Antibacterial activity of xylose-derived LpxC inhibitors - Synthesis, biological evaluation and molecular docking studies.

LpxC inhibitors represent a promising class of novel antibiotics selectively combating Gram-negative bacteria. In chiral pool syntheses starting from D- and L-xylose, a series of four 2r,3c,4t-configured C-furanosidic LpxC inhibitors was obtained. The synthesized hydroxamic acids were tested for antibacterial and LpxC inhibitory activity, the acquired biological data were compared with those of previously synthesized C-furanosides, and molecular docking studies were performed to rationalize the observed structure-activity relationships. Additionally, bacterial uptake and susceptibility to efflux pump systems were investigated for the most promising stereoisomers.

[Biocatalysis of formaldehyde to L-xylose].

It is of great significance to use biosynthesis to transform the inorganic substance formaldehyde into organic sugars. Most important in this process was to find a suitable catalyst combination to achieve the dimerization of formaldehyde. In a recent report, an engineered glycolaldehyde synthase was reported to catalyze this reaction. It could be combined with engineered D-fructose-6-phosphate aldolase, a "one-pot enzyme" method, to synthesize L-xylose using formaldehyde and the conversion rate could reach up to 64%. This process also provides a reference for the synthesis of other sugars. With the increasing consumption of non-renewable resources, it was of great significance to convert formaldehyde into sugar by biosynthesis.

Design, synthesis, cholinesterase inhibition and molecular modelling study of novel tacrine hybrids with carbohydrate derivatives.

A series of hybrids containing tacrine linked to carbohydrate-based moieties, such as d-xylose, d-ribose, and d-galactose derivatives, were synthesized by the nucleophilic substitution between 9-aminoalkylamino-1,2,3,4-tetrahydroacridines and the corresponding sugar-based tosylates. All compounds were found to be potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the nanomolar IC50 scale. Most of the d-xylose derivatives (6a-e) were selective for AChE and the compound 6e (IC50 = 2.2 nM for AChE and 4.93 nM for BuChE) was the most active compound for both enzymes. The d-galactose derivative 8a was the most selective for AChE exhibiting an IC50 ratio of 7.6 for AChE over BuChE. Only two compounds showed a preference for BuChE, namely 7a (d-ribose derivative) and 6b (d-xylose derivative). Molecular docking studies indicated that the inhibitors are capable of interacting with the entire binding cavity and the main contribution of the linker is to enable the most favorable positioning of the two moieties with CAS, PAS, and hydrophobic pocket to provide optimal interactions with the binding cavity. This finding is reinforced by the fact that there is no linear correlation between the linker size and the observed binding affinities. The majority of the new hybrids synthesized in this work do not violate the Lipinski's rule-of-five according to FAF-Drugs4, and do not demonstrated predicted hepatotoxicity according ProTox-II.

Ribose and related sugars from ultraviolet irradiation of interstellar ice analogs.

Ribose is the central molecular subunit in RNA, but the prebiotic origin of ribose remains unknown. We observed the formation of substantial quantities of ribose and a diversity of structurally related sugar molecules such as arabinose, xylose, and lyxose in the room-temperature organic residues of photo-processed interstellar ice analogs initially composed of H2O, CH3OH, and NH3 Our results suggest that the generation of numerous sugar molecules, including the aldopentose ribose, may be possible from photochemical and thermal treatment of cosmic ices in the late stages of the solar nebula. Our detection of ribose provides plausible insights into the chemical processes that could lead to formation of biologically relevant molecules in suitable planetary environments.

TiO2-catalyzed synthesis of sugars from formaldehyde in extraterrestrial impacts on the early Earth.

