- A Reactive, Rigid GdIII Labeling Tag for In-Cell EPR Distance Measurements in Proteins
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The cellular environment of proteins differs considerably from in vitro conditions under which most studies of protein structures are carried out. Therefore, there is a growing interest in determining dynamics and structures of proteins in the cell. A key factor for in-cell distance measurements by the double electron–electron resonance (DEER) method in proteins is the nature of the used spin label. Here we present a newly designed GdIII spin label, a thiol-specific DOTA-derivative (DO3MA-3BrPy), which features chemical stability and kinetic inertness, high efficiency in protein labelling, a short rigid tether, as well as favorable spectroscopic properties, all are particularly suitable for in-cell distance measurements by the DEER method carried out at W-band frequencies. The high performance of DO3MA-3BrPy-GdIII is demonstrated on doubly labelled ubiquitin D39C/E64C, both in vitro and in HeLa cells. High-quality DEER data could be obtained in HeLa cells up to 12 h after protein delivery at in-cell protein concentrations as low as 5–10 μm.
- Yang, Yin,Yang, Feng,Gong, Yan-Jun,Chen, Jia-Liang,Goldfarb, Daniella,Su, Xun-Cheng
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- IMIDAZOPYRIMIDINES AS EED INHIBITORS AND THE USE THEREOF
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The present disclosure provides compounds represented by Formula (I) wherein R1, R2, R3, and R4 are as defined in the specification, and the salts and solvates thereof. Compounds of Formula (I) are FED inhibitors. FED inhibitors are useful for the treatment of cancer and other diseases.
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Paragraph 0460
(2021/02/12)
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- FUSED HETEROCYCLIC DERIVATIVES, THEIR PREPARATION METHODS THEREOF AND MEDICAL USES THEREOF
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The present invention relates to fused heterocyclic derivatives, processes for their preparation and their use in medicine. Specifically, the present invention relates to a novel derivative represented by the formula (I′), or its pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the derivative or its pharmaceutically acceptable salt thereof, and the method for preparing the derivative and its pharmaceutically acceptable salt thereof. The present invention also relates to the use of the derivative and its pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the derivative and its pharmaceutically acceptable salt thereof in the preparation of medicines, in particularly as IDO inhibitor medicines, for treating and/or preventing cancers. Wherein each substituent of the formula (I′) is the same as defined in the specification.
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Paragraph 0246; 0427-0430
(2019/07/03)
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- Full synthesis of natural-product (+/-)-cananga odorata alkali and separation method of enantiomers
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The invention discloses full synthesis of natural-product (+/-)-cananga odorata alkali and a chiral separation method of enantiomers thereof and belongs to the technical field of organic synthesis. The chiral separation method comprises the following steps of: adopting natural-product (+/-)-anthorine G as a substrate, carrying out tetrahydrofuran/methyl lithium reaction to obtain the natural-product (+/-)-cananga odorata alkali and the enantiomers thereof; then using a chiral semi-preparative type high-performance liquid chromatograph to carry out separation on the enantiomers, and obtaining the cananga odorata alkali and the enantiomers with the total yield being 17.9%. The full synthesis and the chiral separation method disclosed by the invention have the beneficial effects that the synthesis method is simplified, the total yield of full synthesis is increased, the structure identification is carried out, and not only is the divergence on the specific rotation of the cananga odorataalkali solved, but also basis and powerful guarantee are provided for further study on the compounds.
