ribose. The anti-adduct of vinylalumination was transformed into pericosine A after RCM, removal of the 4-methoxybenzyl protecting group, and chlorination. The diacetate of the anti-adduct was converted to pericosine C after the palladium-catalyzed, SN2′-type, allylic substitution. However, an unexpected dimeric product was generated in utilizing this approach to prepare pericosine E. [ABSTRACT FROM AUTHOR]

The synthesis of β-carba-xylo and arabino pyranosides of cholestanol is described. The synthetic strategy, which is analogous to the Postema approach to C -glycosides, centers on the ring closing metathesis of an enol ether–alkene precursor to give a cyclic enol ether that is elaborated to a carba-pyranoside via hydroboration–oxidation on the olefin. The method, which is attractive for its modularity and stereoselectivity, may find wider applications to carba-hexopyranosides and other complex cycloalkyl ether frameworks. [ABSTRACT FROM AUTHOR]

2-Deoxy-α- d -ribose-1-phosphate is of great interest as it is involved in the biosynthesis and/or catabolic degradation of several nucleoside analogues of biological and therapeutic relevance. However due to the lack of a stabilising group at its 2-position, it is difficult to synthesize stable prodrugs of this compound. In order to overcome this lack of stability, the synthesis of carbasugar analogues of 2-deoxyribose-1-phosphate was envisioned. Herein the preparation of a series of prodrugs of two carbocyclic analogues of 2-deoxyribose-1-phosphate using the phosphoramidate ProTide technology, along with their biological evaluation against HIV and cancer cell proliferation, is reported. [ABSTRACT FROM AUTHOR]

Cyclooctane-1,2,3,4-tetraols, aminocyclooctanetriol, and chlorocyclooctanetriol were synthesized starting from cis , cis -1,3-cyclooctadiene by a concise and efficient method. Cyclooctene endoperoxide and cyclooctene epoxide obtained by photooxygenation and epoxidation, respectively, of cis , cis -1,3-cyclooctadiene were used as the key intermediates. The other oxygen, nitrogen, and chloro functionalities were introduced via epoxidation of the remaining double bond, ring-opening of epoxide, and cis-hydroxylation reactions. [ABSTRACT FROM AUTHOR]

Abstract: Decahydronaphthalene-1,2,3,4,5,6,7-heptol, a new polycyclitol, was synthesized starting from p-benzoquinone. An endo selective Diels–Alder cycloaddition between p-benzoquinone and 1-acetoxybutadiene followed by stereoselective reduction with NaBH4/CeCl3·7H2O led to the formation of an allylic cis-diol. The formed diol was converted into its acetate with Ac2O/pyridine, in a transformation that required inert atmosphere conditions to suppress a competing aromatization. Controlled oxidation by OsO4 of two olefinic bonds followed by acetylation yielded the heptaacetate whose structure was established unequivocally via application of X-ray crystallographic methods. Removal of the acetate groups by NH3 provided the target heptol. In addition, the carbonic anhydrase inhibitory potency of the title compound was investigated and it was shown to be a potent inhibitor compared to the standard CA inhibitors. [Copyright &y& Elsevier]

Abstract: The total synthesis of (+)-valienamine and (−)-1-epi-valienamine was concisely accomplished from readily available d-glucose via a highly diastereoselective amination of chiral benzylic ether using chlorosulfonyl isocyanate, intramolecular olefin metathesis, and diastereoselective reduction of cyclic enone using l-Selectride as the key steps. [Copyright &y& Elsevier]

Abstract: Described are the efficient syntheses of β-galactose-type unsaturated carbasugar amine, N-octyl-4-epi-β-valienamine (1a, NOEV) and 6-deoxy NOEV (12), starting from (+)-proto-quercitol (2), which is readily provided by the bioconversion of myo-inositol. NOEV is a potent chemical chaperone drug candidate for GM1-gangliosidosis. An intermediate alkadiene benzoate was prepared from 2 in five steps, with the key step being a Wittig reaction with an enol ester. The 6-deoxy derivative 12 was conveniently synthesized from the versatile intermediate dibromo compound 6, which was also an intermediate in the synthesis of NOEV. Enzyme inhibition assays demonstrated that 12 possessed stronger inhibitory activity than the parent 1a, suggesting that the C-6 position of the 4-epi-β-valienamine-type inhibitor could have hydrophobic interactions at the β-galactosidase active site residues. [Copyright &y& Elsevier]

