- 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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Read Online
- 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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Read Online
- 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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Read Online
- 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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Read Online
- Synthesis and characterization of thienorphine and its glucuronide conjugate
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Thienorphine (1) is a very potent oripavine derivative with mixed agonist and antagonist opioid receptor activities. It was prepared with 7α-acetyl-6,14-endoethenotetrahydrothebaine as stated material by Grignard reaction, cyanidation, demethylation, and N-alkylation. The structure of 1 · HCl was elucidated by X-ray analysis. As part of a continuing program to define the metabolism and distribution of thienorphine in animals and man, the putative metabolite, 3-glucuronide, was synthesized.
- Liu, Chun-He,Liu, He,Han, Xiang-Yu,Wu, Bo,Zhong, Bo-Hua,Gong, Ze-Hui
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Read Online
- Chemical synthesis of 5’-β-glycoconjugates of vitamin B6
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Various 5’-β-saccharides of pyridoxine, namely the mannoside, galactoside, arabinoside, maltoside, cellobioside and glucuronide, were synthesized chemically according to KOENIGS-KNORR conditions using α4,3-O-isopropylidene pyridoxine and the respective acetobromo glycosyl donors with AgOTf (3.0 eq.) and NIS (3.0 eq.) as promoters at 0 °C. Furthermore, 5’-β-[13C6]-labeled pyridoxine glucoside (PNG) was prepared starting from [13C6]-glucose and pyridoxine. Additionally, two strategies were examined for the synthesis of 5’-β-pyridoxal glucoside (PLG).
- Bachmann, Thomas,Schnurr, Christian,Zainer, Laura,Rychlik, Michael
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supporting information
(2020/02/15)
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- Preparation method of ethyl glucuronide and ethyl sulfate of ethyl alcohol non-oxidative metabolite
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The invention relates to a preparation method of ethyl glucuronide and ethyl sulfate of ethyl alcohol non-oxidative metabolite, and belongs to the field of compound preparation. According to the preparation method, glucuronolactone is used as a basic reaction raw material, the ethyl glucuronide of the ethyl alcohol non-oxidative metabolite can be obtained by reacting under ultrasonic, water bath heating and other conditions through a triacetyl bromide glucuronic acid methyl ester intermediate, and the preparation method has the advantages of low environmental factors, simple operation and easyrealization; and in addition, absolute ethyl alcohol and sulfuric acid are used as raw materials, and the ethyl sulfate of the ethyl alcohol non-oxidative metabolite is obtained through heating, filtration, precipitation, water bath evaporating and other operations, and the preparation method has the advantages of wide source of raw materials, low requirements for environmental factors, simple operation and easy realization.
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Paragraph 0037-0040; 0044-0047; 0049-0052
(2020/06/09)
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- Practical Synthesis of the Fluorogenic Enzyme Substrate 4-Methylumbelliferyl α- L -Idopyranosiduronic Acid
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A practical and concise synthesis of 4-methylumbelliferyl α- l -idopyranosiduronic acid, a fluorogenic enzyme substrate diagnostic for α- l -iduronidase, was accomplished. It features successive radical bromination and radical reduction of easily accessible methyl 4-methyl umbelliferyl-2,3,4-tri- O -acetyl-β- d -glucouronate in four steps with 28percent overall yield.
- Bai, Jiang,Ding, Haixin,He, Yanling,Ning, Qianqian,Ouyang, Wenliang,Tian, Jiameng,Xiao, Qiang
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supporting information
p. 1083 - 1086
(2020/07/03)
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- COMPOUNDS, COMPOSITIONS, METHODS, AND USES FOR TREATING CANCER AND IMMUNOLOGICAL DISORDERS
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The present disclosure provides novel polypeptide-therapeutic compound or hormone-therapeutic compound conjugates using cleavable or non-cleavable linkers, whereby the polypeptide or hormone serves to target specific cells using receptor expression on the targeted cell to bind the ligand (polypeptide or hormone) carrying the therapeutic compound unlike antibody drug conjugates. Upon binding, the ligand and the therapeutic compound (multiples of the therapeutic compound in some embodiments) enter the cell by receptor-mediated endocytosis, and release drugs conjugated to the ligand by linkers, to interact with intracellular components to enhance, restore, or block a signal transduction process. The ligands for the polypeptide-therapeutic compound or hormone-therapeutic compound conjugates include, but are not limited to: cytokines, growth factors and hormones among other proteins with corresponding cell surface specific receptors. The disorders targeted by such polypeptide-therapeutic compound or hormone-therapeutic compound conjugates include, but are not limited to: immunological disorders (e.g., allergy and autoimmune disorders) and cancer.
