Novel Perbutyrylated Glucose Derivatives of (-)-Epigallocatechin-3-Gallate Inhibit Cancer Cells Proliferation by Decreasing Phosphorylation of the EGFR: Synthesis, Cytotoxicity, and Molecular Docking.

Lung cancer is one of the most commonly occurring cancer mortality worldwide. The epidermal growth factor receptor (EGFR) plays an important role in cellular functions and has become the new promising target. Natural products and their derivatives with various structures, unique biological activities, and specific selectivity have served as lead compounds for EGFR. D-glucose and EGCG were used as starting materials. A series of glucoside derivatives of EGCG (7-12) were synthesized and evaluated for their in vitro anticancer activity against five human cancer cell lines, including HL-60, SMMC-7721, A-549, MCF-7, and SW480. In addition, we investigated the structure-activity relationship and physicochemical property-activity relationship of EGCG derivatives. Compounds 11 and 12 showed better growth inhibition than others in four cancer cell lines (HL-60, SMMC-7721, A-549, and MCF), with IC50 values in the range of 22.90-37.87 µM. Compounds 11 and 12 decreased phosphorylation of EGFR and downstream signaling protein, which also have more hydrophobic interactions than EGCG by docking study. The most active compounds 11 and 12, both having perbutyrylated glucose residue, we found that perbutyrylation of the glucose residue leads to increased cytotoxic activity and suggested that their potential as anticancer agents for further development.

Synthesis and biological screening of thiosemicarbazones of substituted 3-acetylcoumarins having d-glucose moiety.

Thiosemicarbazones 5a-j were synthesized with yields of 45-68% by condensation of 3-acetylcoumarins 3a-j and tetra-O-acetyl-ß-d-thiosemicarbazide 4. All obtained thiosemicarbazones were screened for anti-microorganic activities against bacteria (B. subtilis, S. aureus, S. epidermidis, E. coli, P. aeruginosa, K. pneumoniae, S. typhimurium) and fungi (A. niger, C. albicans, S. cerevisiae, and A. flavus). Some compounds had significant inhibitory activity with MICs of 0.78-3.125 µM in comparison with 5a, including 5e,h,i for S. aureus, and 5c,f,i for S. epidermidis (Gram-(+) bacteria), 5c,f,g for E.coli, 5f for K. pneumoniae, 5b,c,g for P. aeruginosa, and 5i for S. typhimurium (Gram-(-) bacteria), 5d,h,i for A. niger, 5i for A. flavus, 5b,d,e,h for C. albicans, and 5i for S. cerevisiae. Compounds exhibited excellent activity against tested microorganism with MIC = 0.78 µM, including 5h,i (against S. aureus), 5h (against C. albicans), and 5i (against S. cerevisiae).

Addressing the Biochemical Foundations of a Glucose-Based "Trojan Horse"-Strategy to Boron Neutron Capture Therapy: From Chemical Synthesis to In Vitro Assessment.

Boron neutron capture therapy (BNCT) for cancer is on the rise worldwide due to recent developments of in-hospital neutron accelerators which are expected to revolutionize patient treatments. There is an urgent need for improved boron delivery agents, and herein we have focused on studying the biochemical foundations upon which a successful GLUT1-targeting strategy to BNCT could be based. By combining synthesis and molecular modeling with affinity and cytotoxicity studies, we unravel the mechanisms behind the considerable potential of appropriately designed glucoconjugates as boron delivery agents for BNCT. In addition to addressing the biochemical premises of the approach in detail, we report on a hit glucoconjugate which displays good cytocompatibility, aqueous solubility, high transporter affinity, and, crucially, an exceptional boron delivery capacity in the in vitro assessment thereby pointing toward the significant potential embedded in this approach.

Design, synthesis and evaluation of novel levoglucosenone derivatives as promising anticancer agents.

A series of levoglucosenone-derived 1,2,3-triazoles and isoxazoles featuring a flexible spacer between the heteroaromatic and anhydropyranose cores have been designed and synthesized following an hetero Michael // 1,3-dipolar cycloaddition path. The use of a design of experiments approach allowed the optimization of the oxa-Michael reaction with propargyl alcohol as nucleophile, a key step for the synthesis of the target compounds. All of the compounds were tested for their anticancer activity on MDA-MB-231 cells, featuring mutant p53. The results highlighted the importance of the introduction of the flexible spacer as well as the higher activity of oxa-Michael isoxazole-derivatives. The most prominent compounds also showed anti-proliferative activities against lung and colon cancer cell lines. The compounds showed enhanced cytotoxic effects in the presence of mutant p53, determined both by endogenous mutant p53 knock down (R280K) and by reintroducing p53 R280K in cells lacking p53 expression.