Abstract: [5+2] Cycloaddition followed by asymmetric dihydroxylation procedure have been utilized to prepare novel cyclitols. Accordingly, rac-2α-hydroxy-6α-ethoxy-1,5-anhydro cyclohept-3-ene, 10 derived from [5+2] cycloaddition of 3-oxidopyrylium ylide and vinyl ether has been recognized as a seven-membered carbasugar equivalent and elaborated to 1,4,5-tribenzoyloxy-2-ethoxy cycloheptanes through a flexible, regio- and stereoselective strategy involving Sharpless asymmetric dihydroxylation conditions to resolve the compounds obtained. The structures and relative configurations of newly synthesized (+)-2α-acetoxy-6α-ethoxy-3β,4β-dihydroxy-1,5-anhydro cycloheptane ((+)-12)); (−)-1β,4β,5β-tribenzoyloxy-6α-ethoxy cycloheptane ((−)-17) and (+)-1α,4α,5α-tribenzoyloxy-6β-ethoxy cycloheptane ((+)-17) are unambiguously established by single crystal X-ray analysis and duly supported by 1H and 13C NMR spectroscopy data. [Copyright &y& Elsevier]

Abstract: C-Aryl 5a-carba-β-d-glucopyranose derivatives were synthesized and evaluated for inhibition activity against hSGLT1 and hSGLT2. Modifications to the substituents on the two benzene rings resulted in enhanced hSGLT2 inhibition activity and extremely high hSGLT2 selectivity versus SGLT1. Using the created superimposed model, the reason for the high hSGLT2 selectivity was speculated to be that additional substituents occupied a new space, in a different way than known inhibitors. Among the tested compounds, the ethoxy compound 5h with high hSGLT2 selectivity exhibited more potent and longer hypoglycemic action in db/db mice than our O-carbasugar compound (1) and sergliflozin (2), which could be explained by its improved PK profiles relative to those of the two compounds. These results indicated that 5h might be a promising drug candidate for the treatment of type 2 diabetes. [Copyright &y& Elsevier]

Abstract: (+)-proto-Quercitol (1) and (−)-vibo-quercitol (2), both of which could be readily prepared by the bioconversion of myo-inositol, were successfully converted into the corresponding 4-methylenecyclohex-5-ene-1,2,3-triol derivatives. These compounds were demonstrated to be suitable precursors, preserving their configurations, for bioactive carba-aminosugars such as the potent chemical chaperone drug candidates, N-octyl-4-epi-β-valienamine (NOEV, 3) and N-octyl-β-valienamine (NOV, 4). [Copyright &y& Elsevier]

Abstract: A stereodivergent route, starting from d-glyceraldehyde derivative, employing Wittig olefination–Claisen rearrangement protocol is reported for the synthesis of six novel carbahexofuranoses—carba-α-d-glucofuranose, carba-β-d-altrofuranose, carba-α-d-allofuranose, carba-β-d-idofuranose, carba-α-d-galactofuranose and carba-β-d-talofuranose in enantiomerically pure form. [Copyright &y& Elsevier]

Abstract: 5a-Carba-β-d-glucopyranose derivatives were synthesized and identified as novel SGLT2-selective inhibitors. These inhibitors exhibited potent SGLT2 inhibition with high selectivity over SGLT1. Among the tested compounds, 6f indicated the most potent hSGLT2 inhibition and the highest selectivity over hSGLT1. Moreover, the pharmacokinetics data also showed that 6h, which had the same aglycon structure as sergliflozin-active (3-active), had a threefold longer half-life time (T 1/2) than sergliflozin (3) with a high distribution volume in db/db mice. Subsequently, 6h lowered blood glucose levels as much as 3 and showed longer hypoglycemic action than 3 in db/db mice. [Copyright &y& Elsevier]