Recent synthetic efforts aimed at reconstructing the beginning of life on our planet point at the plausibility of scenarios fueled by extraterrestrial energy sources. In the current work we show that beyond nucleobases the sugar components of the first informational polymers can be synthesized in this way. We demonstrate that a laser-induced high-energy chemistry combined with TiO2 catalysis readily produces a mixture of pentoses, among them ribose, arabinose and xylose. This chemistry might be highly relevant to the Late Heavy Bombardment period of Earth's history about 4-3.85 billion years ago. In addition, we present an in-depth theoretical analysis of the most challenging step of the reaction pathway, i.e., the TiO2-catalyzed dimerization of formaldehyde leading to glycolaldehyde.

Chemistry of xylopyranosides.

Xylose is one of the few monosaccharidic building blocks that are used by mammalian cells. In comparison with other monosaccharides, xylose is rather unusual and, so far, only found in two different mammalian structures, i.e. in the Notch receptor and as the linker between protein and glycosaminoglycan (GAG) chains in proteoglycans. Interestingly, simple soluble xylopyranosides can not only initiate the biosynthesis of soluble GAG chains but also function as inhibitors of important enzymes in the biosynthesis of proteoglycans. Furthermore, xylose is a major constituent of hemicellulosic xylans and thus one of the most abundant carbohydrates on Earth. Altogether, this has spurred a strong interest in xylose chemistry. The scope of this review is to describe synthesis of xylopyranosyl donors, as well as protective group chemistry, modifications, and conformational analysis of xylose.

Effect of steam explosion on waste copier paper alone and in a mixed lignocellulosic substrate on saccharification and fermentation.

This study evaluated steam (SE) explosion on the saccharification and simultaneous saccharification and fermentation (SSF) of waste copier paper. SE resulted in a colouration, a reduction in fibre thickness and increased water absorption. Changes in chemical composition were evident at severities greater than 4.24 resulting in a loss of xylose and the production of breakdown products known to inhibit fermentation (particularly formic acid and acetic acid). SE did not improve final yields of glucose or ethanol, and at severities 4.53 and 4.83 reduced yields probably due to the effect of breakdown products and fermentation inhibitors. However, at moderate severities of 3.6 and 3.9 there was an increase in initial rates of hydrolysis which may provide a basis for reducing processing times. Co-steam explosion of waste copier paper and wheat straw attenuated the production of breakdown products, and may also provide a basis for improving SSF of lignocellulose.

Carboxybenzyl group as an o-nucleophile in the C-H allylic oxidation: total synthesis of (-)-castanospermine.

The first palladium-mediated C-H allylic oxidation with a Cbz group acting as an O-nucleophile is reported. It was found that this transformation is promoted by rare-earth metal triflates: Yb(OTf)(3) or Sc(OTf)(3). A possible catalytic cycle is proposed. This reaction was applied in the synthesis of a d-xylose derived oxazolidinon, a versatile intermediate used further in the stereoselective synthesis of unnatural (-)-castanospermine. Cyclization of the key intermediate with PhSeBr afforded the desired bicyclic scaffold. In an alternative route, hydroboration/oxidation followed by DPPA-mediated cyclization was used.

Synthesis of hydroxycinnamoyl ß-D-xylopyranosides and evaluation of their antioxidant properties.

Various hydroxycinnamoyl ß-d-xylopyranosides were efficiently prepared from 2,3,4-tri-O-acetyl-α-d-xylopyranosyl bromide (TAXB) with amine by amine-promoted glycosylation. The resulted acetylated hydroxycinnamoyl ß-d-xylopyranosides with acetoxy groups at C-2, C-3, and C-4 were regioselectively deacetylated at C-4 position with Novozym 435. Antioxidant activities of free hydroxycinnamic acids and the respective ß-d-xylopyranosides were evaluated by DPPH radical scavenging activity as well as their inhibitory effect on autoxidation of bulk methyl linoleate. The radical scavenging activity on 1,1-diphenyl-2-picrylhydrazyl (DPPH) decreased in the order ferulic acid>caffeic acid≈caffeoyl ß-d-xylopyranosides≈sinapinic acid>sinapoyl ß-d-xylopyranosides≈feruloyl ß-d-xylopyranosides>p-coumaric acid>p-coumaroyl ß-d-xylopyranosides. In bulk methyl linoleate, the antioxidant activity order against autoxidation was almost consistent with the scavenging activity order. The results showed that caffeoyl ß-d-xylopyranosides and sinapoyl ß-d-xylopyranosides were as effective as free caffeic acid, sinapinic acid, and ferulic acid.