Inspired by Sea Urchins: Warburg Effect Mediated Selectivity of Novel Synthetic Non-Glycoside 1,4-Naphthoquinone-6S-Glucose Conjugates in Prostate Cancer.

The phenomenon of high sugar consumption by tumor cells is known as Warburg effect. It results from a high glycolysis rate, used by tumors as preferred metabolic pathway even in aerobic conditions. Targeting the Warburg effect to specifically deliver sugar conjugated cytotoxic compounds into tumor cells is a promising approach to create new selective drugs. We designed, synthesized, and analyzed a library of novel 6-S-(1,4-naphthoquinone-2-yl)-d-glucose chimera molecules (SABs)-novel sugar conjugates of 1,4-naphthoquinone analogs of the sea urchin pigments spinochromes, which have previously shown anticancer properties. A sulfur linker (thioether bond) was used to prevent potential hydrolysis by human glycoside-unspecific enzymes. The synthesized compounds exhibited a Warburg effect mediated selectivity to human prostate cancer cells (including highly drug-resistant cell lines). Mitochondria were identified as a primary cellular target of SABs. The mechanism of action included mitochondria membrane permeabilization, followed by ROS upregulation and release of cytotoxic mitochondrial proteins (AIF and cytochrome C) to the cytoplasm, which led to the consequent caspase-9 and -3 activation, PARP cleavage, and apoptosis-like cell death. These results enable us to further clinically develop these compounds for effective Warburg effect targeting.

Synthesis and Antiproliferative Activities of Novel Substituted 5-Anilino-α-Glucofuranose Derivatives.

In order to find novel antitumor candidate agents with high efficiency and low toxicity, 14 novel substituted 5-anilino-α-glucofuranose derivatives have been designed, synthesized and evaluated for antiproliferative activities in vitro. Their structures were characterized by NMR (1 H and 13 C) and HR-MS, and configuration (R/S) at C(5) was identified by two-dimensional 1 H,1 H-NOESY-NMR spectrum. Their antiproliferative activities against human tumor cells were investigated by MTT assay. The results demonstrated that most of the synthesized compounds had antiproliferative effects comparable to the reference drugs gefitinib and lapatinib. In particular, (5R)-5-O-(3-chloro-4-{[5-(4-fluorophenyl)thiophen-2-yl]methyl}anilino)-5-deoxy-1,2-O-(1-methylethylidene)-α-glucofuranose (9da) showed the most potent antiproliferative effects against SW480, A431 and A549 cells, with IC50 values of 8.57, 5.15 and 15.24 µm, respectively. This work suggested 5-anilino-α-glucofuranose as an antitumor core structure that may open a new way to develop more potent anti-cancer agents.

In Vivo Veritas: 18F-Radiolabeled Glycomimetics Allow Insights into the Pharmacological Fate of Galectin-3 Inhibitors.

Glycomimetic drugs have attracted increasing interest as unique targeting vectors or surrogates for endogenous biomolecules. However, it is generally difficult to determine the in vivo pharmacokinetic profile of these compounds. In this work, two galectin-3 inhibitors were radiolabeled with fluorine-18 and used as surrogate PET tracers of TD139 and GB1107. Both compounds are promising drugs for clinical applications. In vivo evaluation revealed that both surrogates strongly differed with respect to their biodistribution profile. The disaccharide (TD139 surrogate) was rapidly eliminated from blood while the monosaccharide (GB1107 surrogate) showed no sign of excretion. The data obtained allowed us to infer the different in vivo fate of TD139 and GB1107 and rationalize how different administration routes could boost efficacy. Whereas the fast excretion profile of the TD139 surrogate indicated that systemic application of disaccharides is unfavorable, the extended biological half-life of the GB1107 surrogate indicated that systemic administration is possible for monosaccharides.

Production of D-allose from D-fructose using immobilized L-rhamnose isomerase and D-psicose 3-epimerase.