Abstract: Two new deoxycarbaheptopyranoses, 5a-carba-6-deoxy-α-dl-galacto-heptopyranose and 5a-carba-6-deoxy-α-dl-gulo-heptopyranose were prepared starting from cyclohexa-1,4-diene. The addition of dichloroketene to cyclohexa-1,4-diene followed by the subsequent reductive elimination and Baeyer–Villiger oxidation in turn led to the formation of a bicyclic lactone. Reduction of the lactone moiety followed by acetylation gave a diacetate with cis-configuration. The introduction of additional acetate functionality into the molecule was achieved by singlet oxygen ene-reaction. The formed hydroperoxide was reduced and then acetylated. The triacetate was further functionalized either by direct cis-hydroxylation using OsO4 or by epoxidation followed by a ring-opening reaction to give the title heptopyranose derivatives. One of the synthesized molecules, galacto-heptopyranose exhibited enzyme specific inhibition against α-glycosidase. On the other hand, they did not show any inhibition for α-amylase. However, both compounds, gulo-heptopyranose and galacto-heptopyranose increased the activity of α-amylase. [ABSTRACT FROM AUTHOR]

Practical synthesis of a new chiral endo-exo cross-conjugated cyclohexadienone was achieved, and its synthetic utility was illustrated by highly exo-β-selective conjugate addition with various nucleophiles. Further diastereoselective transformation of the adduct to an unprecedented 5a-substituted carbaallose is also described. [ABSTRACT FROM AUTHOR]

Abstract: A versatile intermediate for the synthesis of galactose-mimicking carbasugars was synthesised from tetrabenzyl galactose in five steps and 30% overall yield. The reaction sequence uses an l-proline-mediated aldol reaction as key step. The reaction sequence was run on several grams of material. [Copyright &y& Elsevier]

Abstract: Cyclitol [RCAI-37 (1), 59 (5), 92 (7), and 102 (2)] and carbasugar analogs [RCAI-56 (3), 60 (4), and 101 (6)] of KRN7000 were synthesized through coupling reactions of the corresponding cyclitol or carbasugar derivatives with a cyclic sulfamidate (9) as the key step. Bioassay showed RCAI-56 (3, carbagalactose analog of KRN7000), 59 (5, 1-deoxy-neo-inositol analog), and 92 (7, 1-O-methylated 5) to be remarkably potent stimulants of mouse lymphocytes to produce Th1-biased cytokines, such as interferon-γ, in vivo. RCAI-60 (4, carbafucose analog) and RCAI-101 (6, 6-O-methylated 3) showed strong bioactivity, on the other hands, RCAI-37 (1, myo-inositol analog) and 102 (2, neo-inositol analog) induced little cytokine production. [Copyright &y& Elsevier]

The synthesis of a novel carbasugar amino acid (15), starting from D-glucose and using the Ferrier rearrangement as a key step, is reported. Compound 15 is implemented as dipeptide isostere in the synthesis of a Leu-enkephalin analog. [ABSTRACT FROM AUTHOR]

Abstract: 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 α- and β-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. [Copyright &y& Elsevier]

A family of novel carbasugar analogues (bicyclitols) based on cis-hydrindane and cis-decalin frameworks has been conceptualized. These novel entities can be regarded as conduritol and carbasugar hybrids. Syntheses of these polyhydroxylated entities have been achieved in stereo- and regioselective manners, starting from the readily available Diels–Alder adducts of 5,5-dimethoxy-1,2,3,4-tetrachlorocyclopentadiene and appropriate dienophiles like cyclopentadiene or p-benzoquinone, that embody a masked 7-ketonorbornenone moiety. Thermally induced chelotropic elimination of CO from the appropriately functionalized 7-ketonorbornenone derivatives to deliver annulated bicyclic 1,3-cyclohexadiene derivatives was the key step in this synthetic endeavor. Further oxy-functionalization of the 1,3-cyclohexadiene moiety delivered the targeted polycyclitols. A preliminary investigation of the glycosidase inhibitory potency of these bicyclitols, identified compounds 18 and 54 as potent and selective inhibitors of α-glucosidase (yeast). [ABSTRACT FROM AUTHOR]