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Paragraph 0546; 0568
(2020/02/06)
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- METABOLITES OF BICTEGRAVIR
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The present invention provides metabolites of the antiviral drug bictegravir, including compositions and salts thereof, which are useful in the prevention and/or treatment of HIV as well as analytical methods related to the administration of bictegravir.
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Paragraph 0096; 0097
(2019/08/02)
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- Green chemical preparation method of alpha-tri-O-acetyl glucuronic acid methyl ester brominated substance
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The invention provides a green chemical preparation method of an alpha-tri-O-acetyl glucuronic acid methyl ester brominated substance. A sodium bromide, sulphuric acid and methyl tert-butyl ether system is used for replacing a traditional hydrobromic acid or titanium bromide method, the system is thorough in reactions, products can be directly crystallized and separated from the system, the products are high in yield and high in purity, by-products namely sodium sulphate can be recycled, distilled-out methyl tert-butyl ether and crystallized concentrated mother liquid can be in cyclic utilization, zero release and zero pollution can be achieved, large-scale preparation of the alpha-tri-O-acetyl glucuronic acid methyl ester brominated substance can be performed, and research and developmentas well as production of glucuronic acid related medicines and functional compounds are facilitated.
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Paragraph 0011; 0014-0015
(2019/12/25)
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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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- 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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- 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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- 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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- GLUCURONIDE PRODRUGS OF TOFACITINIB
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The invention relates to glucuronide prodrug compounds of the Janus kinase (JAK) inhibitor tofacitinib having formula (I): (Formula (I)) where A1 and R1 are as defined. The invention also relates to pharmaceutical compositions comprising such compounds; methods of using such compounds to treat gastrointestinal inflammatory diseases; and processes and intermediates for preparing such compounds.
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Page/Page column 40
(2018/09/28)
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- GLUCURONIDE PRODRUGS OF JANUS KINASE INHIBITORS
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The invention relates to glucuronide prodrug compounds of Janus kinase (JAK) inhibitors having formula I: where W1, R1 and A1 are as defined. The invention also relates to pharmaceutical compositions comprising such compounds; methods of using such compounds to treat gastrointestinal inflammatory diseases; and processes and intermediates for preparing such compounds.
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Paragraph 0258; 0259
(2018/12/11)
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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 0029-0031
(2018/07/06)
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- OLIGONUCLEOTIDE DERIVATIVE, OLIGONUCLEOTIDE CONSTRUCT USING THE SAME, AND METHODS FOR PRODUCING THEM
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The oligonucleotide derivative of the present invention is represented by Formula (1). This derivative is considered to be introduced into cells by binding of its amino sugar chain moiety to a ligand on cell surfaces, and have selective drug delivery function. The oligonucleotide derivative can be easily synthesized and introduced into cells without using a lipofection reagent. wherein—A and B are independently modified or unmodified oligonucleotides whose total chain length is 3 or more, and A and B do not contain hydroxyl groups at 3′ and 5′ ends of the oligonucleotide; S represents a sugar substituent, a peptide chain, or a tocopherol-binding group; and an alkyl group may be bound instead of hydrogen bound to a benzene ring.
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Paragraph 0170
(2018/04/19)
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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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- 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 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; 183
(2017/08/08)
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- CONJUGATES AND PRODRUGS FOR TREATING OF CANCER AND INFLAMMATORY DISEASES
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The present invention relates to the field of cancer and inflammatory diseases. More particularly, it aims to provide, for these purposes, novel conjugated forms of active ingredients belonging to the dolastatin family and having the formula as follows: It is also directed towards prodrug forms of these conjugates.
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Paragraph 0172; 0173
(2017/08/01)
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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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- 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 0201; 0202
(2016/08/03)
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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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- Synthesis of 5α-androstane-3α,17β-diol 17-O-glucuronide histaminyl conjugate for immunoassays
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Simple method of preparation of 5α-androstane-3α,17β-diol 17-O-glucuronide N-histaminyl amide was developed for the construction of immunoanalytical kit. Improved method of glucuronide derivative synthesis was used, followed by hydroxybenzotriazole-dicyclohexylcarbodiimide coupling with histamine.
