105990-41-8

This paper describes a new strategy for the synthesis of polyfuncticnalized pyrrolidines via the ring-closing metathesis reaction of substituted 3-allyl-4-vinyl-2-oxazolindones and subsequent diastereoselective cis-dihydroxylation of the resulting pyrrolo

Here, we report a chemoenzymatic approach for the preparation of a small panel of biologically important iminosugars from readily available aldoses. Our approach involves anin vitrotransaminase-mediated amination of aldoses in combination with anin vivose

Disclosed herein are novel uses of ADMDP stereoisomers or their derivatives for the manufacture of a medicament for treating Pompe disease. Accordingly, the present disclosure provides a method of treating Pompe disease in a subject. The method includes the step of, administering to the subject a therapeutically effective amount of a compound of formula (I), or a salt, an ester or a solvate thereof, wherein R1 and R2 are independently H or alkyl optionally substituted by -NH2 or -OH, so as to ameliorate, alleviate mitigate and/or prevent symptoms associated with the Pompe disease. According to certain embodiments of the present disclosure, the compound of formula (I) may serve a stabilizer of α-glucosidase via preventing its denaturalization of deactivation.

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 along with factors influencing cell penetration. To achieve these goals we modified nitrogen heterocycles in terms of ring size, side chains present and ring nitrogen derivatization. By reducing the inhibitor interactions with the active site down to the essentials we were able to determine that besides the established 2S,3R trans-relationship, the presence and stereochemistry of the CH2OH side chain is of crucial importance for activity. In terms of cellular penetration, N-butyl side chains favour cellar uptake, while hydroxy- and carboxy-group bearing sidechains on the ring nitrogen retarded cellular penetration. Furthermore we show an early proof of principle study that β-N-acetylhexosaminidase inhibitors can be applicable to use in a potential anti-invasive anti-cancer strategy.

A highly efficient method for the synthesis of 1,4-dideoxy-1,4-imino-d- and l-arabinitol (d-AB1, 1 and l-AB1, 3) and 1,4-dideoxy-1,4-imino-d- and l-xylitol (d-DIX, 2 and l-DIX, 4) starting from commercially available chiral aziridines was developed. The g

The aldol addition of unphosphorylated dihydroxyacetone (DHA) to aldehydes catalyzed by L-rhamnulose-1-phosphate aldolase (RhuA), a dihydroxyacetone phosphate-dependent aldolase, is reported. Moreover, a single point mutation in the phosphate binding site

The synthesis of (2S,3S,4S)-2-(hydroxymethyl)pyrrolidine-3,4-diol (LAB1) from Garners aldehyde is described using the Sharpless asymmetric dihydroxylation as the key step. Georg Thieme Verlag Stuttgart - New York.

A highly diastereoselective synthesis of enantio-enriched all trans-3,4-dibenzyloxyl-5-benzyloxymethyl-2-pyrrolidinone 13a was developed based on SmI2-mediated benzyloxymethylation of O,O′-dibenzyltartarimide. The versatility of 13a and its antipode as the key building blocks for the asymmetric synthesis of pyrrolidine azasugars and homoazasugars has been demonstrated by elaborating them into naturally occurring DAB 1 (1), LAB 1 (2), N-hydroxyethyl-DAB 1 (4), 6-deoxy-DMDP 7, and 5-epi-radicamine B 36 as well as the reductive ring-opening product 35.

Dihydroxyacetone phosphate (DHAP)-dependent aldolases have been widely used for the organic synthesis of unnatural sugars or derivatives. The practicality of using DHAP-dependent aldolases is limited by their strict substrate specificity and the high cost and instability of DHAP. Here we report that the DHAP-dependent aldolase L-rhamnulose 1-phosphate aldolase (RhaD) accepts dihydroxyacetone (DHA) as a donor substrate in the presence of borate buffer, presumably by reversible in situ formation of DHA borate ester. The reaction appears to be irreversible, with the products thermodynamically trapped as borate complexes. We have applied this discovery to develop a practical one-step synthesis of the non-caloric sweetener L-fructose. L-Fructose was synthesized from racemic glyceraldehyde and DHA in the presence of RhaD and borate in 92% yield on a gram scale. We also synthesized a series of L-iminocyclitols, which are potential glycosidase inhibitors, in only two steps.

