- Synthesis of a Macrocyclic Conjugate of the Diterpenoid Isosteviol and Glucuronic Acid
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A macrocyclic conjugate of the natural diterpenoid isosteviol (16-oxo-ent-beyeran-19-oic acid) and glucuronic acid was synthesized for the first time. The conjugate contained two molecules of dihydroisosteviol β-D-glucuronoside joined by 1,8-octanedicarboxylate and 1,8-octanedicarbazoyl spacers.
- Andreeva,Sharipova,Garifullin,Strobykina, I. Yu.,Kataev
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Read Online
- Synthesis and antitubercular activity of first glucuronosyl phosphates and amidophosphates containing polymethylene chains
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Novel phosphorylated glycolipids based on glucuronic acid have been synthesized and shown to inhibit M. Tuberculosis H37Rv in vitro at a minimum inhibitory concentration of 12.5 μg/mL.
- Izmest’ev,Andreeva,Sharipova,Kravchenko,Garifullin,Strobykina, I. Yu.,Kataev,Mironov
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Read Online
- Bile alcohol glucuronides: Regioselective O-glucuronidation of 5β-cholestane-3α,7α,12α,25-tetrol and 24-nor-5β-cholestane-3α,7α,12α,25-tetrol
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A facile and regiocontrolled procedure for the preparation of 5β-cholestane-3α,7α,12α,25-tetrol-3-O-β-D-glucuronide and its corresponding C-26 analogue is described. The method involves direct coupling of bile alcohols, namely, 5β-cholestane-3α,7α,12α,25-tetrol and 24-nor-5β-cholestane-3α,7α,12α,25-tetrol to methyl (tetra-O-acetyl-β-D-glucopyranuronate) in the presence of a Lewis acid, tin(IV) chloride, in dichloromethane. The resulting anomeric pairs of 1,2-trans- and 1,2-cis-glucuronides of tetrols were resolved by analytical and preparative thin-layer chromatography, and their identities were established by high-resolution 1H NMR spectroscopy and by chemical-ionization and fast-atom-bombardment mass spectrometry. The method described has a practical advantage over the traditional two-step synthesis involving bromides as it is more efficient and uses inexpensive and less toxic materials. It is suggested that these compounds will be useful for studying permeability of the blood-brain barrier in cerebrotendinous xanthomatosis (CTX). A facile and regiocontrolled procedure for the preparation of 5β-cholestane-3α, 7α, 12α, 25-tetrol-3-O-β-D-glucuronide and its corresponding C-26 analogue is described. The method involves direct coupling of bile alcohols, namely, 5β-cholestane-3α,7α,12α,25-tetrol and 24-nor-5β-cholestane-3α,7α,12α 25-tetrol to methyl (tetra-O-acetyl-β-D-glucopyranuronate) in the presence of a Lewis acid, tin(IV) chloride, in dichloromethane. The resulting anomeric pairs of 1,2-trans- and 1,2-cis-glucuronides of tetrols were resolved by analytical and preparative thin-layer chromatography, and their identities were established by high-resolution 1H NMR spectroscopy and by chemical-ionization and fast-atom-bombardment mass spectrometry. The method described has a practical advantage over the traditional two-step synthesis involving bromides as it is more efficient and uses inexpensive and less toxic materials. It is suggested that these compounds will be useful for studying permeability of the blood-brain barrier in cerebrotendinous xanthomastosis (CTX).
- Dayal,Salen,Padia,Shefer,Tint,Sasso,Williams
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- Solid state structure of sodium β-1-thiophenyl glucuronate identifies 5-coordinate sodium with three independent glucoronates
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Glucuronic acid is a key component of the glycosaminoglycans (GAGs) Chrondroitin Sulfate (CS), Heparin/Heparan sulfate (HS) and Hyaluronic Acid (HA), as well an important metabolite derivative. In biological systems the carboxylate of uronic acids in GAGs is involved in important H-binding interactions, and the role of metal coordination, such as sodiated systems, has indications associated with a number of biological effects, and physiological GAG-related processes. In synthetic approaches to GAG fragments, thioglycoside intermediates, or derivatives from these, are commonly employed. Of the reported examples of sodium coordination in carbohydrates, 6-coordinate systems are usually observed often with water ligands involved, Herein we report an unexpected 5-coordinate sodiated GlcA crystal structure of the parent GlcA, but as a thioglycoside derivative, whose crystal coordination differs from previous examples, with no involvement of water as a ligand and containing a distorted trigonal bypramidal sodium with each GlcA having five of 6 oxygens sodium-coordinated.
- Alharthi, Fahad Ayesh,Whitehead, George F.S.,Vitórica-Yrezábal, I?igo J.,Gardiner, John M.
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- Design, synthesis and biological evaluation of carbohydrate-based sulphonamide derivatives as topical antiglaucoma agents through selective inhibition of carbonic anhydrase II
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A series of new carbohydrate-based sulphonamide derivatives were designed, synthesised by employing the so-call ‘sugar-tail’ approach. The compounds were evaluated in vitro against a panel of CAs. Compared to their parent compound p-sulfamoylbenzoic acid, these compounds showed nearly 100-fold improvement in their binding affinities against hCA II in vitro. All of compounds showed great water solubility and the pH value of their water solutions of compounds is 7.0. Such properties are advantageous to make them much less irritating to the eye when applied topical glaucomatous drugs, compared to the relatively highly acidic dorzolamide preparations (pH 5.5). Notably, compounds 7d, 7 g, 7 h demonstrated to topically lower intraocular pressure (IOP) in glaucomatous animals better than brinzolamide when applied as a 1% solution directly into the eye. Low cytotoxicity on human cornea epithelial cell was observed in the tested concentrations by the MTT assay.