Silyl migrations in D-xylose derivatives: total synthesis of a marine quinoline alkaloid.

A versatile method for the synthesis of orthogonally protected D-xylose 1-thioethers is described using unusual silyl group migrations which were pivotal in the synthesis of 4,8-dimethyl-6-O-(2',4'-di-O-methyl-ß-D-xylopyranosyl)hydroxyquinoline confirming the structure and absolute configuration of the natural product.

Xylans are a valuable alternative resource: production of D-xylose, D-lyxose and furfural under microwave irradiation.

The influence of microwave irradiation on hydrolysis of xylan and simultaneous epimerization of the D-xylose to D-lyxose has been studied. An acidic solution of xylan was treated with catalytic amount of sodium molybdate and the composition of the reaction mixture was analyzed. Short reaction times of hydrolysis and subsequent epimerization reaction provided an equilibrium reaction mixture of D-xylose and D-lyxose (1.6:1) without significant formation of undesirable side products. Obtained pentoses can be reduced to the corresponding alditols (D-xylitol and D-lyxitol) in very good yields (88% and 85%) or can be further dehydrated to furfural (53%). Combined use of Mo(VI) catalyst and microwave irradiation allows better conversions and substantial reduction of reaction times (400-fold) compared to that obtained by conventional heating. Studied stereospecific transformation of xylan proceeds with high selectivity, short reaction times and very good yields that makes this approach attractive also for preparative purposes.

Enhanced xylose recovery from oil palm empty fruit bunch by efficient acid hydrolysis.

Oil palm empty fruit bunch (EFB) is abundantly available in Malaysia and it is a potential source of xylose for the production of high-value added products. This study aimed to optimize the hydrolysis of EFB using dilute sulfuric acid (H2SO4) and phosphoric acid (H3PO4) via response surface methodology for maximum xylose recovery. Hydrolysis was carried out in an autoclave. An optimum xylose yield of 91.2 % was obtained at 116 °C using 2.0 % (v/v) H2SO4, a solid/liquid ratio of 1:5 and a hydrolysis time of 20 min. A lower optimum xylose yield of 24.0 % was observed for dilute H3PO4 hydrolysis at 116 °C using 2.4 % (v/v) H3PO4, a solid/liquid ratio of 1:5 and a hydrolysis time of 20 min. The optimized hydrolysis conditions suggested that EFB hydrolysis by H2SO4 resulted in a higher xylose yield at a lower acid concentration as compared to H3PO4.

Liquid hot water pretreatment of sugarcane bagasse and its comparison with chemical pretreatment methods for the sugar recovery and structural changes.

Liquid hot water (LHW), dilute hydrochloric acid (HCl) and dilute sodium hydroxide (NaOH) were applied to sugarcane bagasse (SB). Application of the same analytical methods and material balance approaches facilitated meaningful comparisons of glucose and xylose yields from combined pretreatment and enzymatic hydrolysis. All pretreatments enhanced sugar recovery from pretreatment and subsequent enzymatic hydrolysis substantially compared to untreated sugarcane bagasse. Adding Tween80 in the enzymatic hydrolysis process increased the conversion level of glucan/xylan by 0.3-fold, especially for the low pH pretreatment where more lignin was left in the solids. The total sugar recovery from sugarcane bagasse with the coupled operations of pretreatment and 72 h enzymatic digestion reached 71.6% for LHW process, 76.6% for HCl pretreatment and 77.3% for NaOH pretreatment. Different structural changes at the plant tissue, cellular, and cell wall levels might be responsible for the different enzymatic digestibility. Furthermore, a combined LHW and aqueous ammonia pretreatment was proposed to reduce energy input and enhance the sugar recovery.