- Vin?, Petr,?erny, Ivan,Mik?átková, Petra,Dra?ar, Pavel
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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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- 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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- 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 0034
(2017/01/12)
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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 0104
(2015/02/18)
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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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- Convenient synthesis of glycosyl bromide from 1-O-acetyl sugars by photo-irradiative phase-vanishing reaction of molecular bromine
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The synthesis of glycosyl bromides from 1-O-acetyl sugars using a photo-irradiative phase-vanishing method involving molecular bromine was achieved. A bottom phase of molecular bromine was overlaid first with perfluorohexanes (FC-72), followed by overlaying with ethyl acetate containing a 1-O-acetyl sugar. Upon irradiation, the bromine layer gradually disappeared, leaving two phases. Glycosyl bromide was obtained in good yield from the ethyl acetate phase.
- Tojino, Mami,Hirose, Yuriko,Mizuno, Mamoru
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supporting information
p. 7124 - 7126
(2013/12/04)
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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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- 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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p. 3103 - 3110
(2012/04/10)
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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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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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- Synthesis and anti-human hepatocellular carcinoma activity of new nitric oxide-releasing glycosyl derivatives of oleanolic acid
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A series of nitric oxide (NO)-releasing glycosyl derivatives (2-14) of oleanolic acid were synthesized to improve the aqueous solubility and cytotoxicity of the parent compound 1. Derivative 3 exhibited better solubility and strong cytotoxicity against human hepatocellular carcinoma (HCC) in vitro. Furthermore, 3 displayed low acute toxicity to mice and significantly inhibited the growth of HCC tumors in vivo, indicating that 3 may be a promising candidate for the treatment of human HCC.
- Huang, Zhangjian,Zhang, Yihua,Zhao, Li,Jing, Yongwang,Lai, Yisheng,Zhang, Luyong,Guo, Qinglong,Yuan, Shengtao,Zhang, Jianjun,Chen, Li,Peng, Sixun,Tian, Jide
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body text
p. 632 - 639
(2010/05/02)
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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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- Glycoside modification of oleanolic acid derivatives as a novel class of anti-osteoclast formation agents
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Oleanolic acid, a natural product, possesses an anti-osteoclast formation activity. Targeting at discovery of novel and potent anti-bone resorption agents, 22 glycosides of oleanolic acid derivatives (including d-galactopyranosides, d-glucopyranosides, d-xylopyranoses, d-arabopyranoses and d-glycuronic acids) were synthesized at phase-transfer-catalyzed conditions (K2CO3, Bu4NBr, CH2Cl2-H2O) and their inhibitory activity on the formation of osteoclast-like multinucleated cells (OCLs) induced by 1α, 25-dihydroxy vitamin D3 was evaluated in a co-culture assay system. The structure-activity relationships of these compounds were also discussed.
- Li, Jun-Feng,Chen, Song-Jie,Zhao, Yu,Li, Jian-Xin
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body text
p. 599 - 605
(2009/05/27)
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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-[(E)-2-(5,6,7,8-TETRAHYDRO-5,5,8,8-TETRAMETHYL-2-NAPTHALENYL)-1-PROPENYL]BENZOIC ACID ANALOGS AND METHOD OF MANUFACTURE AND AND USE THEREOF
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Analogs of 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1 - propenyl]benzoic acid and methods of manufacture and use thereof, such as for use in cancer prevention and treatment.
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Page/Page column 16
(2008/06/13)
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- Development of sensitive immunoassays for the detection of the glucuronide conjugate of 3-phenoxybenzyl alcohol, a putative human urinary biomarker for pyrethroid exposure
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Pyrethroids are widely used in agriculture as insecticides. This study describes a sensitive enzyme-linked immunosorbent assay for the detection of the glucuronide conjugate of 3-phenoxybenzyl alcohol, a putative pyrethroid metabolite that may be used as a biomarker of exposure to pyrethroids. Four antisera were elicited against two different immunizing haptens. Antisera were characterized in combination with several coating haptens. The lowest IC 50 value (0.5 ng/mL) was obtained with antiserum 1891 and 3-phenoxybenzoic acid-BSA conjugate as the coating antigen. Antiserum 1891 was highly selective for the target compound with an overall cross-reactivity of 50 was observed using a 10-fold concentrated phosphate-fuffered saline as the assay buffer. Compared to assays conducted in normal phosphate-fuffered saline, the maximal absorbance was almost identical. A good correlation (r2 = 0.99 and 0.97 for urine samples A and B, respectively) was observed between spiked levels and the levels detected by the immunoassay.