- Fan, Zhanfang,Guo, Chun,Hou, Zhuang,Li, Chuanchao,Lin, Bin,Liu, Yang,Liu, Yichuang,Wang, Yitong,Zhang, Miao
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p. 383 - 390
(2019/12/30)
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- Potent and Prolonged Innate Immune Activation by Enzyme-Responsive Imidazoquinoline TLR7/8 Agonist Prodrug Vesicles
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Synthetic immune-stimulatory drugs such as agonists of the Toll-like receptors (TLR) 7/8 are potent activators of antigen-presenting cells (APCs), however, they also induce severe side effects due to leakage from the site of injection into systemic circulation. Here, we report on the design and synthesis of an amphiphilic polymer-prodrug conjugate of an imidazoquinoline TLR7/8 agonist that in aqueous medium forms vesicular structures of 200 nm. The conjugate contains an endosomal enzyme-responsive linker enabling degradation of the vesicles and release of the TLR7/8 agonist in native form after endocytosis, which results in high in vitro TLR agonist activity. In a mouse model, locally administered vesicles provoke significantly more potent and long-lasting immune stimulation in terms of interferon expression at the injection site and in draining lymphoid tissue compared to a nonamphiphilic control and the native TLR agonist. Moreover, the vesicles induce robust activation of dendritic cells in the draining lymph node in vivo.
- Wang, Bi,Van Herck, Simon,Chen, Yong,Bai, Xiangyang,Zhong, Zifu,Deswarte, Kim,Lambrecht, Bart N.,Sanders, Niek N.,Lienenklaus, Stefan,Scheeren, Hans W.,David, Sunil A.,Kiessling, Fabian,Lammers, Twan,De Geest, Bruno G.,Shi, Yang
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supporting information
p. 12133 - 12139
(2020/08/06)
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- Efficient Synthesis of Muramic and Glucuronic Acid Glycodendrimers as Dengue Virus Antagonists
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Carbohydrates are involved in many important pathological processes, such as bacterial and viral infections, by means of carbohydrate-protein interactions. Glycoconjugates with multiple carbohydrates are involved in multivalent interactions, thus increasing their binding strengths to proteins. In this work, we report the efficient synthesis of novel muramic and glucuronic acid glycodendrimers as potential Dengue virus antagonists. Aromatic scaffolds functionalized with a terminal ethynyl groups were coupled to muramic and glucuronic acid azides by click chemistry through optimized synthetic strategies to afford the desired glycodendrimers with high yields. Surface Plasmon Resonance studies have demonstrated that the compounds reported bind efficiently to the Dengue virus envelope protein. Molecular modelling studies were carried out to simulate and explain the binding observed. These studies confirm that efficient chemical synthesis of glycodendrimers can be brought about easily offering a versatile strategy to find new active compounds against Dengue virus.
- García-Oliva, Cecilia,Cabanillas, Alfredo H.,Perona, Almudena,Hoyos, Pilar,Rumbero, ángel,Hernáiz, María J.
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supporting information
p. 1588 - 1596
(2020/02/05)
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- Mirabegron metabolite synthesis method
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The invention discloses a mirabegron metabolite synthesis method and belongs to the field of drug metabolism. The mirabegron metabolite synthesis method can prepare a mirabegron metabolite from glucurolactone (1R)-2-2[2-(4-nitrophenyl)ethylamino]-1-phenylethanol as starting materials through eight-step reaction. The mirabegron metabolite synthesis method has the advantages that the synthesis method is reasonable in process design and strong in operability on the basis of optimal preparation steps and reaction conditions screened by a great number of experiments; the synthesis method is high inyield and can reach high chemical purity above 99% and therefore can be applied to industrial production of mirabegron metabolite; the mirabegron metabolite can provide a standard substance for metabolic mechanism research of the mirabegron drug, can be used for exploring the metabolic process of the drugs in vivo, and has high application research value in clinical pharmacokinetic study.
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Paragraph 0010; 0011; 0012; 0013; 0014
(2019/07/04)
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- Extended scaffold glucuronides: En route to the universal synthesis of O -aryl glucuronide prodrugs
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We demonstrate that an extended scaffold based on a self-immolative linker (SIL) enables the universal production of O-aryl glucuronide prodrugs: high yield glucuronidation is performed on a precursor substrate (SIL) and the subsequent drug conjugation proceeds via less challenging chemical reactions.
- Walther, Raoul,Jarlstad Olesen, Morten T.,Zelikin, Alexander N.
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supporting information
p. 6970 - 6974
(2019/08/01)
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- GLUCOSYRINGIC ACID ANALOGS AS SWEETNESS PROFILE MODIFIERS
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The present disclosure provides novel sweetener compositions comprising a compound having a structure according to Formula I: wherein R1, R2, R3, and R4 are described herein. Also provided are methods of modulating sweetness profile of a product by adding a compound of Formula I to the product, such as a beverage product or a food product. For example, the compound described herein can be added to increase the overall sweetness of a nutritive sweetener sweetened beverages; decrease the sweetness time-of-onset for high potency sweeteners such as rebaudioside A; decreasing bitter, metallic and licorice off-notes of high potency sweeteners; and improve the sweet quality of sweetened products.
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Paragraph 0246-0247
(2018/04/02)
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- Syntheses and anti-cancer activity of CO-releasing molecules with targeting galactose receptors
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CO-releasing molecules (CORMs) containing cobalt have many bioactivities, but most of them do not dissolve in water and have no selectivity to tissue and organs. On the basis of the specific recognition of galactose or sialic acid by a receptor, a series of CORMs based on carbohydrates were synthesized and evaluated. The test results show that all the complexes displayed anticancer activity. Among them, the effects of the complexes of galactose (1), GalNAc (8) and sialic acid (10) were very distinct. Complex 1 displayed higher activity against HeLa, HePG2, MCF-7 and HT-29 cell proliferation than cis-platin (DDP), and its selectivity was far much better than DDP compared with normal cell W138. Furthermore, the uptakes of complexes 1, 8 and 10 by HePG2, HT-29, A549 and RAW264.7 cell lines were studied. The uptake ratio of each cell line for complex 1 was different, and the order of uptake ratio in the four cell lines was HePG2 > HT-29 > RAW264.7 > A549. The HePG2 cells absorbed complex 1 beyond 60% after incubation for 8 h, while A549 absorbed only 27.8%. For complex 8, the uptake trend was similar to that of complex 1 with it being absorbed by all the four cancer cells, but the uptake rate was lower. However, differently, complex 10 was absorbed heavily by macrophage RAW264.7, followed by HePG2; after 8 h incubation, the uptake ratio of RAW264.7 was over 50%. In addition, the mechanism of action was explored, and the results showed that the complexes inhibited cell cycle arrest at the G2/M phase; complex 1 up-regulated the expression levels of caspase-3 and Bax, and down-regulated the Bcl-2 expression, giving rise to HePG2 cell apoptosis.