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Paragraph 0056; 0069; 0082
(2018/07/07)
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- DO3A type highly stable paramagnetic probe capable of being used for intracellular magnetic resonance research and preparation method of DO3A type highly stable paramagnetic probe
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The invention provides a DO3A type highly stable paramagnetic probe T1 capable of being used for intracellular magnetic resonance research and a preparation method of the DO3A type highly stable paramagnetic probe T1. The structural formula of the paramag
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Paragraph 0055-0059
(2019/01/15)
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- INDOLE AND AZAINDOLE HALOALLYLAMINE DERIVATIVE INHIBITORS OF LYSYL OXIDASES AND USES THEREOF
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The present invention relates to novel compounds which are capable of inhibiting certain amine oxidase enzymes. These compounds are useful for treatment of a variety of indications, e.g., fibrosis, cancer and/or angiogenesis in human subjects as well as i
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Paragraph 0317
(2017/09/05)
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- Method for totally synthesizing natural product (+/-)-rupestine G and resolving enantiomers
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The invention relates to a method for totally synthesizing a natural product (+/-)-rupestine G and resolving enantiomers. The method comprises the following steps: oxidizing the raw material 2-methyl-5-bromopyridine (1) by m-chloroperoxybenzoic acid to obtain a nitrogen oxidation product compound 2, carrying out a Reissert-Henze reaction to perform cyano substitution so as to obtain a compound 3, carrying out a decarboxylation reaction on the compound 3 and potassium monoethyl malonate to obtain beta-ketoester 4, carrying out alkylation under the condition of sodium ethylate to obtain a compound 5, carrying out a coupling reaction to obtain a compound 6, carrying out an intramolecular olefin double replacement reaction on the compound 6 to obtain a key intermediate compound 7, carrying out reduction with sodium borohydride to obtain a compound 8, carrying out a reaction under the condition of pyridine/MsCl to obtain a compound 9, hydrolyzing the compound 9 under the action of lithium hydroxide, carrying out methyl esterification by using iodomethane to obtain a compound 10, carrying out palladium-carbon catalytic hydrogenation to obtain a pair of diastereoisomers 11 and 12, and carrying out resolution by a semi-preparative high performance liquid chromatograph to obtain the natural product rupestine G and three stereoisomers, namely a compound 13, a compound 14 and a compound 15.
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Paragraph 0053; 0040
(2017/09/13)
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- Preparation method of 3-bromo-6-methyl-2-pyridylaldehyde
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The invention relates to a preparation method of 3-bromo-6-methyl-2-pyridylaldehyde. The 3-bromo-6-methyl-2-pyridylaldehyde is an important medical intermediate and has wide market prospects. The 3-bromo-6-methyl-2-pyridylaldehyde can be condensed with amino groups to form an N-containing Schiff alkali conjugated system; and both N atoms on the pyridine ring and N atoms on imino C=N outside the ring can be coordinated with metal ions to form functional complexes. The preparation method comprises the following step: by using 5-bromo-2-methylpyridine as an initial raw material, carrying out N-oxidation, cyanation, acidification, esterification, reduction and aldehyde reaction to obtain the product 3-bromo-6-methyl-2-pyridylaldehyde. The 3-bromo-6-methyl-2-pyridylaldehyde synthesized by the method has the advantages of high purity, high yield and lower production cost. The synthesis method is simple and easy to implement, is green and environment-friendly, and provides theoretical and experimental references for industrial production.
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Paragraph 0003; 0026
(2016/12/12)
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- Homogenous suspension of immunopotentiating compounds and uses thereof
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The present invention generally relates to homogeneous suspensions of small molecule immune potentiators (SMIPs) that are capable of stimulating or modulating an immune response in a subject in need thereof. The homogeneous suspensions may be used in combinations with various antigens or adjuvants for vaccine therapies.
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Page/Page column 69
(2016/09/12)
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- AROMATIC RING COMPOUND
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Provided is an aromatic ring compound having a GPR40 agonist activity. A compound represented by the formula (I): wherein each symbol is as described in the DESCRIPTION, or a salt thereof has a GPR40 agonist activity, and is useful as an agent for the prophylaxis or treatment of diabetes and the like.
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Paragraph 0294; 0295
(2015/01/18)
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- Discovery of potent and selective pyrazolopyrimidine Janus kinase 2 inhibitors
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The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the p
- Hanan, Emily J.,Van Abbema, Anne,Barrett, Kathy,Blair, Wade S.,Blaney, Jeff,Chang, Christine,Eigenbrot, Charles,Flynn, Sean,Gibbons, Paul,Hurley, Christopher A.,Kenny, Jane R.,Kulagowski, Janusz,Lee, Leslie,Magnuson, Steven R.,Morris, Claire,Murray, Jeremy,Pastor, Richard M.,Rawson, Tom,Siu, Michael,Ultsch, Mark,Zhou, Aihe,Sampath, Deepak,Lyssikatos, Joseph P.