The D-glucose derived aziridine carboxylate 5 was obtained from (E)-ethyl-6-bromo-1,2-O-isopropylidene-3-O-benzyl-5-deoxy-α-D-xylo-5-eno- heptofuranuronate 4 through conjugate addition of benzylamine and in situ intramolecular nucleophilic expulsion of br

The potential of L-fuculose-1-phosphate aldolase (FucA) as a catalyst for the asymmetric aldol addition of dihydroxyacetone phosphate (DHAP) to N-protected amino aldehydes has been investigated. First, the reaction was studied in both emulsion systems and

The present invention provides methods of treatment and prevention of early cardiac and early cardiovascular diseases, for instance of ischemic origin, such as left ventricular hypertrophy, coronary artery disease, essential hypertension, acute hypertensive emergency, cardiomyopathy, heart insufficiency, exercise tolerance, chronic heart failure, arrhythmia, cardiac dysrhythmia, syncopy, arteriosclerosis, mild chronic heart failure, angina pectoris, cardiac bypass reocclusion, intermittent claudication (arteriosclerosis oblitterens), diastolic dysfunction and systolic dysfunction, as well as improving the success of heart transplantations, through administration of glycogen phosphorylase inhibitor compounds.

Polyadenosine diphosphoribose glycohydrolase (PARG) catalyzes the intracellular hydrolysis of adenosine diphosphoribose polymers. Because structure-activity data are lacking for PARG, the specific inhibitor adenosine diphosphate (hydroxymethyl)pyrrolidinediol (ADP-HPD) was utilized to determine the effects of structure on inhibitor potency using PARG isolated from bovine thymus (bPARG) and recombinant bovine PARG catalytic fragment (rPARG-CF). Both enzymes were strongly inhibited by submicromolar levels of ADP-HPD, but ADP and the phosphorylated pyrrolidine displayed no activity. Utilizing ADP-HPD analogues containing 2-, N6, or 8-adenosyl substituents or guanine instead of adenine, the importance of adenine ring recognition as well as a correlation between loss of PARG inhibition and the length and bulkiness of 8-adenosyl substituents was shown. Utilization of ADP-HPD analogues lacking one or both pyrrolidine cis-hydroxyls demonstrated their importance for inhibitor binding. Last, the similarity between naturally occurring bPARG and heterologously expressed rPARG-CF was demonstrated. Therefore, readily available rPARG-CF is suitable for use in future studies to determine the structural aspects of PARG.

The aza-C-nucleosides, Immucillin-H and Immucillin-G, are transition state analogue inhibitors of purine nucleoside phosphorylase, a therapeutic target for the control of T-cell proliferation. Immucillin analogues modified at the 2′-, 3′-, or 5′-positions of the azasugar moiety or at the 6-, 7-, or 8-positions of the deazapurine, as well as methylene -bridged analogues, have been synthesized and tested for their inhibition of human purine nucleoside phosphorylase. All analogues were poorer inhibitors, which reflects the superior capture of transition state features in the parent immucillins.

The potential of dihydroxyacetone phosphate (DHAP)-dependent aldolases to catalyze stereoselective aldol additions is, in many instances, limited by the solubility of the acceptor aldehyde in aqueous/co-solvent mixtures. Herein, we demonstrate the efficiency of emulsion systems as reaction media for the class I fructose-1,6-b isphosphate aldolase (RAMA) and class II recombinant rhamnulose-1-phosphate aldolase from E. coli (RhuA)catalyzed aldol addition between DHAP and N-benzyloxycarbonyl (N-Cbz) aminoaldehydes. The use of emulsions improved the RAMA-catalyzed aldol conversions by three to tenfold relative to those in conventional DMF/ water mixtures. RhuA was more reactive than RAMA towards the N-Cbz aminoaldehydes regardless of the reaction medium. With (S)- or (R)-Cbz-alaninal, RAMA exhibited preference for the R enantiomer, while RhuA had no enantiomeric discrimination. The linear N-Cbz aminopolyols thus obtained were submitted to catalytic intramolecular reductive amination to afford the corresponding iminocyclitols. This reaction was diastereoselective in all cases examined; the face selectivity was controlled by the stereochemistry of the newly formed hydroxyl group originating from the aldehyde. Characterization of the resulting iminocyclitols allowed the assessment of the diastereoselectivity of the enzymatic aldol reactions with respect to the N-protected aminoaldehyde. RAMA formed single diastereoisomers from N-Cbz-glycinal and from both enantiomers of N-Cbz-alaninal, while 14% of the epimeric product was observed from N-Cbz-3-aminopropanal. Diastereoselectivity from RhuA was lower than that observed from RAMA. Interestingly, a single diastereoisomer was formed from (S)-Cbz-alaninal, whereas only a 34% diastereomeric excess was observed from its enantiomer (i.e., (R)-Cbz-alaninal).