- Li, Jili,Zhang, Jinlong,Zhang, Qiuping,Bai, Zhongjie,Zhao, Quanyi,He, Dian,Wang, Zhen,Chen, Yonglin,Liu, Bin
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p. 8115 - 8129
(2018/11/23)
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- Indole-glucoside substrate and preparation method and application thereof in detection of aerobe vaginitis (AV)
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The invention discloses a glycosyl donor synthetic process, aiming to overcome defects in detection of aerobe vaginitis (AV) by the prior art. Glycosyl donor is connected with chromogen indole to generate glucosides, and an indole-glucoside substrate with good effect, high flexibility, high stability and high specificity is then synthetized. According to inspection standards, as a comparison result between the color rendering property of the synthetized substrate and that of conventional AV detection reagents, the color rendering property of the substrate is superior to that of a Chromagar AVdetection reagent. With innovation of the glycosyl donor synthetic process and the synthetic process of gluocosides by connection for synthesis of the indole-glucoside chromogenic substrate, innovation of extraction and purification and application verification, reaction yield of each stage of products is increased greatly, the products are white nearly, influence from color of the substrate to identification process is reduced, and flexibility and accuracy of AV detection are both improved greatly.
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Paragraph 0016
(2018/09/11)
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- A combinatorial approach towards the synthesis of non-hydrolysable triazole-iduronic acid hybrid inhibitors of human α-l-iduronidase: Discovery of enzyme stabilizers for the potential treatment of MPSI
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Preparation of substituent-diverse, triazole-iduronic acid hybrid molecules by click reaction of an azido iduronic acid derivative with randomly chosen alkynes is described. Library members were screened for their ability to inhibit α-l-iduronidase, and hit molecules and analogues were then investigated for their ability to stabilize rh-α-IDUA in a thermal denaturation study. This work resulted in the discovery of the first small molecules that can be used to stabilize exogenous rh-α-IDUA protein in vitro.
- Cheng, Wei-Chieh,Lin, Cheng-Kun,Li, Huang-Yi,Chang, Yu-Chien,Lu, Sheng-Jhih,Chen, Yu-Shin,Chang, Shih-Ying
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supporting information
p. 2647 - 2650
(2018/03/21)
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- Preparation method of substituted benzyl or substituted phenyl beta-D-hexuronic acid glucoside
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The invention relates to the technical field of pharmaceutical and chemical industries, and discloses a preparation method of substituted benzyl or substituted phenyl beta-D-hexuronic acid glucoside.The preparation method comprises the steps of taking hexuronic acid as a raw material, and performing acetylation, selective acyl removal, methyl esterification, bromization, aethrization and alkalinealcoholysis to form substituted benzyl or substituted phenyl beta-hexuronic acid glucoside with a structural formula as follows as shown in the description, wherein n is equal to 0-1; and R is o-, m-or para-hydrogen, nitryl, methoxy or halogen. The method is mild in reaction condition, simple in step and suitable for large-scale preparation, and a reaction reagent is easy to obtain.
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- Combatting implant-associated biofilms through localized drug synthesis
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Bacterial contamination of implantable biomaterials is a significant socioeconomic and healthcare burden. Indeed, bacterial colonization of implants after surgery has a high rate of incidence whereas concurrent prophylaxis using systemic antibiotics has limited clinical success. In this work, we develop enzyme-prodrug therapy (EPT) to prevent and to treat bacteria at interfaces. Towards the overall goal, novel prodrugs for fluoroquinolone antibiotics were developed on a privileged glucuronide scaffold. Whereas carbamoyl prodrugs were not stable and not suitable for EPT, glucuronides containing self-immolative linker between glucuronic acid masking group and the antibiotic were stable in solution and readily underwent bioconversion in the presence of β-glucuronidase. Surface coatings for model biomaterials were engineered using sequential polymer deposition technique. Resulting coatings afforded fast prodrug conversion and mediated antibacterial measures against planktonic species as evidenced by pronounced zone of bacterial growth inhibition around the biomaterial surface. These biomaterials coupled with the glucuronide prodrugs also effectively combatted bacteria within established biofilms and also successfully prevented bacterial colonization of the surface. To our knowledge, this is the first report of EPT engineered to the surface of biomaterials to mediate antibacterial measures.
- Walther, Raoul,Nielsen, Signe Maria,Christiansen, Rikke,Meyer, Rikke L.,Zelikin, Alexander N.
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- Substrate for detecting beta-D-glucuronidase and preparation method thereof as well as kit
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The invention discloses a substrate for detecting beta-D-glucuronidase. The substrate is specifically thymolphthalein-alpha-D-glucuronic acid. A preparation method comprises the following steps: preparing thymolphthalein-alpha-D-methyl glucuronate through reaction of thymolphthalein and acetyl bromide-alpha-D-methyl gluconate, removing acetyl to obtain the thymolphthalein-alpha-D-methyl gluconate,and then performing hydrolysis reaction, so as to obtain the thymolphthalein-alpha-D-glucuronic acid. As the substrate for detecting the beta-D-glucuronidase, the thymolphthalein-alpha-D-glucuronic acid disclosed by the invention has the advantages of stable property, difficulty in deterioration and sensitivity to development; furthermore, a synthesis process is simple, and the cost can be obviously reduced.