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p. 10090 - 10107
(2013/01/16)
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- PYRAZOLOPYRIMIDINE JAK INHIBITOR COMPOUNDS AND METHODS
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A compound of Formula I, enantiomers, diasteriomers, tautomers or pharmaceutically acceptable salts thereof, wherein R1, R2 and R3 are defined herein, are useful as inhibitors of one or more Janus kinases. A pharmaceutical
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Page/Page column 83
(2011/02/24)
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- Inhibition of 1-deoxy-d-xylulose-5-phosphate reductoisomerase by lipophilic phosphonates: SAR, QSAR, and crystallographic studies
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1-Deoxy-d-xylulose-5-phosphate reductoisomerase (DXR) is a novel target for developing new antibacterial (including antituberculosis) and antimalaria drugs. Forty-one lipophilic phosphonates, representing a new class of DXR inhibitors, were synthesized, among which 5-phenylpyridin-2-ylmethylphosphonic acid possesses the most activity against E. coli DXR (EcDXR) with a K i of 420 nM. Structure-activity relationships (SAR) are discussed, which can be rationalized using our EcDXR:inhibitor structures, and a predictive quantitative SAR (QSAR) model is also developed. Since inhibition studies of DXR from Mycobacterium tuberculosis (MtDXR) have not been performed well, 48 EcDXR inhibitors with a broad chemical diversity were found, however, to generally exhibit considerably reduced activity against MtDXR. The crystal structure of a MtDXR:inhibitor complex reveals the flexible loop containing the residues 198-208 has no strong interactions with the 3,4-dichlorophenyl group of the inhibitor, representing a structural basis for the reduced activity. Overall, these results provide implications in the future design and development of potent DXR inhibitors.
- Deng, Lisheng,Diao, Jiasheng,Chen, Pinhong,Pujari, Venugopal,Yao, Yuan,Cheng, Gang,Crick, Dean C.,Prasad, B. V. Venkataram,Song, Yongcheng
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experimental part
p. 4721 - 4734
(2011/09/19)
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- COMPOUNDS AND COMPOSITIONS AS TLR ACTIVITY MODULATORS
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The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with Toll-Like Receptors, including TLR7 and TLR8. In one aspect, the compounds are useful as adjuvants for enhancing the effectiveness of a vaccine (formula I) wherein: X3 is N; X4 is N Or CR3; X5 is -CR4=CR5.
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Page/Page column 177
(2009/10/22)
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- INHIBITORS OF AKT ACTIVITY
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Invented are novel pyrazole compounds, the use of such compounds as inhibitors of protein kinase B activity and in the treatment of cancer and arthritis.
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Page/Page column 55
(2008/12/04)
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- GONADOTROPIN-RELEASING HORMONE RECEPTOR ANTAGONISTS AND METHODS RELATING THERETO
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GnRH receptor antagonists are disclosed which have utility in the treatment of a variety of sex-hormone related conditions in both men and women. The compounds of this invention have the structure, wherein R1a, R1b, R1c, R1d, R2, R2a, and A are as defined herein, including stereoisomers, esters, solvates and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for antagonizing gonadotropin-releasing hormone in a subject in need thereof.
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Page/Page column 48
(2008/12/04)
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- GONADOTROPIN-RELEASING HORMONE RECEPTOR ANTAGONISTS AND METHODS RELATING THERETO
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GnRH receptor antagonists are disclosed which have utility in the treatment of a variety of sex-hormone related conditions in both men and women. The compounds of this invention have the structure: wherein R1a, R1b, R1c, R1d, R2, R2a, and A are as defined herein, including stereoisomers, esters, solvates, and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for antagonizing gonadotropin-releasing hormone in a subject in need thereof.