Asymmetric synthesis of 1,4-dideoxy-1,4-imino-D-ribitol was achieved utilizing the stereoselective addition of allylphenylsulfone to a chiral N-sulfinyl-2-furfuryl imine and ring-closing metathesis reactions as key steps.

A short synthesis of 1,4-dideoxy-1,4-imino-L-arabinitol (LAB1) (4) and of 1,4-dideoxy-1,4-imino-D-galactitol (5), two azasugars active as enzymatic inhibitors, is reported. The key reaction is the addition of vinylmagnesium chloride to (3S,4S)-3,4-bis(benzyloxy)-3,4-dihydro-2H-pyrrole 1-oxide (3), a nitrone easily available from L-tartaric acid. Unexpectedly, the reaction affords the corresponding (2S,3S,4S)-1-hydroxy-2-ethenyl-3,4-bis(benzyloxy)pyrrolidine (9) in very good yield and in 93/7 diastereomeric ratio (dr) independently of the reaction temperature, thus representing a unique case of entropy-controlled reaction in a 100 K interval (from +20°C to -80°C). The trans intermediate 9 is converted in two steps (reduction, N-protection) into the common intermediate (2S,3S,4S)-1-(benzyloxycarbonyl)-3,4-bis(benzyloxy)-2-ethenylpyrrolidine (11). Double bond oxidation followed by reductive debenzylation opens a route to the target pyrrolidine azasugars 4 and 5.

Synthesis or glucosidase inhibitors, DAB-1 (1) and LAB-1 (2) from diethyl tartrate is described. The procedure afforded an epimerizable mixture of diastereomeric intermediates 8 and ent. 8, and opened the door not only to the selective synthesis or DAB-1 and LAB-1 but for giving various related analogs.

Beginning with (+)-serine or (-)-serine, as appropriate, convenient, high-yield, enantioselective synthesis of all eight stereoisomeric 2-hydroxymethyl-3,4-dihydroxypyrrolidines (the enantiomeric pairs of iminoribitol, -arabinitol, -xylitol, and -lyxitol) can be effected. The absolute configuration of the starting amino acid defines the set of azasugars produced.

(2R,3R,4S)-2-Hydroxymethylpyrrolidine-3,4-diol (1,4-dideoxy-1,4-imino-D-ribitol) was synthesized in five steps from N-protected (2S)-3,4-dehydroproline methyl esters.The stereoselective reaction of osmium tetraoxide with dehydroproline derivatives gave hi

The dihydropyrrole 2 was synthesized in four steps from a protected lyxose derivative.This compound exists as one component of a complex equilibrium that may also contain the hydrated forms, 7, as well as a dimeric form.The mixture comprises a potent inhi

The use of readily available sugar lactones in the synthesis of polyhydroxylated pyrrolidines is illustrated by the preparation of the glucosidase inhibitor 1,4-dideoxy-1,4-imino-D-glucitol from D-galactonolactone and by the conversion of D-gulonolactone into 1,4-dideoxy-1,4-imino-D-allitol, 1,4-dideoxy-1,4-imino-D-ribitol, and (2S,3R,4S)-3,4-dihydroxyproline.

Both enantiomers of 1,4-dideoxy-1,4-iminoarabinitol are specific inhibitors of glucosidases.The synthesis of 1,4-dideoxy-1,4-imino-D-arabinitol involves connecting C2 and C5 of xylose together with nitrogen, whereas the synthesis of 1,4-dideoxy-1,4-imino-

The D-xylo and L-arabino isomers of 1,4-dideoxy-1,4-iminopentitol have been synthesised from L-arabinose, and the L-arabino isomer was found to be the enantiomer of the alkaloid from Angylocalyx Boutiqueanus.The alkaloid from Arachniodes Standishii, recently reported to have the xylo configuration, was also shown to be the D-arabino isomer.

The syntheses of 1,4-dideoxy-1,4-imino-D-lyxitol (3), 1,4-dideoxy-1,4-imino-D-arabinitol (4) and 1,4-dideoxy-1,4-imino-L-arabinitol (5) are reported; (3) is a potent competitive inhibitor of α-galactosidase (green coffee beans) and (4) a competitive inhibitor of α-glucosidase (Brewer's yeast) suggesting that iminopentitols have considerable potential as glycosidase inhibitors. (4) was found to be identical to an alkaloid recently isolated from Angylocalyx boutiqueanus.