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Paragraph 0026-0028
(2018/07/06)
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- A Mechanism-Based Approach to Screening Metagenomic Libraries for Discovery of Unconventional Glycosidases
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Functional metagenomics has opened new opportunities for enzyme discovery. To exploit the full potential of this new tool, the design of selective screens is essential, especially when searching for rare enzymes. To identify novel glycosidases that employ cleavage strategies other than the conventional Koshland mechanisms, a suitable screen was needed. Focusing on the unsaturated glucuronidases (UGLs), it was found that use of simple aryl glycoside substrates did not allow sufficient discrimination against β-glucuronidases, which are widespread in bacteria. While conventional glycosidases cannot generally hydrolyze thioglycosides efficiently, UGLs follow a distinct mechanism that allows them to do so. Thus, fluorogenic thioglycoside substrates featuring thiol-based self-immolative linkers were synthesized and assessed as selective substrates. The generality of the approach was validated with another family of unconventional glycosidases, the GH4 enzymes. Finally, the utility of these substrates was tested by screening a small metagenomic library.
- Nasseri, Seyed Amirhossein,Betschart, Leo,Opaleva, Daria,Rahfeld, Peter,Withers, Stephen G.
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supporting information
p. 11359 - 11364
(2018/08/28)
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- Design, synthesis and in vitro evaluation of β-glucuronidase-sensitive prodrug of 5-aminolevulinic acid for photodiagnosis of breast cancer cells
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Treatment of cancer cells by clinically approved hexyl ester of 5-aminolevulinic acid (ALA-Hex) induces accumulation of fluorescent porphyrins in tumors. This allows fluorescence photodiagnosis (PD) of bladder cancer by blue light illumination. However, PD of other cancers is hampered by acute toxicity of the compound limiting its use to local applications. We have designed and synthesized a new prodrug of ALA-Hex that tackles the stability-activity paradox of amino-modified 5-ALA prodrugs. The glucuronide prodrug Glu-ALA-Hex demonstrates excellent stability under physiological conditions and activation in the presence of the target enzyme. β-glucuronidase-triggered release of 5-ALA is programmed to yield fluorescence in tumor environment with elevated β-glucuronidase activity, a characteristic of many solid tumors. Glu-ALA-Hex produces similar levels of fluorescence as ALA-Hex in breast cancer MCF7 cells in vitro but with much lower non-specific cell toxicity.
- Herceg,Adriouach,Janikowska,Allémann,Lange,Babi?
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p. 372 - 380
(2018/04/10)
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- COMPOSITIONS AND METHODS RELATED TO ANTI-CD19 ANTIBODY DRUG CONJUGATES
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In some aspects, the invention relates to an antibody-drug conjugate, comprising an anti-CD 19 antibody; a linker; and an active agent. The antibody-drug conjugate may comprise a self-immolative group. The linker may comprise an O-substituted oxime, e.g., wherein the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the active agent; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the antibody.
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Page/Page column 27; 28
(2017/04/11)
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- COMPOSITIONS AND METHODS RELATED TO ANTI-EGFR ANTIBODY DRUG CONJUGATES
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In some aspects, the invention relates to an antibody-drug conjugate, comprising an anti-epidermal growth factor receptor ("EGFR") antibody; a linker; and an active agent. The antibody-drug conjugate may comprise a self-immolative group. The linker may comprise an O-substituted oxime, e.g., wherein the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the drug; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the antibody.
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Page/Page column 27; 28
(2017/04/11)
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- A mechanistic study of the non-oxidative decarboxylation catalyzed by the radical S-adenosyl-l-methionine enzyme BlsE involved in blasticidin S biosynthesis
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Decarboxylation is a fundamentally important reaction in biology and involves highly diverse mechanisms. Here we report a mechanistic study of the non-oxidative decarboxylation catalyzed by BlsE, a radical S-adenosyl-l-methionine (SAM) enzyme involved in blasticidin S biosynthesis. Through a series of biochemical analysis with isotopically labeled reagents, we show that the BlsE-catalyzed reaction is initiated by the 5′-deoxyadenosyl (dAdo) radical-mediated hydrogen abstraction from a sugar carbon of the substrate cytosylglucuronic acid (CGA), and does not involve a carboxyl radical as has been proposed for 4-hydroxyphenylacetate decarboxylase (HPAD). Our study reveals that BlsE represents a mechanistically new type of radical-based decarboxylase.
- Liu, Lei,Ji, Xinjian,Li, Yongzhen,Ji, Wenjuan,Mo, Tianlu,Ding, Wei,Zhang, Qi
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supporting information
p. 8952 - 8955
(2017/08/15)
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- Synthesis and Antitubercular, Antimicrobial, and Hemolytic Activity of Methyl D-Glucopyranuronate and Its Simplest Derivatives
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Methyl glucuronate and some of its simplest derivatives have been synthesized, and their antitubercular, antimicrobial, and hemolytic activities have been studied. The simplest derivatives of glucuronic acid have been shown for the first time to exhibit a high antitubercular activity which is comparable with the activity of isoniazid.
- Belenok,Andreeva,Garifullin,Strobykina,Kravchenko,Voloshina,Kataev
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p. 2816 - 2825
(2018/02/21)
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- CONJUGATES COMPRISING SELF-IMMOLATIVE GROUPS AND METHODS RELATED THERETO
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In some aspects, the invention relates to an antibody-drug conjugate, comprising an antibody; a linker; and an active agent. The antibody-drug conjugate may comprise a self- immolative group. The linker may comprise an O-substituted oxime, e.g., wherein the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the active agent; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the antibody.