- Kim, Hee-Joo,Ki, Chang Ahn,Seung, Jin Ma,Gee, Shirley J.,Hammock, Bruce D.
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p. 3750 - 3757
(2008/02/07)
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- X-ray diffraction and high-resolution NMR spectroscopy of methyl 3,4-di-O-acetyl-1,5-anhydro-2-deoxy-d-arabino-hex-1-enopyranuronate
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Single-crystal X-ray diffraction and high-resolution 1H and 13C NMR spectral data for methyl 3,4-di-O-acetyl-1,5-anhydro-2-deoxy-d-arabino-hex-1-enopyranuronate are reported. The 5H4 conformation was found to be the preferred form for this glycal, both in the crystal lattice and in solution. The factors determining the 4H5 ? 5H4 conformational equilibrium for acetylated glycals are discussed.
- Liberek, Beata,Tuwalska, Dorota,Konitz, Antoni,Sikorski, Artur
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p. 1280 - 1284
(2008/02/02)
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- Glucuronic acid-based ulosyl donors for introducing α-d-GlcA and β-d-ManA units
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Practical protocols are described for a five-step conversion of d-glucuronolactone into α-d-arabino-2-ketoglucuronyl bromides, which due to their α-selective or β-specific glycosidation, and gluco- or manno-specific carbonyl reductions of the glucurono-2-ulosides formed, are expedient indirect donor substrates for the efficient introduction of α-d-GlcA or β-d-ManA residues.
- Lergenmueller, Matthias,Lichtenthaler, Frieder W.
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p. 2132 - 2137
(2008/02/10)
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- Synthesis of bromophenyl β-D-glucuronides: Hydrophilic precursors of lipophilic standards in the analysis of environmental polychlorinated biphenyls
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A rapid PCB-screening protocol, based on a combination of extraction techniques and instrumental nuclear activation analysis (INAA), required water soluble brominated internal standard that undergoes facile hydrolysis to a lipophilic brominated counterpart. Bromophenyl glucuronic acids 2, 3, 7 were synthesized for this application. Glucuronic acids 2 and 3 were prepared by bromination of phenyl β-D-glucopyranosiduronic acid in 81 and 54%, respectively, whereas compound 7 was prepared by coupling methyl 2,3,4-tri-O-acetyl-α-D-glucopyranosyluronate bromide (5) with 2,4,6-tribromophenol. Incubation with β-glucuronidase indicated that tribromophenyl derivative 7 is an excellent substrate, with near quantitative conversion to tribromophenol within seconds of incubation with the enzyme.
- Tandon, Manju,Kumar, Piyush,Xia, Haiyan,Wang, Lili,Wiebe, Leonard I.
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p. 1042 - 1050
(2008/02/07)
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- Self-immolative magnetic resonance imaging contrast agents sensitive to beta-glucuronidase
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The present invention relates to magnetic resonance imaging (MRI) contrast agent. In particular, the present invention provides MRI contrast agents that are sensitive to the enzyme beta-glucoronidase. The MRI contrast agents provide compositions and methods for non-invasive diagnostic imaging of tissues, including necrotic tumors.
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Page/Page column 2 fig. 2A
(2010/11/08)
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- DIFFERENTIATION MODULATING AGENTS AND USES THEREFOR
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This invention discloses methods and agents for modulating the differentiation potential and/or proliferation of preadipocytes. More particularly, the present invention discloses methods and agents for modulating a fibroblast growth factor (FGF) signalling pathway, especially the FGF-1 or FGF-2 signalling pathway, for treating or preventing adiposity-related conditions including, but not limited to, obesity, lipoma and lipomatosis.
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Page/Page column 183
(2010/02/12)
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- Novel efficient routes to heparin monosaccharides and disaccharides achieved via regio- and stereoselective glycosidation
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A new methodology for the synthesis of heparin building blocks has been developed. We describe novel efficient routes to both L-iduronic acid and D-glucuronic acid acceptors. Glycosylation with thioglycosides donors gave corresponding disaccharides in a regio- and stereoselective fashion. An improved approach to synthesizing azido-glucose thioglycoside donor to render azido-sugar from mannose via nucleophilic substitution is described.
- Yu, Henry N.,Furukawa, Jun-Ichi,Ikeda, Tsuyoshi,Wong, Chi-Huey
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p. 723 - 726
(2007/10/03)
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