Combination of liquid hot water pretreatment and wet disk milling to improve the efficiency of the enzymatic hydrolysis of eucalyptus.

Combination of liquid hot water pretreatment (LHWP) and wet disk milling (WDM) was investigated in this study to enhance the sugar recovery yield both in prehydrolyzate and enzymatic hydrolyzate. The results show that WDM with LHWP at 180 °C for 20 min produced maximum xylose and glucose yields of 91.62% and 88.12%, respectively, which are higher than that of dilute acid pretreatment or individual LHWP. Corresponding concentration of fermentation inhibitors such as acetic acid, HMF, and furfural in the prehydrolyzate are about 0.98, 0.07 and 0.78 g/L, respectively, which indicated that the detoxification may be not required in the next fermentation step. The acid-insoluble lignin recovery in the insoluble solid resulting from enzymatic hydrolysis, was 25.67/100g raw material, representing 90.7% of acid-insoluble lignin in the eucalyptus biomass. It can be concluded that liquid hot water pretreatment combined with wet disk milling can be successfully applied to eucalyptus.

Allyloxy and propargyloxy group migration: role of remote group participation in the synthesis of 5-C-nucleosides and other sugar derivatives.

In 1-deoxy-xylofuranose derivatives possessing a good leaving group at 2-C, participation of allyloxy and propargyloxy substituents at 5-C results in loss of the 2-C substituent and attack of various nucleophiles at 5-C of the oxonium intermediate. Such participation of a benzyloxy or crotyloxy group leads to dioxabicyclo[2.2.1]heptane rings.

Enhanced production of glucose and xylose with partial dissolution of corn stover in ionic liquid, 1-Ethyl-3-methylimidazolium acetate.

Partial dissolution of corn stover in ionic liquid (IL) was employed for pretreating biomass and achieving enhanced glucose and xylose yield. The xylan recovery in solid fraction after IL pretreatment decreased as temperature increased. Xylose yield was significantly increased at a relatively low temperature (110 °C) compared with the high-temperature (over 130 °C) pretreatment, which resulted in a significant xylan degradation. A maximum total sugar yield of 88.0%, with glucose yield of 93.9% and xylose yield of 75.9% based on untreated biomass, was obtained at 110 °C for 3h pretreatment without complete dissolution of biomass. A sugar yield of 78.0% was obtained with IL pretreatment at 70 °C for 24 h. Synchrotron wide-angle X-ray diffraction was employed to investigate the crystalline structure of biomass. Both cellulose crystallinity and remaining lignin amount were correlated with cellulose digestibility.

Efficient synthesis, structural characterization and anti-microbial activity of chiral aryl boronate esters of 1,2-O-isopropylidene-α-D-xylofuranose.

A simple and efficient synthetic approach toward a series of chiral aryl boronate esters, starting from D-xylose, as anti-microbial agents, is described herein. Minimum inhibitory concentration and zone of inhibition revealed that these derivatives exhibit potent anti-bacterial and anti-fungal properties. Herein, we report the first anti-microbial activity of this class of compounds. All products have been characterized by NMR ((1)H, (13)C and (11)B), IR, elemental and mass spectral study.

A new method of comprehensive utilization of rice husk.