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Page/Page column 172; 173
(2017/06/27)
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- CONJUGATES COMPRISING PEPTIDE GROUPS AND METHODS RELATED THERETO
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In some aspects, the invention relates to an antibody-drug conjugate, comprising an antibody; a linker; and at least two active agents. In preferred embodiments, the linker comprises a peptide sequence of a plurality of amino acids, and at least two of the active agents are covalently coupled to side chains of the amino acids. The antibody-drug conjugate may comprise a self-immolative group, preferably two-self-immolative groups. The linker may comprise an O-substituted oxime, e.g., wherein the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the active agent; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the antibody.
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Page/Page column 182
(2017/08/08)
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- Synthesis and Antimicrobial Activity of Glucuronosyl Derivatives of Steviolbioside from Stevia rebaudiana
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Glucuronosyl derivatives of the glycoside steviolbioside from Stevia rebaudiana were synthesized for the first time. Steviolbioside exhibited selective bacteriostatic and bactericidal activity against S. aureus ATCC 209p with minimum inhibitory concentration (MIC) of 62.5 μg/mL, which corresponded to the activity of the antibiotic chloramphenicol.
- Sharipova,Andreeva,Strobykina, I. Yu.,Voloshina,Strobykina,Kataev
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p. 1107 - 1111
(2017/11/27)
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- Synthesis and evaluation of a series of 6-chloro-4-methylumbelliferyl glycosides as fluorogenic reagents for screening metagenomic libraries for glycosidase activity
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Screening of large enzyme libraries such as those derived from metagenomic sources requires sensitive substrates. Fluorogenic glycosides typically offer the best sensitivity but typically must be used in a stopped format to generate good signal. Use of fluorescent phenols of pKa 7, such as halogenated coumarins, allows direct screening at neutral pH. The synthesis and characterisation of a set of nine different glycosides of 6-chloro-4-methylumbelliferone are described. The use of these substrates in a pooled format for screening of expressed metagenomic libraries yielded a "hit rate" of 1 in 60. Hits were then readily deconvoluted with the individual substrates in a single plate to identify specific activities within each clone. The use of such a collection of substrates greatly accelerates the screening process.
- Chen, Hong-Ming,Armstrong, Zachary,Hallam, Steven J.,Withers, Stephen G.
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- Synthesis and positive inotropic activity evaluation of liguzinediol metabolites
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2,5-Dihydroxymethyl-3,6-dimethylpyrazine (liguzinediol) has been recently discovered as a potential agent for treatment of heart failure with low safety risk. In the present study, four main metabolites of liguzinediol were synthesized and their positive inotropic activities were evaluated. Synthetic compounds were identical with the isolated metabolites of liguzinediol. Pharmacological examinations showed that the four major metabolites were not observed positive inotropic activity, and revealed that the positive inotropic activity of liguzinediol was essentially attributed to the parent agent.
- Zhu, Hao-Hao,Chen, Yu-Qing,Cheng, Dong,Li, Wei,Wang, Tian-Lin,Wen, Hong-Mei,Chen, Long,Liu, Jian
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supporting information
p. 882 - 884
(2016/05/24)
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- N-4-phenylsulphonamides yl-N ' - 1-deoxy-β-D-pyran glucose aldehyde acid radical -thiourea compound preparation method and medical use
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The invention discloses a preparation method of novel N-4-benzenesulfonamido-N'-1-deoxy-beta-D-pyran glucuronyl-thiourea compounds which have the effect of inhibiting carbonic anhydrase activity so as to realize the anti-tumor metastasis and invasion effect and have structures shown as formulae (I) and (II). The compounds structurally have three active segments: sulfanilamide, substituted glucuronic acid and thiourea, and can respectively form coordinate bonds and hydrogen bonds with Zn ions and residues of aspartic acid in carbonic anhydrase so as to realize the catalytic activity of an inhibitory enzyme and exert the anti-tumor metastasis and invasion effect. The compounds have a potential application as anti-tumor medicines. R, X and M in the formulae (I) and (II) provided by the invention are defined in the specification.
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Paragraph 0032; 0033
(2017/01/12)
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- The stereoselectivities of tributyltin hydride-mediated reductions of 5-bromo-d-glucuronides to l-iduronides are dependent on the anomeric substituent: Syntheses and DFT calculations
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One of the shortest synthetic routes to l-iduronic acid derivatives is via free radical reduction of the C-5 bromide of the corresponding protected d-glucuronic acid derivative. The epimerization of such C-5 bromides to the l-ido derivatives via reaction with tributyltin hydride was investigated. It was found that the stereoselectivity of the reaction was dependent on the anomeric substituent. If the substituent was fluoride the l-ido product was obtained exclusively in 65-72% yield whereas the O-methyl or O-acetyl derivatives led to isomeric mixtures of both the l-ido and d-gluco products in different ratios depending on the reaction conditions. DFT calculations were performed to determine the stereoelectronic factors that favour formation of the l-ido isomer from the fluoride and suggest the selectivity is due to a transition state gauche effect and an Sn-F interaction.
- Mohamed, Shifaza,Krenske, Elizabeth H.,Ferro, Vito
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p. 2950 - 2960
(2016/03/12)
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- COMPOUNDS COMPRISING SELF-IMMOLATIVE GROUP
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Provided are compounds comprising a self-immolative group, and the compounds comprising a self-immolative group according to the present invention may include a protein (for example, an oligopeptide, a polypeptide, an antibody, or the like) having substrate-specificity for a target and an active agent (for example, a drug, a toxin, a ligand, a detection probe, or the like) having a specific function or activity.
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Paragraph 0199; 0200
(2016/08/03)
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- Methyl tetra-O-acetyl-α-D-glucopyranuronate: crystal structure and influence on the crystallisation of the β anomer
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Methyl tetra-O-acetyl-β-D-glucopyranuronate (1) and methyl tetra-O-acetyl-α-D-glucopyranuronate (3) were isolated as crystalline solids and their crystal structures were obtained. That of the β anomer (1) was the same as that reported by Root et?al., while anomer (3) was found to crystallise in the orthorhombic space group P212121with two independent molecules in the asymmetric unit. No other crystal forms were found for either compound upon recrystallisation from a range of solvents. The α anomer (3) was found to be an impurity in initially precipitated batches of β-anomer (1) in quantities a crystallographic direction in the absence of the α impurity, while the presence of the α anomer (3) enhanced this elongation.