D-Allose is a rare sugar, can be used as an ingredient in a range of foods and dietary supplements, has alimentary activities, especially excellent anti-cancer effects and used in assisting cancer chemotherapy and radiotherapy, etc. To develop a simple and low-cost process for D-allose production, a one-pot enzymatic process using the substrate of D-fructose, and the recombinant enzymes of D-psicose 3-epimerase (DPE) and L-rhamnose isomerase (L-RhI) was developed. These enzymes were cloned from Ruminococcus sp. and B. subtilis, respectively, successfully expressed in E. coli, extracted and immobilized using anion exchange resin and amino resin, respectively. The mass ratio of D-fructose, D-psicose and D-allose was 6.6:2.4:1.0 when the reaction reached equilibrium after 5 h of reaction. Using the low-cost substrate of D-fructose, the reusable immobilized enzymes and the one-pot reaction, the production process is simplified and the production cost is decreased. In addition, to simplify the enzyme extraction and immobilization processes, new methods for enzyme capture and immobilization were developed especially for DPE immobilization. This is the first report for one-pot D-allose production using immobilized L-RhI and DPE.

Enantiomeric glycosylated cationic block co-beta-peptides eradicate Staphylococcus aureus biofilms and antibiotic-tolerant persisters.

The treatment of bacterial infections is hindered by the presence of biofilms and metabolically inactive persisters. Here, we report the synthesis of an enantiomeric block co-beta-peptide, poly(amido-D-glucose)-block-poly(beta-L-lysine), with high yield and purity by one-shot one-pot anionic-ring opening (co)polymerization. The co-beta-peptide is bactericidal against methicillin-resistant Staphylococcus aureus (MRSA), including replicating, biofilm and persister bacterial cells, and also disperses biofilm biomass. It is active towards community-acquired and hospital-associated MRSA strains which are resistant to multiple drugs including vancomycin and daptomycin. Its antibacterial activity is superior to that of vancomycin in MRSA mouse and human ex vivo skin infection models, with no acute in vivo toxicity in repeated dosing in mice at above therapeutic levels. The copolymer displays bacteria-activated surfactant-like properties, resulting from contact with the bacterial envelope. Our results indicate that this class of non-toxic molecule, effective against different bacterial sub-populations, has promising potential for the treatment of S. aureus infections.

Radiosynthesis of 18F-labeled d-allose.

Rare sugars are defined as monosaccharides that exist in nature but are only present in limited quantities. d-Allose is a rare sugar that has been reported to have some unique physiological effects. The present study describes suitable synthetic procedures for novel rare sugars of d-allose that are 18F-labeled at the C-3 and C-6 positions and the preparation of the appropriate labeling precursors. The goal is to facilitate in vivo, noninvasive positron emission tomography (PET) investigation of the behavior of rare sugar analogs of d-allose in organs. We found five precursors that were practical for labeling, three for 3-deoxy-3-[18F]fluoro-d-allose ([18F]3FDA) and two for 6-deoxy-6-[18F]fluoro-d-allose ([18F]6FDA). With manual operation synthesis, the highest radiochemical conversion rates were 75% for [18F]3FDA with a precursor of 1,2,4,6-tetra-O-acetyl-3-O-trifluoromethanesulfonyl-ß-d-glucopyranose and 69% for [18F]6FDA with a precursor of 1,2,3,4-tetra-O-acetyl-6-O-trifluoromethanesulfonyl-ß-d-allopyranose. Furthermore, the practical yields of [18F]3FDA and [18F]6FDA using an automated synthesizer were also investigated. Radiochemical yields of 67% and 49% were obtained for [18F]3FDA and [18F]6FDA, respectively, in an automated synthesizer. As basic assessment of stability for use in PET scanning, high performance liquid chromatography analysis showed no decomposition of [18F]3FDA and [18F]6FDA after up to 6 h in rabbit blood plasma.

Antitumor Effect of a Novel Photodynamic Therapy With Acetylated Glucose-conjugated Chlorin for Gastrointestinal Cancers.

BACKGROUND/AIM: We previously synthesized a glucose-conjugated chlorin compound e6 (G-chlorin e6), and reported that it has very strong antitumor effects. The aim of the present study was to synthesize acetylated glucose-conjugated chlorin (AcN003HP) and evaluate its antitumor effect and excretion. MATERIALS AND METHODS: To evaluate the antitumor effect of AcN003HP, its IC50 was calculated as well as its accumulation in cancer cells was examined by flow cytometry. Confocal microscopy was used to observe the intracellular localization of AcN003HP. The excretion and antitumor effects of AcN003HP were also evaluated in vivo. RESULTS: AcN003HP showed stronger antitumor effects and accumulation into cancer cells compared to talaporfin sodium, a conventional photosensitizer. AcN003HP was localized in the endoplasmic reticulum. In a xenograft tumor mouse model, AcN003HP showed longer excretion time from the body than G-chlorin e6, and photodynamic therapy using AcN003HP showed very strong antitumor effects. CONCLUSION: The safety, improved controllability, and robust antitumor effects suggest AcN003HP as a good next-generation photosensitizer.