The synthesis of carbasugars and various aminocyclitols, related to voglibose and acarbose used in the treatment of non-insulino-dependant diabetes, is described from C2-symmetrical bis-epoxides derived from d-mannitol. The methodology involves two key steps: a domino alkylation–cyclization with 2-lithio-1,3-dithiane derivatives, and reduction or reductive amination with a primary amine. These compounds have been evaluated as inhibitors of several glycosidases, and this study indicates notably that the l-ido or d-manno 1-aminocycloheptane-3,4,5,6-tetrol are inhibitors of α-d-glucosidase with Ki in the micromolar range. [Copyright &y& Elsevier]

Intercellular communication is governed by interactions between surface oligosaccharides and glycoproteins. The biosynthesis of these molecules involves glycosidations catalyzed by glycosyltransferases and hydrolysis of O-glycosyl linkages catalyzed by glycosidases. Monosaccharide and disaccharide mimics such as carbasugars, iminosugars and C-linked disaccharides can be glycosidase or glycosyltransferase inhibitors. They are leads as new drugs to treat infective diseases and cancer. The preparation of a conduramine, a pentahydroxyindolizidine, and two C-linked disaccharides are outlined.

(−)-Quinic acid was used as a starting material in the hemisynthesis of two epimeric carbasugars isolated from Streptomyces lincolnensis. Previous 10–12 steps syntheses for the carbasugars have been herein shortened to 4–6 steps by using quinic acid as a chiron, based on a regioselective reduction step, with stereoinversion of a tertiary center. Both C-5 epimers of (1 R , 2 R , 3 R)-5-(hydroxymethyl)cyclohexane-1,2,3-triol were obtained in up to 76% overall yield. Image 1 [ABSTRACT FROM AUTHOR]

Glycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series of new cyclopentanoid β-galactosidase inhibitors were prepared and their inhibitory and pharmacological chaperoning activities determined and compared with those of lipophilic analogs of the potent β-d-galactosidase inhibitor 4-epi-isofagomine. Structure-activity relationships were investigated by X-ray crystallography as well as by alterations in the cyclopentane moiety such as deoxygenation and replacement by fluorine of a "strategic" hydroxyl group. New compounds have revealed highly promising activities with a range of β-galactosidase-compromised human cell lines and may serve as leads towards new pharmacological chaperones for GM1-gangliosidosis and Morquio B disease. [ABSTRACT FROM AUTHOR]

In this study, novel 1,2,3-triazole compounds containing carbasugar frameworks (5 and 6) were synthesized by the copper-catalyzed azide-alkyne cycloaddition reactions and their in vitro inhibition effects on the enzyme xanthine oxidase were investigated. All of the synthesized compounds were characterized by spectroscopic methods. According to the enzyme inhibition results, compounds 5 (IC 50 = 0.586 ± 0.017 μM) and 6 (IC 50 = 0.751 ± 0.021 μM) showed stronger inhibition effects than allopurinol (IC 50 = 1.143 ± 0.019 μM), which is a standard drug used for inhibition of xanthine oxidase. The binding modes of the 1,2,3-triazole compounds (5 and 6) with the active site of xanthine oxidase were explained based on molecular docking studies. The molecular docking studies showed that the aromatic structure, π-π interactions and hydrophobic interactions play a major role in xanthine oxidase inhibition for compounds 5 and 6. • Novel 1,2,3-triazole compounds (5 and 6) were synthesized by the copper-catalyzed azide-alkyne cycloaddition reactions. • In vitro inhibition effects on the enzyme xanthine oxidase of the synthesized compounds were investigated. • 1,2,3-Triazoles (5 and 6) showed stronger inhibition effects than allopurinol, the reference agent. • Molecular docking studies were carried. [ABSTRACT FROM AUTHOR]