- Hayes, John A.,Eccles, Kevin S.,Lawrence, Simon E.,Moynihan, Humphrey A.
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- A NEW QUINOLINE DERIVATIVE FOR USE IN THE TREATMENT AND PREVENTION OF VIRAL INFECTIONS
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The present invention relates to a quinoline derivative of formula (1) or one of its pharmaceutically acceptable salts. The present invention further relates to said quinoline derivative for medicament and for use in the treatment or prevention of a viral or retroviral infection and in particular AIDS or an AIDS-related condition or Human Immunodeficiency virus (HIV). The present invention also relates to a pharmaceutical composition comprising said quinoline derivative and to the process for preparing it as to a novel intermediate compound.
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Page/Page column 23; 24
(2016/09/26)
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- 5-ALA DERIVATIVES AND USE THEREOF
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The present invention is directed to new 5-ALA derivatives, particles and formulation thereof, related methods of preparation and methods of use thereof. In particular, the invention relates to compounds of the invention, particles and formulation thereof useful in the treatment of a cancer and/or the diagnosis of a cancer cell such as in photodynamic therapy or photodynamic diagnosis.
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Page/Page column 66
(2016/12/07)
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- METHODS FOR MAKING BIOCOMPATIBLE POLYMERIZABLE ACRYLATE PRODUCTS
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Sugar-acrylic monomers are synthesized to have a carbohydrate moiety linked to an acrylate group. The sugar-acrylic monomers may be polymerized to form polymers, adhesives, hydrogels, and the like. The sugar-acrylic monomers and polymers may be used in tissue engineering, adhesives and sealers, wound healing, and the like.
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Paragraph 0103
(2015/02/18)
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- Development of synthetic approaches to macrocyclic glycoterpenoids on the basis of glucuronic acid and diterpenoid isosteviol
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An approach has been developed to the synthesis of macrocyclic glycoterpenoids containing diterpenoid isosteviol and glucuronic acid fragments. Selective screening revealed compounds exhibiting antitubercular activity against H37RV, M. Avium, and M. Terrae strains at a level comparable to the known antitubercular drugs isoniazid, ofloxacin, and pyrazinamide. The compound possessing the highest antitubercular activity is non-cytotoxic toward human erythrocytes.
- Andreeva,Sharipova,Strobykina, I. Yu.,Kravchenko,Strobykina,Voloshina,Musin,Kataeva
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p. 1324 - 1333
(2015/11/09)
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- Selective and Sensitive Sensing of Free Bilirubin in Human Serum Using Water-Soluble Polyfluorene as Fluorescent Probe
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The adherence of serum protein on conjugated polymer is a major bottleneck in the application of the latter for selective sensing of small biomolecules in blood serum. In this report, we present new polyfluorenes with d-glucuronic acid appendage that is a nonreceptor for any serum protein, thereby providing a platform for selective sensing of free bilirubin in the clinically relevant range of 50 μmol/L in human blood serum. The appended d-glucuronic acid formed noncovalent interactions with bilirubin, which in conjunction with favorable spectral overlap between the polymers and bilirubin facilitated efficient FRET process in aqueous solutions. Addition of bilirubin resulted in the quenching of the polyfluorene emission with simultaneous appearance of bilirubin emission exhibiting visual emission color change from blue to light green. The polymer remained stable in serum even under severe basic conditions and exhibited high selectivity with visual sensitivity only toward free bilirubin in human serum in the presence of crucial interferences such as hemoglobin, proteins, biliverdin, glucose, cholesterol, and metal ions. Nanomolar sensing of bilirubin could also be demonstrated successfully using one of the d-glucuronic acid appended polymer (PF-Ph-GlcA), which could sense ～150 nm of bilirubin in human serum. The combined role of energy transfer and noncovalent interaction highlights the potential of the new polymer design for highly selective sensing activity in complex biofluids.
- Senthilkumar,Asha
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p. 3449 - 3461
(2015/06/22)
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- CHEMOENZYMATIC SYNTHESIS OF HEPARIN AND HEPARAN SULFATE ANALOGS
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The present invention provides a one-pot multi-enzyme method for preparing UDP-sugars from simple sugar starting materials. The invention also provides a one-pot multi-enzyme method for preparing oligosaccharides from simple sugar starting materials.
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Paragraph 0343; 0344; 0345; 0346
(2014/09/03)
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- Improved and large-scale synthesis of different protected d-glucuronals
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Although different protected d-glucuronals are used as precursors for the preparation of many compounds, standard procedures and large-scale syntheses are still not described in the literature. In the course of the development of different protected d-glucuronyl donors we developed several versatile methods that can be used for fast and reproducible preparation of large amounts of the key intermediates. d-Glucuronolactone was converted to methyl 3,4-di-O-acetyl-d-glucuronal applying a novel one-pot protocol, which allowed for large-scale synthesis. Introduction of silyl and benzyl groups was achieved using optimized procedures. Furthermore 3,4,6-tri-O-acetyl-d-glucal was used as starting material for an improved preparation of benzyl protected d-glucuronal, which significantly accelerates and simplifies similar methods described in the literature.