A dandelion-like liposomes-encoded magnetic bead probe-based toehold-mediated DNA circuit for the amplification detection of MiRNA.

The development of facile and sensitive miRNA quantitative detection methods is a central challenge for the early diagnosis of miRNA-related diseases. Herein, we propose a strategy for a liposome-encoded magnetic bead-based DNA toehold-mediated DNA circuit for the simple and sensitive detection of miRNA based on a toehold-mediated circular strand displacement reaction (TCSDR) coupled with a personal glucometer (PGM ). In this strategy, a glucoamylase-encapsulated liposomes (GELs)-encoded magnetic bead (GELs-MB) probe is designed to integrate target binding, magnetic separation, and signal response. Upon sensing the target miRNA-21, a GELs-MB probe-based toehold-mediated circular strand displacement reaction (TCSDR) was initiated with the help of fuel-DNA, constructing a DNA circuit system, and realizing target recycling amplification and the disassembly of the liposomes. The disassembled liposomes were finally removed via magnetic separation, and the encapsulated glucoamylase was liberated to catalyze amylose hydrolysis with multiple turnovers to glucose for a PGM readout. Benefiting from target recycling amplification initiated by the toehold-mediated DNA circuit and the liposome multiple-label amplification, a small quantity of target miRNA-21 can be transformed into a large glucose signal. The strategy realized the quantification of miRNA-21 down to a level of 0.7 fM without enzymatic amplification or precise instrumentation. Moreover, the high-density GELs-MB probe allows the sensitive detection of miRNA-21 to be accomplished within 1.5 h. Furthermore, this strategy exhibits the advantages of specificity and simplicity, since a toehold-mediated strand displacement reaction, magnetic separation and portable PGM were used. Importantly, this strategy has been demonstrated to allow the high-confidence quantification of miRNA. Therefore, with the advantages of low cost, ease of use, portability, and sensitivity, the reported method holds great potential for the early diagnosis of miRNA-related diseases.

Production of reducing sugar from cassava starch waste (CSW) using solution plasma process (SPP).

The cassava starch processing plays an important role in food industries. During starch processing stage, a large amount of cassava starch waste (CSW) which mainly contains lost starch product and solid residue such as cassava bagasse are produced. Starch and cassava bagasse can be hydrolyzed into fermentable sugar such as glucose. In the present study, the solution plasma process (SPP) is used to treat CSW to prepare reducing sugar. The investigated parameters are treatment time, solvent concentration, applied pulsed frequency, and CSW concentration. The %yield of total reducing sugar (TRS) and glucose were calculated by DNS method and glucose assay kit, respectively. The chemical structure, morphology, and crystal structure of plasma-treated CSW were investigated. The results showed that the %yield of TRS was greatly enhanced by SPP treatment compared to that of acid hydrolysis. The CSW powder completely broke down into pieces after SPP treatment was applied. The amorphous and crystalline regions of CSW were destroyed during SPP treatment. SPP treatment of CSW with light sulfuric acid concentration of 0.08 M, applied pulsed frequency of 30 kHz, and CSW concentration of 0.5%w/v provided 99.0% TRS and 47.9% glucose.

Capturing CO2 to reversible ionic liquids for dissolution pretreatment of cellulose towards enhanced enzymatic hydrolysis.

To overcome the natural recalcitrance of cellulose for glucose production in aqueous media catalyzed by enzyme, in this study, a dissolution pretreatment strategy was developed by using in situ formed CO2-based reversible ionic compounds (RICs)/DMSO mixed organic electrolytes under mild conditions. The influences of the constitution of RICs, CO2 pressure, dissolution pretreatment time on the physic-chemical structure of cellulose were investigated systematically by FTIR, XRD, SEM, AFM towards in-depth understanding of the correlations between the pretreatment conditions, micro-scale structure and enzymatic saccharification of cellulose. The results showed that the tetramethyl guanidine (TMG) based RICs solvent system [TMGH]2+[O2COCH2CH2OCO2]2-/DMSO (XRICs = 0.1, XRICs: the mole fraction of the formed RICs in the mixture) presented the best performance, which was evidenced by 100% glucose yield after the dissolution-regeneration pretreatment strategy under mild conditions (T = 60 °C, Pco2 = 2.0 MPa, t = 2 h). Furthermore, the solvent system have good recyclability and usability.