Rice husk is an abundant agricultural byproduct. The research on comprehensive utilization of rice husk to prepare xylose, activated carbon and silica was carried out. The hydrolysis conditions of xylan in rice husk to produce xylose were as follows: the concentration of H(2)SO(4) was 3.6% (wt.%), the temperature was 100°C, the ratio of rice husk mass (g) to H(2)SO(4) solution (ml) was 1:5 and the time was 3 h. The hydrolysis degree of xylan reached 95.6%. The resulting residues were used to prepare activated carbons with the BET surface area of 1763 m(2)/g when 50% H(3)PO(4) was impregnated with rice husk with the ratio of 5:1 at 500°C for 0.5 h. The produced carbons had effective adsorption capability to purify the xylose solution. Furthermore, they exhibited good electrochemical performance. After adsorption, activated carbons were calcined to produce silica with the diameter of 30 nm.

Enzymatic synthesis of ß-xylosyl-oligosaccharides by transxylosylation using two ß-xylosidases of glycoside hydrolase family 3 from Aspergillus nidulans FGSC A4.

Two ß-xylosidases of glycoside hydrolase family 3 (GH 3) from Aspergillus nidulans FGSC A4, BxlA and BxlB were produced recombinantly in Pichia pastoris and secreted to the culture supernatants in yields of 16 and 118 mg/L, respectively. BxlA showed about sixfold higher catalytic efficiency (k(cat)/K(m)) than BxlB towards para-nitrophenyl ß-D-xylopyranoside (pNPX) and ß-1,4-xylo-oligosaccharides (degree of polymerisation 2-6). For both enzymes k(cat)/K(m) decreased with increasing ß-1,4-xylo-oligosaccharide chain length. Using pNPX as donor with 9 monosaccharides, 7 disaccharides and two sugar alcohols as acceptors 18 different ß-xylosyl-oligosaccharides were synthesised in 2-36% (BxlA) and 6-66% (BxlB) yields by transxylosylation. BxlA utilised the monosaccharides D-mannose, D-lyxose, D-talose, D-xylose, D-arabinose, L-fucose, D-glucose, D-galactose and D-fructose as acceptors, whereas BxlB used the same except for D-lyxose, D-arabinose and L-fucose. BxlB transxylosylated the disaccharides xylobiose, lactulose, sucrose, lactose and turanose in upto 35% yield, while BxlA gave inferior yields on these acceptors. The regioselectivity was acceptor dependent and primarily involved ß-1,4 or 1,6 product linkage formation although minor products with different linkages were also obtained. Five of the 18 transxylosylation products obtained from D-lyxose, D-galactose, turanose and sucrose (two products) as acceptors were novel xylosyl-oligosaccharides, ß-D-Xylp-(1→4)-D-Lyxp, ß-D-Xylp-(1→6)-D-Galp, ß-D-Xylp-(1→4)-α-D-Glcp-(1→3)-ß-D-Fruf, ß-D-Xylp-(1→4)-α-D-Glcp-(1→2)-ß-D-Fruf, and ß-D-Xylp-(1→6)-ß-D-Fruf-(2→1)-α-D-Glcp, as structure-determined by 2D NMR, indicating that GH3 ß-xylosidases are able to transxylosylate a larger variety of carbohydrate acceptors than earlier reported. Furthermore, transxylosylation of certain acceptors resulted in mixtures. Some of these products are also novel, but the structures of the individual products could not be determined.

Discovery of novel N-ß-D-xylosylindole derivatives as sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the management of hyperglycemia in diabetes.

A novel series of N-linked ß-D-xylosides were synthesized and evaluated for inhibitory activity against sodium-dependent glucose cotransporter 2 (SGLT2) in a cell-based assay. Of these, the 4-chloro-3-(4-cyclopropylbenzyl)-1-(ß-D-xylopyranosyl)-1H-indole 19m was found to be the most potent inhibitor, with an EC(50) value similar to that of the natural SGLT2 inhibitor phlorizin. Further studies in Sprague-Dawley (SD) rats indicated that 19m significantly increased urine glucose excretion in a dose-dependent manner with oral administration. The antihyperglycemic effect of 19m was also observed in streptozotocin (STZ) induced diabetic SD rats. These results described here are a good starting point for further investigations into N-glycoside SGLT2 inhibitors.