- Mikula, Hannes,Matscheko, Dominik,Schwarz, Markus,Hametner, Christian,Fr?hlich, Johannes
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- Tailored design and synthesis of heparan sulfate oligosaccharide analogues using sequential one-pot multienzyme systems
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Heparan sulfate analogues: Highly efficient one-pot multienzyme (OPME) chemoenzymatic systems for the activation and transfer of N-acetylglucosamine (GlcNAc) and glucuronic acid (GlcA) have been developed. They were applied to the sequential tailored synt
- Chen, Yi,Li, Yanhong,Yu, Hai,Sugiarto, Go,Thon, Vireak,Hwang, Joel,Ding, Li,Hie, Liana,Chen, Xi
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supporting information
p. 11852 - 11856
(2013/11/19)
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- An activity-based near-infrared glucuronide trapping probe for imaging β-glucuronidase expression in deep tissues
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β-glucuronidase is an attractive reporter and prodrug-converting enzyme. The development of near-IR (NIR) probes for imaging of β-glucuronidase activity would be ideal to allow estimation of reporter expression and for personalized glucuronide prodrug cancer therapy in preclinical studies. However, NIR glucuronide probes are not yet available. In this work, we developed two fluorescent probes for detection of β-glucuronidase activity, one for the NIR range (containing IR-820 dye) and the other for the visible range [containing fluorescein isothiocyanate (FITC)], by utilizing a difluoromethylphenol-glucuronide moiety (TrapG) to trap the fluorochromes in the vicinity of the active enzyme. β-glucuronidase- mediated hydrolysis of the glucuronyl bond of TrapG generates a highly reactive alkylating group that facilitates the attachment of the fluorochrome to nucleophilic moieties located near β-glucuronidase-expressing sites. FITC-TrapG was selectively trapped on purified β-glucuronidase or β-glucuronidase-expressing CT26 cells (CT26/mβG) but not on bovine serum albumin or non-β-glucuronidase-expressing CT26 cells used as controls. β-glucuronidase-activated FITC-TrapG did not interfere with β-glucuronidase activity and could label bystander proteins near β-glucuronidase. Both FITC-TrapG and NIR-TrapG specifically imaged subcutaneous CT26/mβG tumors, but only NIR-TrapG could image CT26/mβG tumors transplanted deep in the liver. Thus NIR-TrapG may provide a valuable tool for visualizing β-glucuronidase activity in vivo.
- Cheng, Ta-Chun,Roffler, Steve R.,Tzou, Shey-Cherng,Chuang, Kuo-Hsiang,Su, Yu-Cheng,Chuang, Chih-Hung,Kao, Chien-Han,Chen, Chien-Shu,Harn, I-Hong,Liu, Kuan-Yi,Cheng, Tian-Lu,Leu, Yu-Ling
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supporting information; experimental part
p. 3103 - 3110
(2012/04/10)
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- Koenigs-Knorr reaction of fusel alcohols with methyl (1-bromo-2,3,4-tri-O- acetyl-α-d-glucopyranosid)uronate leading to the protected alkyl glucuronides - Crystal structures and high resolution 1H and 13C NMR data
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Crystal structures and high resolution 1H and 13C NMR spectral data for methyl (alkyl 2,3,4-tri-O-acetyl-β-d-glucopyranosid) uronates (alkyl = methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, n-pentyl, 2-methyl-1-butyl and 3-methyl-1-butyl) are presented.
- M?nch, Bettina,Gebert, Antje,Emmerling, Franziska,Becker, Roland,Nehls, Irene
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scheme or table
p. 186 - 190
(2012/05/04)
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- Self-assembling properties of all γ-cyclic peptides containing sugar amino acid residues
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In this study, a novel dimer-forming cyclic peptide composed exclusively by cyclic γ-amino acids with a saccharide-like outer surface is described. The antiparallel β-sheet type hydrogen bonding interactions responsible for the large association constant in non-polar solvents constitute a suitable model for a novel class of self-assembling peptide nanotubes.
- Guerra, Arcadio,Brea, Roberto J.,Amorín, Manuel,Castedo, Luis,Granja, Juan R.
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p. 8762 - 8766
(2013/01/15)
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- Glycoside cleavage by a new mechanism in unsaturated glucuronyl hydrolases
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Unsaturated glucuronyl hydrolases (UGLs) from GH family 88 of the CAZy classification system cleave a terminal unsaturated sugar from the oligosaccharide products released by extracellular bacterial polysaccharide lyases. This pathway, which is involved in extracellular bacterial infection, has no equivalent in mammals. A novel mechanism for UGL has previously been proposed in which the enzyme catalyzes hydration of a vinyl ether group in the substrate, with subsequent rearrangements resulting in glycosidic bond cleavage. However, clear evidence for this mechanism has been lacking. In this study, analysis of the products of UGL-catalyzed reactions in water, deuterium oxide, and dilute methanol in water, in conjunction with the demonstration that UGL rapidly cleaves thioglycosides and glycosides of inverted anomeric configuration (substrates that are resistant to hydrolysis by classical glycosidases), provides strong support for this new mechanism. A hydration-initiated process is further supported by the observed UGL-catalyzed hydration of a C-glycoside substrate analogue. Finally, the observation of a small β-secondary kinetic isotope effect suggests a transition state with oxocarbenium ion character, in which the hydrogen at carbon 4 adopts an axial geometry. Taken together, these observations validate the novel vinyl ether hydration mechanism and are inconsistent with either inverting or retaining direct hydrolase mechanisms at carbon 1.
- Jongkees, Seino A. K.,Withers, Stephen G.
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supporting information; experimental part
p. 19334 - 19337
(2012/01/31)
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- THE TUMOR-SELECTIVE ANTI-CANCER PRODRUG BQC-G
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The invention relates to the synthesis of a second-generation camptothecin glucuronide prodrug (BQC-G) of a potent anticancer camptothecin derivative 5,6- dihydro-4H-benzo[de]quinoline-camptothecin (BQC). BQC-G was over 4000 times more water soluble than BQC, displayed good stability in human plasma and was an excellent substrate for enzymatic hydrolysis by bacterial and human β-glucuronidases. BQC-G was about 30 times less toxic than BQC, but was as toxic as BQC after hydrolysis of the glucuronide moiety by β-glucuronidase. In the presence of human serum albumin, BQC-G displayed lower cytotoxicity (IC50 = 1080 nM) but could be activated by β-glucuronidase to display potent activity (IC50 = 13.3 nM).