Synthesis of protected glucose derivatives from levoglucosan by development of common carbohydrate protecting group reactions under continuous flow conditions.

Common carbohydrate protecting group reactions under continuous flow processes are reported in the context of producing partially-protected glucose building blocks from levoglucosan. Benzyl ether protection was demonstrated without the use of NaH using barium oxide, which, however, pointed to the need for forms of this catalyst not as susceptible to close packing under flow. Acylation conditions were developed under continuous flow in acetonitrile and avoiding pyridine. Ring-opening the derivatized levoglucosan with propanethiol was also demonstrated producing S-alkyl 2,4-di-O-benzyl-glucopyranoside building block in 2 rather than 12 steps in increased overall yield.

Glycosyl nitrates in synthesis: streamlined access to glucopyranose building blocks differentiated at C-2.

In an attempt to refine a CAN-mediated synthesis of 1,3,4,6-tetra-O-acetyl-α-d-glucopyranose (2-OH glucose) we unexpectedly discovered that this reaction proceeds via the intermediacy of glycosyl nitrates. Improved mechanistic understanding of this reaction led to the development of a more versatile synthesis of 2-OH glucose from a variety of precursors. Also demonstrated is the conversion of 2-OH glucose into a variety of building blocks differentially protected at C-2, a position that is generally hard to protect regioselectively in the glucopyranose series.

Recent research on the physiological functions, applications, and biotechnological production of D-allose.

D-Allose is a rare monosaccharide, which rarely appears in the natural environment. D-Allose has an 80% sweetness relative to table sugar but is ultra-low calorie and non-toxic and is thus an ideal candidate to take the place of table sugar in food products. It displays unique health benefits and physiological functions in various fields, including food systems, clinical treatment, and the health care fields. However, it is difficult to produce chemically. The biotechnological production of D-allose has become a research hotspot in recent years. Therefore, an overview of recent studies on the physiological functions, applications, and biotechnological production of D-allose is presented. In this review, the physiological functions of D-allose are introduced in detail. In addition, the different types of D-allose-producing enzymes are compared for their enzymatic properties and for the biotechnological production of D-allose. To date, very little information is available on the molecular modification and food-grade expression of D-allose-producing enzymes, representing a very large research space yet to be explored.

Extending the Scope of GTFR Glucosylation Reactions with Tosylated Substrates for Rare Sugars Synthesis.

Functionalized rare sugars were synthesized with 2-, 3-, and 6-tosylated glucose derivatives as acceptor substrates by transglucosylation with sucrose and the glucansucrase GTFR from Streptococcus oralis. The 2- and 3-tosylated glucose derivatives yielded the corresponding 1,6-linked disaccharides (isomaltose analogues), whereas the 6-tosylated glucose derivatives resulted in 1,3-linked disaccharides (nigerose analogue) with high regioselectivity in up to 95 % yield. Docking studies provided insight into the binding mode of the acceptors and suggested two different orientations that were responsible for the change in regioselectivity.

Synthesis and revised stereochemical assignment of C-allyl glucopyranosides and derivatives.

α- and ß-C-allylglucopyranosides and hydroxy-, bromo- and azido-derivatives were prepared through allylation at C-1 of methyl 2,3,4,6-tetra-O-benzyl-D-glucopyranoside or 1-O-acetyl-2,3,4,6-tetra-O-benzyl-D-glucopyranose and subsequent chemical modifications of the alkene on the anomeric arm. However, we picked out some discordance between some recent published studies and our results. After a thorough work of characterization and NMR analysis, we unambiguously confirmed α and ß stereochemistry of the two series of compounds and fully described for the first time ß-C-propyl alcohol, bromide and azide of 2,3,4,6-tetra-O-benzyl-D-glucopyranose.

Syntheses and structure-membrane active antimicrobial activity relationship of alkylamino-modified glucose, maltooligosaccharide, and amylose.

Antimicrobial alkylamine-modified sugars were prepared. Microwave-assisted click reaction efficiently achieved poly-functionalization of oligo- and polysaccharides. The sugars exhibited a unique relationship of their bacterial membrane permeabilization and antimicrobial activity with the number of functional groups and the structure of the molecular scaffold. It shows that the assembly of the functional groups is necessary for being antimicrobial. The amylose derivatives also exhibited synergy to minimize the necessary dose of conventional antibiotics and increase their antimicrobial potency.