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Page/Page column 40
(2008/12/04)
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- MCH receptor antagonists
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Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of obesity, hyperphagia, anxiety, depression and related disorders and diseases.
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Page/Page column 11-12; 18-19
(2008/06/13)
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- ISOINDOLONE COMPOUNDS AND THEIR USE AS METABOTROPIC GLUTAMATE RECEPTOR POTENTIATORS
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The present invention is directed to compounds of formula (I), wherein R1 is a ring and n is a number from 1 to 8. The invention also relates to use of the compounds in therapy as metabotropic glutamate receptor modulators, particularly in neurological and psychiatric disorders.
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Page/Page column 113-114
(2008/06/13)
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- Synthesis of a Non-Heme Template for Attaching Four Peptides: An Approach to Artificial Iron (II)-Containing Peroxidases
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We are developing all-synthetic model cofactor-protein complexes in order to define the parameters controlling non-natural cofactor activity. The long-term objective is to establish the theoretical and practical basis for designing novel enzymes. A non-heme pentadentate ligand (N4Py) is being developed as a template for the site-specific attachment of a designed four-helix bundle. Previously, we attached two unprotected peptides via CH 2Cl handles to N4Py. In the presence of hydrogen peroxide, the iron(II) complex of this ligand (2a) generates an FeIIIOOH intermediate (3a) that can oxidize a wide variety of organic compounds. Here, we describe the synthesis of 27, a N4Py derivative in which four three-carbon spacers have been introduced, and show that four copies of an unprotected, single-cysteine peptide can be coupled via a thioether linkage to the ligand. In addition, a divergent synthesis route to tetrabromide ligand lb has also been developed, providing the opportunity to prepare alternative pentadentate ligands efficiently by four cross-coupling reactions on a single molecule. Also, two of the four bromides of lb can be selectively addressed by magnesium-bromide exchange.
- Van Den Heuvel, Marco,Van Den Berg, Tieme A.,Kellogg, Richard M.,Choma, Christin T.,Feringa, Ben L.
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p. 250 - 262
(2007/10/03)
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- 2-[[(4-Amino-2-pyridyl)methyl]sulfinyl]benzimidazole H+/K+-ATPase inhibitors. The relationship between pyridine basicity, stability, and activity
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The benzimidazole sulfoxide class of antisecretory H+/K+-ATPase inhibitors need to possess high stability under neutral physiological conditions yet rearrange rapidly at low pH to the active sulfenamide 2. Since the initial reaction involves internal nucleophilic attack by the pyridine nitrogen, control of the pyridine pK(a) is critical. In this paper we show that by utilizing the powerful electron-donating effect of a 4-amino substituent on the pyridine, moderated by the electron-withdrawing effect of a 3- or 5-halogen substituent, a combination of high potency (as inhibitors of histamine-stimulated gastric acid secretion) and good stability under physiological conditions can be obtained. Furthermore, the role of the steric interaction between the 3/5-substituents and the 4-substituent in modifying the electron-donating ability of the 4-amino group is exemplified, and additional factors affecting stability are identified. One compound, in particular, 2-[[(3-chloro-4-morpholino-2-pyridyl)methyl]sulfinyl]-5-methoxy-(1H)- benzimidazole (3a, SK and F 95601), was chosen for further development and evaluation in man.
- Ife,Dyke,Keeling,Meenan,Meeson,Parsons,Price,Theobald,Underwood
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p. 1970 - 1977
(2007/10/02)
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- Benzimidazoles
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Compounds of structure (I) and pharmaceutically acceptable salts thereof, in which R5 and R6 are the same or different and are each hydrogen, C1-6alkyl or C3-6cycloalkyl or together with the nitrogen atom to which they are attached form an acetidino, pyrrolidino, piperidino, piperazino, N-C1-4alkylpiperazino or morpholino group and one of R7 and R8 is halogen, and the other is hydrogen, halogen or C1-6alkyl; processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them and their use as inhibitors of gastric acid secretion.
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