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Page/Page column 23
(2011/06/23)
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- First synthesis and full characterization of mexiletine N-carbonyloxy β-d-glucuronide
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A simple, convergent synthesis of the N-carbonyloxy β-d-glucuronide of mexiletine (sodium salt) in moderate yield is described. The compound is now available as an authentic reference standard for analytical studies, enabling more detailed investigation on the metabolism of mexiletine.
- Cavalluzzi, Maria Maddalena,Lentini, Giovanni,Lovece, Angelo,Bruno, Claudio,Catalano, Alessia,Carocci, Alessia,Franchini, Carlo
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scheme or table
p. 5265 - 5268
(2010/11/03)
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- SnCl4- and TiCl4-catalyzed anomerization of acylated O - And S -glycosides: Analysis of factors that lead to higher α: β d reaction rates
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The quantification of factors that influence both rates and stereoselectivity of anomerization reactions catalyzed by SnCl4 and TiCl4 and how this has informed the synthesis of α-O- and α-S-glycolipids is discussed. The SnCl4-catalyzed anomerization reactions of β-S- and β-O-glycosides of 18 substrates followed first order equilibrium kinetics and kf + kr values were obtained, where kf is the rate constant for the forward reaction (β → α) and kr is the rate constant for the reverse reaction (α → β). Comparison of the kf + k r values showed that reactions of glucuronic acid or galacturonic acid derivatives were ～10 to 3000 times faster than those of related glucoside and galactopyranoside counterparts and α:β ratios were generally also higher. Stereoelectronic effects contributed from galacto-configured compounds were up to 2-fold faster than those of corresponding glucosides. The introduction of groups, including protecting groups, which are increasingly electron releasing generally led to rate enhancements. The anomerization of S-glycosides was consistently faster than that of corresponding O-glycosides. Reactions were generally faster for reactions with TiCl4 than those with SnCl4. Anomeric ratios depended on the Lewis acid, the number equivalents of the Lewis acid, temperature, and substrate. Very high ratios of α-products for both O- and S-glucuronides were observed for reactions promoted by TiCl4; for these substrates TiCl4 was superior to SnCl4. Anomeric ratios from anomerization of S-glucosides were higher with SnCl4 than with TiCl4. The dependence of equilibrium ratio on Lewis acid and the number of equivalents of Lewis acid indicated that the equilibrium ratio is determined by a complex of the saccharide residue bound to the Lewis acid and not the free glycoside. The high α:β ratios observed for anomerization of both O- and S-glycuronic acids can be explained by coordination of the C-1 heteroatom and C-6 carbonyl group of the product to the Lewis acid, which would enhance the anomeric effect by increasing the electron-withdrawing ability of the anomeric substituent and lead to an increase in the proportion of the α-anomer. Such an observation would argue against the existence of a reverse anomeric effect. Support for a chelation-induced endocyclic cleavage mechanism for the anomerization is provided by the trapping of a key intermediate. The data herein will help predict the tendency of β-glycosides to undergo anomerization; this includes cases where 1,2-trans glycosides are initial products of glycosidation reactions catalyzed by TiCl4 or SnCl4.
- Pilgrim, Wayne,Murphy, Paul V.
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supporting information; experimental part
p. 6747 - 6755
(2010/12/25)
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- TISSUE DEGENERATION PROTECTION
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The present invention provides isolated or essentially pure diterpenoic tetrahydropyran, such as steviol-19-glucuronide, steviol, stevioside and rebaudioside processes for obtaining the same and methods for obtaining stable pharmaceutically acceptable salts of the same for use of such compounds or compositions in a treatment of cardiovascular disorders or vascular disease or for the manufacture of medicaments to treat a condition of a cardiovascular disorder or vascular disease.
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- Pyrrolo[2,1-c][1,4]benzodiazepine-β-glucuronide prodrugs with a potential for selective therapy of solid tumors by PMT and ADEPT strategies
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Pyrrolo[2,1-c][1,4]benzodiazepine-β-glucuronide prodrugs 15a-b, with a potential for selective therapy of solid tumors by PMT and ADEPT have been designed, synthesized and evaluated for selective cytotoxicity in the presence of the enzyme β-glucuronidase. The prodrugs have been found to possess reduced cytotoxicity compared to the parent moieties, and are excellent substrates for the enzyme, exhibiting cytotoxicity selectively in the presence of the enzyme. Enhanced water solubility and improved stability are the other important outcomes upon modifying these molecules as their prodrugs.
- Kamal, Ahmed,Tekumalla, Venkatesh,Raju,Naidu,Diwan, Prakash V.,Sistla, Ramakrishna
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scheme or table
p. 3769 - 3773
(2009/04/04)
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- A METHOD OF PREPARATION OF QUATERNARY NITROGEN COMPOUNDS
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The invention relates to a method of preparation of a quaternary amine having formula 2, by reacting an epoxide having formula 3, Formula 3 with an aliphatic tertiairy amine group in the presence of a suitable Lewis acid.
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Page/Page column 5
(2009/01/20)
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- New antifungal flavonoid glycoside from Vitex negundo
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Flavonoids are ubiquitous in photosynthesizing cells and are common part of human diet. For centuries, preparations containing these compounds as the principal physiologically active constituents have been used to treat human diseases. Increasingly, this class of natural products is becoming the subject of anti-infective research. Our bioactivity guided fractionation of ethanolic extract of leaves of Vitex negundo resulted in the isolation of new flavone glycoside (4) along with five known compounds 1-3, 5 and 6. All the isolated compounds were evaluated for their antimicrobial activities. The new flavone glycoside 4 and compound 5 were found to have significant antifungal activity against Trichophyton mentagrophytes and Cryptococcus neoformans at MIC 6.25 μg/ml.
- Sathiamoorthy,Gupta, Prasoon,Kumar, Manmeet,Chaturvedi, Ashok K.,Shukla,Maurya, Rakesh
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p. 239 - 242
(2007/10/03)
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